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Curcumin in combination with anti-cancer drugs: A nanomedicine review
Accepted Manuscript Title: Curcumin in Combination with Anti-Cancer Drugs: A Nanomedicine Review Authors: Harshul Batra, Shrikant Pawar, Dherya Bahl PII: DOI: Reference:
S1043-6618(18)30436-5 https://doi.org/10.1016/j.phrs.2018.11.005 YPHRS 4054
To appear in:
Pharmacological Research
Received date: Revised date: Accepted date:
28 March 2018 31 October 2018 4 November 2018
Please cite this article as: Batra H, Pawar S, Bahl D, Curcumin in Combination with Anti-Cancer Drugs: A Nanomedicine Review, Pharmacological Research (2018), https://doi.org/10.1016/j.phrs.2018.11.005 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Curcumin in Combination with Anti-Cancer Drugs: A Nanomedicine Review
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Neuroscience Institute & Center for Behavioral Neuroscience, Georgia State University, 789 Petit Science Center, Atlanta, GA, 30303
Department of Computer Science, Georgia State University, 34 Peachtree Street, Atlanta, GA, 30303. 3
Department of Biology, Georgia State University, 34 Peachtree Street, Atlanta, GA, 30303.
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Division of Pharmaceutics and Translational Therapeutics, University of Iowa, Iowa City, Iowa 52242
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Harshul Batra1, Shrikant Pawar2, 3, and Dherya Bahl4
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Article Type: Review.
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*Correspondence author:
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Dr. Harshul. Batra, Neuroscience Institute & Center for Behavioral Neuroscience, Georgia State University, 789 Petit Science Center Atlanta, GA, 30303.
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Graphical abstract
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Email address: [email protected]
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Abstract
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A huge surge of research is being conducted on combination therapy with anticancer compounds formulated in the form of nanoparticles (NPs). Numerous advantages like dose minimalization and synergism, reversal of multi drug resistance (MDRs), enhanced efficacy have emerged with
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nanoencapsulation of chemotherapeutic agents with chemo-sensitizing agent like curcumin. Within last couple of years various nano-sized formulations have been designed and tested both in vitro with cell lines for different types of cancers and in vivo with cancer types and drug resistance models. Despite the combinatorial models being advanced, translation to human trials has not been as smooth as one would have hoped, with as few as twenty ongoing clinical trials
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with curcumin combination, with less than 1/10th being nano-particulate formulations. Mass
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production of nano-formulation based on their physico-chemical and pharmacokinetics deficits
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poses as major hurdle up the ladder. Combination of these nano-sized dosage with poorly
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bioavailable drugs, unspecific target binding ability and naturally unstable curcumin further complicates the formulation aspects. Emphasis is now therefore being laid on altering natural
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forms of curcumin and usage of formulations like prodrug or coating of curcumin to overcome
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stability issues and focus more on enhancing the pharmaceutical and therapeutic ability of the
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nano-composites. Current studies and futuristic outlook in this direction are discussed in the review, which can serve as the basis for upcoming research which could boost commercial
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translational of improved nano-sized curcumin combination chemotherapy.
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Abbreviations
MDR, multi drug resistance; NPs, nanoparticles; PTX, paclitaxel, Dox, doxorubicin; P-gp, pglycoprotein; PEG, polyethylene glycol; PLGA, poly(lactic-co-glycolic acid); PLA, polylactic acid; BTZ, Bortezomib; PLACL, poly L-lactic acid-co-ε-caprolactone; DDP, cisplatin Keywords: Curcumin, Nano-formulations, combination therapy, Cancer, Drug Delivery
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1. Introduction One-fifth of the deaths worldwide annually are caused by various type of cancers [1]. Cancer is a
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result of successive genetic and epigenetic alterations resulting in apoptosis, uncontrolled cell proliferation, metastasis, and angiogenesis [2, 3]. Several strategies have been employed in recent years to combat cancer evasion, including surgery, hormonal therapy, chemotherapy, and radiation therapy. Chemotherapy which involves usage of cytotoxic antineoplastic drugs (alkylating agents and antimetabolites), although effective in most cases, has immense side-
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effects and lead to drug resistance (intrinsic and acquired). Acquired resistance is considered
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more severe and is caused by mutations induced by over-expression of therapeutic targets or
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stimulation of cancer-promoting pathway. Also, tumors contain a high degree of molecular
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heterogeneity leading to enhanced drug resistance [4].
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Curcumin is a natural phenolic antioxidant [5]. At high concentrations, it functions as
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cardioprotective, neuroprotective and antidiabetic agent [6-8]. It has shown pharmacological effects against diseases like type II diabetes, Alzheimer's disease, atherosclerosis and human
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immunodeficiency virus (HIV) replication [6-8]. Anti-cancer activity of curcumin has been
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extensively investigated recently, and significant improvements in gastrointestinal, melanoma, genito-urinary, breast, and lung cancers have been seen [9-12] (Insert Figure 1 here). It has
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pleiotropic properties, due to which it is seen to be most effective against single pathway targeted cancers [13, 14] (Insert Figure 2 here). It has also shown anti-inflammatory activity with a tolerance dose of at 12 g/day [15, 16]. The significance of curcumin to be considered as a possible drug lies in its free passage through cellular membranes due to its high lipophilicity. However, it does have low aqueous solubility making it susceptible to alkaline degradation. This 4
could be a probable reason for its low bioavailability and an increased dose for reaching therapeutic optimal blood concentrations [17-20]. Almost half a century ago, nanomedicine emerged as a specific niche for drug delivery, within
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the multidisciplinary field of nanotechnology. A principal focus for the last 20 years has been on the development of nano-formulation driven drug delivery of nanocarriers [21, 22]. Various nanocarriers that have been investigated for drug delivery [21, 22] include polymeric micelles, liposomes,
magnetic
nanoparticles,
conjugates,
and
peptide
carriers.
Integration
of
Nanotechnology within cancer research has proved to be advantageous in several ways,
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including (a) cancer treatment and detection (diagnostics and imaging agents); (b) biomarker
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identification for disease prediction; and (c) mechanism of cancer progression [23-25]. A narrow
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therapeutic window of drugs however is one of the major challenges with anticancer drugs and is
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the reason for serious side effects due to non-specific drug uptake by healthy cells. The efficacy
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of cancer drugs is also restrained due to multidrug resistance (MDR), often associated with
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chemotherapy. To overcome these issues the primary strategy of combination chemotherapy along with drug delivery systems using nanoparticles (NPs) is being actively explored [26].
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Curcumin could be a potential elementary candidate to be used for combination chemotherapy as
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it could overcome the issues associated with anti-cancer therapeutics. This article tries to summarize current research on combination of curcumin with several anticancer compounds
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with different mechanisms, as a possible target for treating various cancers. We provide a global overview of the role of nanoparticles (NPs) in oncology and different NPs currently used in cancer clinically. We briefly describe advantages of combination therapy in nanomedicine and summarize the current data on curcumin nano-formulations with an emphasis on its effect in invitro and in-vivo studies. Finally, we discuss futuristic clinical outlook, challenges, and 5
perspectives of developing nanoparticle-based curcumin combination therapy in cancer. This work envisions to serve as an up to date comprehensive literature basis, which could be utilized to build upon any future studies for better understanding of mechanism and ADME of curcumin
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along with a selection of proper combinational drug and fabrication of appropriate delivery technology. This review could be used as the go-to reference, to begin with in-vitro and in-vivo studies for successful development and in-clinic adaptation of nano-sized curcumin combination therapy.
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2. Nanoparticles in oncology
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Nanomedicine today is an entire field of research and development, with oncology as one of its
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major application. Lack of specificity is a primary drawback of cancer therapeutics for which
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nano-strategies based designing of personalized cancer treatment could be a solution. Recent decades have noticed emergence and approval of several nanoparticulate dosage forms by U.S.
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Food and Drug Administration (FDA). They overpower traditional delivery techniques with
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improved drug delivery, reduced toxicity, better safety profile, targeted therapy and extended
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product life-cycles [27].
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2.1. Type of Nanoparticles in Cancer therapy There are two categories of therapeutic and diagnostic nanoparticles: (a) organic (e.g., polymeric,
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liposomes, micelles, etc. (b) inorganic (e.g., gold, silica, iron oxide, etc.). Natural or synthetic organic molecules are the template for the formation of organic NPs. Organic and inorganic NPs differ in their technique of fabrication. For organic NPs, the encapsulation technique of biodegradable materials used are relatively simple and require several self-organizing or chemical binding organic molecules. Whereas, inorganic NPs involve precipitation of inorganic 6
salts in which atoms are often linked by covalent/metallic/magnetic bonding leading to formation of a three-dimensional array. Broad applications involving organic NPs in the clinic include formulations for hemostasis, vaccination, long-lasting depot delivery systems, and topical agents
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for systemic delivery through the skin [28-30]. Whereas inorganic nanoparticles are typically used in developing formulations for thermal ablation of tumors, intraoperative sentinel lymph node imaging, imaging applications, and anemia treatment [31, 32]. Intravenous organic NP formulations are characterized into two categories: (a) gene therapy applications [33, 34], or (b) small molecule drug delivery for cancer treatment (e.g., head and neck, melanoma, breast,
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metastatic, etc.) [35, 36]. Nanoparticle technologies defeat free drug counterparts as a drug-
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delivery system with an extended circulation of a drug, improved targeting to disease tissues,
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enhanced drug protection, and controlled release [37, 38]. These advantages make the
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nanoparticulate delivery system a potential model to dramatically change clinical care by
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improving current therapies or avail new treatment options (Insert Figure 3 here).
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3. Combination chemotherapy in cancer
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The interconnected pathways in cancer physiology reduce effectivity of monotherapy strategy. Drug resistance and chances of tumor recurrence due to pathway overlapping [39], cross-talk
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[40] and neutralizing response [41, 42] could be various complications hindering full potential of independent drugs. The easiest approach to overcome this issue could involve utilization of
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combination chemotherapy strategy, which has shown to be successful in preliminary clinical trials. Combination chemotherapy design involves an understanding of several principles like non-overlapping toxicity, non-cross resistance, and enhanced tumor cell killing efficacy [43]. Synergistically acting drugs in vitro are governed by molar ratios, vs. Maximal Tolerated Dose
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(MTD) govern drug ratios in-vivo [44, 45]. Nanocarriers like liposomes and polymeric micelles could further help to overcome mono-therapeutic complications. A previous generation of cancer combination chemotherapy comprised of traditional drug combinations including anthracycline,
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methotrexate, and paclitaxel (PTX)-based combinations [46]. A study on one such combination displayed an effective reversal of chemotherapeutic drug resistance with Dox and rapamycin codelivery. This combination leads to complete tumor remission, as compared to dox and rapamycin alone [47]. In another such study, in vivo effects of curcumin combination with antitumor drug was studied and displayed effectively. Docetaxel (DTX) and Curcumin (CUR)
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co-encapsulated lipid nanoparticles (LPN’s) were evaluated on PC3 tumor xenografts in mice
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(human prostate cancer-bearing Balb/c nude mice model). These potent nanoparticles inhibited
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tumor volume growth significantly, when compared to other groups, with no visible side effects.
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It was concluded that this combination could prove to be an effective prostate cancer treatment [166] (insert Figure 4 here). Additionally, nanoparticulate delivery for combination
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chemotherapy could benefit hydrophobic and hydrophilic drug codelivery [48], spatiotemporal
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control release behavior, and ratio-metric drug loading adjustments [49, 50]. The focus of this
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therapy lies in exploring new combinations to provide better insight into molecular and cellular
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mechanisms of cancer treatment.
One of the most challenging approaches towards treating cancers is overcoming MDR. The
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major mechanism of resistance of cancer cells to drugs includes altered apoptosis pathway and overexpression of multidrug transporters [50, 51]. A powerful approach to disrupt MDR and to overcome the negative impact of the anticancer drugs is by co-delivery of chemo-sensitizing and chemotherapeutic agents. One of the major player involved in MDR is efflux of a variety of anticancer drugs by efflux transporter p-glycoprotein (P-gp), which is the adenosine triphosphate 8
(ATP)-binding cassette transporters, encoded by the MDR-1 gene [52]. In liver, pancreatic, gastrointestinal, and ovarian cancer, overexpression of P-gp leads to the reduction in the efficacy of drugs such as vinblastine, doxorubicin, vinblastine, paclitaxel, etc. [53].
In apoptotic
of nuclear factor kappa B (NF-kB) or BCL-2 [54].
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pathway-dependent MDR, the apoptotic response to anticancer drugs dampens by deregulation To combat MDR in cancer, several
nanoparticle formulations are designed to include the combination of drugs with chemosensitizers, MDR cytotoxic, and modulating agents. A Doxorubicin (DOX)-curcumin composite nanoparticle formulation called NanoDoxCurc (NDC) for overcoming DOX
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resistance was developed by Pramanik et al. [168]. Its effectivity in the form of inhibited MDR
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phenotype, is tested in athymic nude mice (DOX resistant) for several models of DOX resistant
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cancers (multiple myeloma, acute leukemia, prostate and ovarian cancers). Additionally, reduced
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cardiac toxicity and bone marrow suppression was further indicated with this course of
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treatment, which was subjected to reduction in DOX induced oxidative stress (Figure 5).
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In the last decade, NPs with multiple chemotherapeutic agents, each with a different mechanism of action forms a basis of combination drug therapy. This approach helps in reducing unwanted
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side effects. Specific interactions with a target sites for a different type of cancer is the main
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advantage of nanomedicine combination therapy. Previously, most combination NPs contained drugs with similar water solubility. Polymeric nanoparticles in their hydrophobic core carry poor
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water-soluble drugs and liposomes contain hydrophilic drugs. Whereas in recent times development of more sophisticated NP drug delivery system has made it possible to deliver hydrophobic and hydrophilic drugs in one system. Several challenges in delivering drugs with different physiochemical attributes remain to be addressed warranting future studies.
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3.1. Advantages of combination therapy For a rational design to achieve optimal efficacy, a proper understanding of specific mechanisms of parent drug and combination strategies used are essential. Combination of two drugs can
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generate a combinatorial effect with lower, equal or higher than the total effects of the individual partner drugs. Combination effects could be synergistic, antagonistic or potentiation. The synergistic combinatorial effect is when the effect produced is larger than the summed effect of the drugs individually, with no cross-reactivity and different acting target sites or pathways. When the effect is greater than or equal to the summed effect of the individual drugs with a final
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target as same site or pathway, the effect is additive. In potentiation effects, alteration of
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activity/effect of one drug by the other is seen. With enhanced activity, a reduction in side effect
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via regulation of ADME properties is also seen [46, 55, 56]. A nanoparticulate combination has
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explored all these effects to achieve a variety of favorable outcomes, including reduction of
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unwanted side effects, drug-resistance prevention, a decrease in dose of individual drugs, and
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enhanced efficacy (Insert Figure 6 here)
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3.2. Formulas used for determining combinatorial effects
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Combination Index (CI) = D1/Dm1 + D2/Dm2
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Where D1 and D2 represent the dose of a drug in combined administration, Dm1 and Dm2 represent the dose required to produce the same effect when used alone. When CI < 1, synergism is indicated; CI = 1, additive nature is indicated; CI > 1, mean antagonism [57].
Reversal fold (RF) =
IC50 anticancer drug alone 10
IC50 anticancer drug + modulator
RF > 1 indicates a synergistic effect, RF = 1 indicates no effect, and RF < 1 indicates an
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antagonistic effect [58]. (IC50 anticancer drug alone in MDR cells - IC50 anticancer drug + modulator in MDR cells) Relative Reversal Rate
(IC50 anticancer drug alone in MDR cells - IC50 anticancer (RRR %) [59]
=
* 100
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drug alone in parental cells)
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In a recent study by Gwade et al [167], synergistic anticancer activity of paclitaxel (PTX) and
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curcumin (CUR) combination was noted against ovarian and cervical cancers. The authors
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performed encapsulation of BSA (bovine serum albumin) nanoparticles which encapsulated PTX and CUR along with a folate receptor ligand conjugation on the nanoparticles. This formulation
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is reported to possess a synergistic cell killing effect and combination effectivity compared to
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control groups, when studied in HeLa and SKOV3 Cell lines. The CI values were reported to be
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less than 0.5 indicating an average synergism, as indicated in Figure 7. High potency of the drugs and different anticancer targeting pathways, make these two drugs apt candidates for
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combination, which then results in lowered dose levels and synergism in their combined
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therapeutics. Other such studies have also been indicated elsewhere [169]
4. Curcumin combination nanomedicine Curcumin has shown to be successful in several types of cancer lines, mainly because of its ubiquitous action on different modulator of anti-cancer effects (Insert Figure 8 here). Curcumin
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alone or in combination is nontoxic and is proposed to accentuate the therapeutic efficiency of chemotherapeutics by inhibiting ABC efflux transporter. Curcumin inhibits tumor growth by arresting cell cycle progression, inducing apoptosis, inhibiting the expression of antiapoptotic
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proteins, inhibiting multiple cell survival signaling pathways and their cross-communication, and modulating immune responses [4, 60, 61]. All these properties make curcumin a promising drug for mono or combination therapy. Table 1 summarizes a few examples of curcumin monotherapy. Although its pharmacokinetic profile is not as appealing as pharmacological profile, nano-based formulations could be a savior and balance this out. Its modulating effects on
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P-gp efflux transporters, which are a major cause of MDR in the first place, makes it a perfect
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adjunct for a combination [62]. Curcumin combination nanoparticulate therapeutic doses tested
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in-vitro and in-vivo for several types of cancers are listed in Table 1.
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Table 1: Selected examples of Curcumin nano-particulate delivery system’s monotherapy in
Nanoparticle platform Hyaluronic Acid linked Nanomicelles
2.
PEG-PLGA NPs
Cancer type
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Serial no. 1.
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cancers
Pancreatic cancer
89.5±2.8
Breast cancer
70-300 nm
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Size
Polymeric micelles
Colon cancer
27.6± 0.7nm
4.
pH-chitosan
Glioblastoma
Not reported
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3.
mesoporous
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Status of investigation In vitro
Observations
Ref
Improved cell killing and internalization in MiaPaca-2 (IC50= 140±2.42 nM ) and AsPc-1(160±2.96 nM) cell line.
[63]
In vitro
Improved cell growth inhibition in MCF-7 (17.86±1.08 µM) cell lines with the formulation.
[64]
In vitro/in vivo
The cytotoxic activity of the nanoformulation was higher than free curcumin. (5.50μg/mL). 70% inhibition of tumor growth in mice inoculated with MCF-7 cells. MTT assay for the formulation showed a higher IC50 value of 5.21 µg/mL for
[65]
In vitro
[66]
silica nanoparticles
the formulation as compared to non-pH and free drug group.
PLGA-PEGFe3O4 NPs
Lung cancer
Not reported
In vitro
Enhanced cytotoxicity observed in A549 with the formulation (IC50=7.3 µM). hTERT downregulated.
[67]
6.
folate-BSA-CDF NPs
Ovarian cancer
279 nm
In vitro
High cell viability (IC50=0.25µM) and cellular uptake compared to free drug and non-targeted nanoformulation.
[68]
7.
Cholesterol-PLA polymeric micelles
Breast cancer
Nearly 1.87 fold higher tumor growth inhibition in B16F10-xenografted tumorbearing mice with the polymeric micelles formulation (627.72 ± 0.9 mm3) as compared to free CUR (1174.68 ± 1.64 mm3).
[69]
8.
Nanoemulsions
Prostate cancer
The results showed that the cell update and cytotoxicity considerably increased with Cur nanoemulsions compared to free Cur. Cur nanoemulsions exhibited a significantly prolonged biological activity and demonstrated better therapeutic efficacy than free Cur.
[70]
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N
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In vitro/in vivo
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5.
In vitro
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34.54±2. 2 nm
4.1. Liver cancer
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Liver cancer is the second most common cause of cancer death among men and the sixth leading cause of cancer death among women. Globally, Hepatocellular Carcinoma (HCC) accounts for 75-80 % of the cancer deaths. Due to metastasis and recurrence, a 5-year survival rate of patients with HCC is at 15 % [71]. Hu et al. investigated the combined effect of nanoparticulate delivery of curcumin (Cur) with a kinase inhibitor, sorafenib, in the treatment of HCC. The combination 13
down-regulated expression of MMP9 via NF-κB/p65 signaling pathway. Furthermore, the population of cancer-initiating cells CD133-positive significantly decreased in both MHCCLM3 (4.82 ± 1.22%) and Huh7 (5.46 ± 0.68%) cells with this combination therapy. In vivo outcomes
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demonstrated lung metastatic tumors to be significantly reduced compared with control treatment (16.7% vs. 100%; P = 0.015) [72]. Combining chemotherapeutic agent and chemosensitizer in nanocarriers to overcome MDR in HCC was a focus of Zhao et al. research. Synthesized DOX/Cur-NPs increased Caspase-3 and Bax/Bcl-2 ratio, and decreased C-myc, PCNA and VEGF as seen in liver tissue. With DOX treatment there was a 46.44-fold increase in Resistance
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Index (RI) of BEL 7402/5-FU cells in comparison with the BEL 7402 cells, significantly
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decreased by DOX/Cur-NPs (2.07). This indicates a modulatory effect of DOX/Cur-NPs on
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MDR. The modulation effect calculated by the reversal fold (RF) value in which IC50 of DOX-
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NPs in BEL 7402/5-FU cells divided by that of DOX/Cur-NPs. The DOX/Cur-NPs showed an
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RF value of 1.94, indicative of a synergistic effect [73].
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Yan et al. developed glycyrrhetinic acid (GA)-modified chitosan-cystamine-poly(є-caprolactone) copolymer (PCL -SS-CTS-GA) micelle for co-delivery of DOX and curcumin to HCC. GA aided
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in target specificity to hepatocytes due to its affinity to the liver membrane [74, 75]. In HepG2
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and HUVEC cell lines, PCL-SS-CTS-GA/DOX/CCM at a DOX-CCM molar ratio of 1:1, 2:1, and 3:1 were used in-vitro. CI value of less than 1 indicated a strong synergistic effect at all
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molar ratios [76]. A PH sensitive prodrug conjugate was produced by conjugation mechanism, with self-assembling property in water at pH 7.4 into nanoparticles (PEG-DOX NPs). Cur being hydrophobic encapsulates into the core through hydrophobic interaction (PEG-DOX-Cur NPs). After internalization of these NPs in tumor cells due to an acidic environment (PH 5.4) inside the tumors, PEG and DOX holding Schiff base breaks open and lead to releasing of both parent 14
drugs CUR and DOX into the tumor cells. HeG 2 and Hela cells used for in vitro cytotoxicity studies. The studies showed higher cytotoxicity values compared to individual drugs. NP formulation for the PEG-DOX-Cur NPs in both the cell lines reported an IC50 value of 1.700
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µg/mL (DOX) and 0.680 µg/mL (Cur) in HEG 2 cells and 1.741 µg/mL (DOX) and 0.697 µg/mL (Cur) in Hela cells respectively. The primary reason for higher toxicity observed was due to internalization and rapid release of drug in tumor cells. Moreover in vivo studies using xenograft mice with hepatic tumors also showed a significant reduction in the tumor volume with the PEG-DOX-Cur NPs [77].
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Recently, Peng et al. designed novel PEGylated lipid/PAA/CaCO3 ternary system encapsulating
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Cur and Dox (LPCCD) with a goal of increasing cancer cell toxicity and reduction of cardiotoxic
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side effect. An in vitro cytotoxicity study in HepG2 cells demonstrated better IC50 with LPCCD
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as compared to free Dox & Cur formulation. Also, cardiotoxicity which is a major side effect of
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DOX treatment was also evaluated in mice cardiac sections by histology. LPCCD group reported
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no inflammatory and hypertrophic cardiac cells [78]. Zhang et al. developed pH-sensitive NPs for co-delivery of DOX and CUR. MTT assay in SMMC 7721 cell line established an increase in
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cell growth inhibition with D+C/NP formulation. Additionally, as noted by flow cytometry, the
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apoptotic rate for the formulation was nearly 1.99-fold higher than that of the free drug treatment. To investigate the anti-tumor efficacy and potential toxicity of Dox & Cur co-loaded
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NPs, in vivo studies were conducted. A significant increase in tumor weight inhibition by formulation compared to a combined free drug (73.37 % and 32.6% and 73.37%, respectively) was observed [79].
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4.2. Colon cancer As the third-most common malignant tumor, colon cancer accounts for more than 1.4 million new cases and over half a million deaths worldwide annually [71]. Surgery, chemotherapy, and
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radiotherapy are the go-to therapeutic approaches against colon cancer with chemotherapy as the first line of treatment [80]. MDR as well as the heterogeneous nature of cancer cells leads to resistance and increase in adverse effects and subsequently results in an increase of effective doses [81]. Like other cancers, combination therapy with NPs drug delivery system helps to overcome issues associated with monotherapy in colon cancer [82]. Xiao et al. developed
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cationic polymeric NPs for co-delivery of camptothecin (CPT) and curcumin. Combination
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index (CI) value of 0.46 indicated a strong synergism with the CPT/CUR at a molar ratio of 4: 1
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after 24 h of incubation [83].
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Overexpression of CD44, a single-chain glycoprotein, has been reported in a variety of colon
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cancer [84-86]. Hyaluronic Acid (HA) is shown to have a high affinity for CD-44 receptors [87].
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So, the addition of HA provided a colon cancer-targeting capability due to more efficient internalization of HA-functionalized NPs in cells through an HA receptor-mediated endocytosis
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pathway by interacting with CD44 receptors [85]. Xia et al. capitalized this property for
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formulating HA-CPT/CUR-NPs. Ex vivo studies in AOM/DSS-induced colon cancer mouse model with the developed NPs showed higher permeation and accumulation of HA-
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functionalized NPs in colon tumor region. Strong synergistic effects observed between CPT and Cur in this formulation, depicted by an IC50 value of 0.7 μM in Colon-26 cells at both 24 and 48 hours [88]. Chrysin (Chr), a naturally occurring flavone, is found in plant extracts. It is one of the most broadly used herbal medicine. Chr has been reported to have several effects such as anti16
inflammatory, antioxidant, antidiabetic, anti-allergic, antibacterial, antiestrogenic, and anticancer [89, 90]. As seen in in-vitro and in-vivo studies, anticancer effect of Chr is mainly due to arresting of the cell cycle, induction of apoptosis, inhibition of angiogenesis, and metastasis with
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no toxicity on normal cells [91]. Lotfi-Attari et al. formulated PLGA/PEG NPs, encapsulating a combination of Cur and Chr for the first time. In vitro studies in Caco-2 cell lines with Cur–Chr– PLGA/PEG NPs demonstrated significant growth arrest of cancer cells and high intracellular concentrations. The CIs value for the formulation was <1 which is indicative of a synergistic effect of the combination [92].
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Anirudhan et al. designed a transdermal drug delivery system (TDDS) to encapsulate 5-
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fluorouracil (5-FU) and curcumin (CUR). Polymer β-Cyclodextrin and aminated nano dextran
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used to entrap CUR and 5-FU respectively which provides flexible kinetics for the release of
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drugs after treatment with specific solvents. Polysaccharides ALG and CS were used to coat the
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surfaces of NP's with opposite charges in the final product. In vitro studies on human carcinoma
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cell lines, HCT-116 depicted a reduction in cell viability from 71.1 to 48.7 % at increasing
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concentrations, when treated with solvent dipped final formulation [93]. Bagheri et al. showed the synergistic effect of co-delivery of Chrysin and CUR nanoparticulate
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delivery in SW480 colon cancer cell line. MTT assay favored the combination depicted by twice the decrease in cell growth inhibition rate as compared to free CUR and chrysin. These effects
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were attributed to downregulation of hTERT by the combinatorial therapy [94].
4.3. Breast cancer Breast cancer is one of the most common types of cancer with more than 508,000 deaths till 2011. In 2012, nearly 1.7 million women diagnosed with breast cancer [71]. In the US alone, 17
246,660 cases of breast cancer are expected to register in 2018 [95]. Doxorubicin is the first line of therapy for several types of cancers including breast cancer [96]. Doxorubicin functions by DNA intercalation leading to disruption of DNA damage repair, causing the release of reactive
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oxygen species and eventually programmed cell death [97]. Like other anti-cancer drugs, drug resistance is a major issue associated with doxorubicin. To overcome MDR associated resistance with DOX, Wang et al. fabricated polymeric micelles and incorporated DOX with CUR to function as P-gp and apoptosis inhibitor. In the MCF-7/Adr (DOX-resistant) breast cancer cell lines, the formulation (DOX/Cur)-PMs compared with DOX-treated cells lead to the 18.29-fold
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increase of apoptotic cells and enhanced invitro toxicity. In vivo studies in 4T1 bearing Balb/c
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mice model for breast cancer showed a significant reduction in tumor weight as compared to
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control and free drugs [98].
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Ruttala et al. designed CUR and albumin-PTX hybrid encapsulation liposomes (CL-APN) and
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performed in vitro cytotoxicity assay in MCF-7 and B16F10 carcinoma cell lines. 1:1 molar ratio
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of the PTX and CUR in formulation showed enhanced cytotoxicity. In cell migration assay CL-
drugs [99].
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APN demonstrated the highest inhibition in both cell lines compared to control and individual
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To target breast cancer, Cui et al. co-delivered CUR and DOX in a pH-sensitive prodrug using transferrin Tf-PEG-CUR. Several malignant tumors overexpress Tf. This property makes it a
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perfect candidate for target-specific delivery to these type of cancers [100-102]. Both drugs being hydrophobic were entrapped in the core of Tf-PEG-CUR/DOX NPs. Mildly acidic pH release of CUR was significantly increased from 33.6% at pH 7.4 to 72.4 % at pH 5. A similar trendas observed for DOX release. In vitro cytotoxicity assay in MCF-7 cell lines showed the highest inhibition by the Tf-PEG-CUR/DOX NPs with IC50 of 2.5 μM. The concentration of 18
DOX and CUR in tumor, lung, and liver, major target areas in breast cancer, was the highest. The preparation also presented fewer adverse effects. Its concentration in heart and kidney was lower than others in the group. This formulation showed a high inhibition rate of tumor growth
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(IRT) (83.5%) [103].
Using curcumin as a theranostic agent (diagnostic + therapeutic) was studied by Nguyen et al. by fabricating Cur-PLA-TPGS NPs (curcumin + paclitaxel) co-loaded with PLA-TPGS NPs (Cur+PTX)- PLA-TPGS NPs. Fluorescence of CUR in MCF7 cell and MCF7 spheroid monitored by confocal fluorescence microscopy. This concluded that the monitoring of the
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delivery and bio-distribution of the drug delivery system, curcumin acted as a potential
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fluorescent probe [104].
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Sahu et al. utilized nanosuspensions technique to co-deliver CUR and DOX. In vitro cytotoxicity in MCF7 cell line with CUR-DOX co-loaded nanosuspension showed the
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highest inhibition rate, compared to individual drug nanosuspensions of 83.31% and 81.65% at
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0.5 and 1.0μg/mL respectively. Moreover, in vivo studies showed a highest tumor inhibition
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ratio (TIR) of 70% compared to groups treated with CUR nanosuspension (34%) and DOX
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nanosuspension (15%) [105]. In vivo stability and increased drug loading capacity are a few advantages of coating super-
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magnetic iron oxide nanoparticles (SPIOs) with albumin. However, synthesis of SPIOs system is complicated and time-consuming. To overcome this limitation, Chen et al. used a one-step synthesis strategy of in situ co-precipitation, to synthesize albumin-stabilized SPIOs (BSASPIOs). Further to test for the effectiveness of this system in-vitro and in vivo, they encapsulated two cytotoxic drugs CUR and Sunitinib in BSA-SPIOs. Values for the free drug Sun and Cur in 19
MCF-7 were 6.15 μM and 23.8 μM respectively. The IC50 values of BSA-SPIOs enclosed CUR and Sunitinib were enhanced to 2.43 μM (for Sun) and 6.79 μM (for Cur). Moreover, an increase in inhibition noted with the application of external magnetic field with IC50 values of 2.03 μM
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(for Sun) and 5.67 μM (for CUR), respectively. In vivo studies showed the highest inhibition of tumor growth with nearly 2.3-fold tumor weight reduction by the BSA-SPIOs SunCUR combination, compared to free SunCUR therapy [106].
Increased sensitivity of MDR tumor cells by addition of small-molecule compounds known as chemosensitizers, which lead to an improvement of the efficacy of chemotherapeutic drugs [107-
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109]. As a novel chemo/photo- co-therapeutic nanomaterial, mesoporous carbon along with a
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chemosensitizer (CUR) can be used to develop mesoporous carbon nanoparticles (MCNs). Some
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advantage of MCNs comprises high pore volume ratio, larger surface area, and efficient drug
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loading capability [110]. The PCDA backbone, which is made up of disulfide bond linked mono-
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curcumin, degrades at a significantly higher concentration of glutathione (GSH) in the cytoplasm
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than in the extracellular environment, leading to a GSH-responsive release of curcumin (CUR) [111]. Li et al. designed PEG-PCDA coated MCN (chemo/photo chemotherapy activity) to
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deliver DOX to drug-resistant MCF-7/ADR cells. In vitro studies on MCF-7/Adr cell lines
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showed the maximum inhibition (IC50= 17.41 mg/mL) with the formulated PEGPCDA/DOX@MCNs. Additionally, the IC50 value reduced to 11.16 mg/mL after NIR laser
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irradiation [112]. Results of this study are illustrated in Figure 6. (Insert Figure 9 here)
Another approach against MDR resistant MCF-7/Adr cells is through Folate conjugation on the surface of nanoparticles. It could become a useful approach to develop target-specific NPs due to its affinity to folate receptors which are overexpressed in several cancers. Baek et al. fabricated
20
2-hydroxypropyl-β-cyclodextrin (HPCD) conjugated with folate for co-delivery of curcumin with paclitaxel (FPCHN-30). The formulation showed enhanced absorption of paclitaxel as compared to that of free drug, which was due to P-gp inhibition of curcumin. In vitro studies in
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MCF-7/Adr cells revealed that FPCHN-30 with folic acid showed the highest cytotoxicity and cellular uptake [113].
Medel et al. tested the efficiency of a biodegradable and biocompatible block copolymer (PEGb-PLA) in co-delivery of the curcumin-bortezomib system to treat breast cancer. NP formulation in MCF-7 and MDAMB-231 breast cancer cells caused significant cytotoxicity with an IC50
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values of 18.8 nM and 122.4 nM respectively [114].
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value of 7.5 nM and 59.2 nM respectively as compared to free Cur-BTZ combination with IC50
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HA can interact with the CD44 receptor. Tumor-specific nano-formulations involve HA conjugation in the final design. Yang et al. designed nanoparticles to directly target breast cancer
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stem cells (bCSCs). They prepared and evaluated targeting co-delivery system of Hyaluronic
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Acid (HA-Hybrid NPs) to the surface of hydrophobic PLGA NPs to co-deliver PTX and CUR. In
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the MCF-7 cells, the formulation exhibited the lowest IC50 values of 0.751×10-3 μg/mL and 0.4318 μg/mL for PTX and CUR respectively. Compared to free PTX+CUR CI (0.77), the CI of
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HA-Hybrid NPs/PTX+CUR was significantly lower at 0.32. In vivo studies pointed out improved tumor growth inhibition (TGI) at 67.5% as compared to other groups. Additionally,
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average tumor volume for HA-Hybrid NP/PTX+CUR group was found to be 2.5 times smaller than control. [115]. Lin et al. used silica-based materials, mesoporous silica with the PEG (PLMSNs) for co-delivery of Tax and Cur. The in-vitro activity in canine breast cancer line showed enhanced IC50 values for the formulation [116].
21
Sudakaran et al. exploited a new synthetic biodegradable/ biocompatible copolymer poly L-lactic acid-co-ε-caprolactone (PLACL) with Aloe Vera (AV) MGO for co-delivery of CUR/β-CD in breast cancer cell lines. In vitro studies on MCF-7 cells showed 52.19% cell growth inhibition by
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PLACL/AV/MgO/CUR/β-CD compared to PLACL/AV/MgO [117].
Yuan et al. designed and fabricated pH-sensitive NPs to co-deliver DOX and CUR to MDR resistance breast cancer cells. In-vitro cytotoxicity assay on MCF-7/ADR cells showed 2.2 and 7.2 times lower IC50 value for CURDOX-NPs as compared to DOX-NPs and DOX solution respectively. In vivo studies revealed the slowest tumor growth and maximum growth inhibition
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rate by CURDOX-NPs. Moreover, the formulation demonstrated a lower percentage of cancer
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stem cells as compared to CUR-NPs formulation alone (15.0% vs. 6.82%) [118].
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4.4. Brain cancer
The most common and aggressive brain tumors in human are malignant glioma with a 5-year
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survival rate of only 5% [119]. Blood-Brain Barrier (BBB) is the principal obstruction for
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delivery for limited glioma chemotherapy (e.g., temozolomide, carmustine). Cui et al. fabricated
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T7-modified magnetic PLGA nanoparticulate system (MNP/T7-PLGA NPs), consisting of hydrophobic magnetic nanoparticles (MNPs), to co-deliver PTX and CUR. In vitro cytotoxicity
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effects were examined in U87 cells. IC50 for the MNP/T7-PLGA NPs loaded with PTX+CUR was reported to significantly improve at 3.06 μg/mL, compared to other groups. In vivo tumor
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studies also revealed superior anti-glioma efficacy for the formulation [120]. Due to a continuous requirement of glucose supply in cancer cells, GLUT-1 is significantly overexpressed [121]. BBB in glioblastoma contains significantly overexpressed GLUT-1 [122, 123]. This could be a good target for the anticancer drug delivery to glioblastoma cells. 22
Sarisozen et al. developed polymeric micelles coated with a single chain fragment variable (scFv) against GLUT-1 to co-deliver CUR and DOX. In vitro cytotoxicity assay was tested in U87MG glioblastoma cells. The CI for polymeric micelles at 0.63 further reduced to 0.46 with
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GLUT1 targeting strategy. Moreover, the formulation leads to a 3-fold increase in nuclear localization of DOX in U87MG cells, which was the apparent reason for enhanced cytotoxicity [124].
4.5. Skin cancer
Every year nearly two million new cases of skin cancer are diagnosed in the United States alone
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[95]. 5-fluorouracil, imiquimod, bleomycin, and interferon alpha are the most widely used
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chemotherapeutic agents against skin cancer [125]. Recently, small interference (siRNA) has
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shown effectivity in preclinical and clinical trials against cancer [126]. Jose et al. fabricated and
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evaluated liposomes for co-delivery of curcumin and STAT3 siRNA, combined with anodal
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iontophoresis technique. Iontophoresis application enhances skin penetration of positively
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charged lipoplexes (liposome-siRNA complexes) by electro-repulsion and electro-osmosis technique [127]. In vitro cytotoxicity assay in A431 cells with the formulation, demonstrated
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higher inhibition of cell growth (72.9±2.3%), compared to individual treatments. Anodal
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iontophoresis applied to reach the target depth of 100 μm inside the skin and for better penetration of the compounds in the ski[128].
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Effect of curcumin in combination with the paclitaxel in folic acid conjugated PLGA-PEG NPs was studied by Kumar et al. In in vivo studies, CUR-PLGA-PEG-FA formulation demonstrated enhanced bioavailability and retention time of curcumin with no effect on toxicity profile. Further, in combination with Paclitaxel on cervical cancer xenograft model revealed enhanced
23
tumor growth inhibition. A nearly 2-fold decrease in tumor volume compared to individual drug treatment groups [129].
Jose et al. exploited the effect of Iontophoresis on a liposomal formulation of CUR and STAT
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siRNA on a melanoma tumor mouse model. In vitro cytotoxicity studies with B16F10 cell lines showed higher growth inhibition (76.3 ± 4.0%) compared to curcumin-loaded cationic liposomes (46.0 ± 3.4%) and cationic liposome-STAT3 siRNA group (58.4 ± 3.0%). In vivo studies on melanoma tumor model also supported the in vitro results with maximum nearly three-fold increase in inhibition on tumor growth and volume by the curcumin-loaded liposome-STAT3
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siRNA complex compared to other groups [130].
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Combination of chemotherapy with phototherapy for the treatment of skin cancer exploited by
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Singh et al. They designed gold coated Hydrogenated Soya Phosphatidyl Choline (HSPC) liposomes encapsulating CUR. In vitro studies on B16F10 cell lines showed the 9-fold increase
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in cell growth inhibition by Au-Lipos Cur NPs compare with free curcumin after laser irradiation
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and ~8 fold compared to non-gold coated/non-irradiated formulation of lipos-Cur NPs [131].
4.6. Pancreatic cancer
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Pancreatic cancer is the second most common cause of cancer-related deaths. It is estimated to account for 55,440 new cases and 44,330 deaths in 2018 in the US alone [95]. New therapeutic
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avenues are essential to overcome an abysmal 5-year survival rate of pancreatic cancerare essential. Kim et al. utilized nanoparticle albumin-bound (NabTM) technology using highpressure homogenization, to co-deliver PTX and Cur. Efficient internalization into MiaPaca-2 cells observed with PTX/CCM Alb-NPs. Moreover in vitro cytotoxicity studies revealed 71%
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increase in IC50 with this formulation in MiaPaca-2 cells [132]. Toxicological study of the formulation containing chitosan-SLNs (c-SLNs) in combination with sulforaphane (ACS combination) on co-delivery of Aspirin and Cur studied by Thakkar et al. for pancreatic cancer.
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This formulation has been previously shown to be effective against pancreatic cancer in in-vitro studies, but the toxicity profile of the c-SLNs and ACS is not studied before. The formulation was found to be safe for long-term oral administration against pancreatic cancer with no signs of toxicity in acute, subacute, and sub-chronic studies. Future direction points in the utilization of cSLNs and ACS technique for formulating other anti-cancer drug combinations [133].
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4.7. Osteosarcoma
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In kids and young adults, Osteosarcoma (OS) accounts for 60% of primary bone cancers [134].
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Currently approved treatments for OS include surgery and chemotherapy [95]. Combination of
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surgery with chemotherapy increases the cure rate of patients with OS from 20 % to 70 % [135].
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The commonly used chemotherapeutics to treat OS include DOX, cisplatin, and methotrexate.
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Even with the combination of chemotherapy and surgery, failure in nearly 30% of stage IV patients due to drug resistance is observed [136]. Polymeric nanoparticles coated with lipid-PEG
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or (LPNs) were constructed to overcome the resistance issues and to inhibit the rapid clearance
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effect of the reticuloendothelial system. Constructed LPNs utilized to co-deliver DOX, and CUR (DOX+CUR LPNs) and tested the formulation for in-vitro and in-vivo effects in OS. In vitro
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cytotoxicity assay was performed in Human osteosarcoma cell lines (KHOS cells). The IC50 of DOX+CUR LPNs was found to be lowest at 0.6 μM as compared to other groups. In-vivo efficacy was observed in BALB/c mice injected with KHOS cell model. On 21-day posttreatment, OX+CUR LPNs group treated mice, the tumor volume was lowest at about 182 mm3,
25
compared to the saline-treated group (973 mm3). Moreover, with DOX+CUR LPNs, the Tumor Growth Inhibition (TGI) was significantly higher at 81.3% compared to other groups [137].
4.8. Gastrointestinal cancer
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Gastrointestinal cancers are the third leading cause of cancer-related deaths worldwide [138]. Intravenous (IV) administration is the most common route of chemotherapeutic delivery in GI cancer patients. IV route has several disadvantages like discomfort, stress to patients, multiple hospitalizations trip, high cost, and high risk of hospital-acquired infections [139, 140]. To overcome this problem, Bar-Zeev et al. developed a novel oral delivery nano-delivery system
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using self-assembling β-casein (CN) enclosing hydrophobic chemotherapeutic drugs (PTX) and
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MDR (TQD) chemosensitizers. In vitro cytotoxicity assays were performed in EPG85-257RDB
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(P-gp overexpressing) and EPG85-257P gastric carcinoma cell lines. The β-CM formulation with
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combination showed significantly lower IC50 value with MDR resistance EPG85-257RDB cell
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4.9. Prostate cancer
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line (111 nM) compared to EPG85-257P cell line (2185 nM) [141].
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Prostate cancer is the second most common cause of cancer-related deaths. In 2018, nearly 164, 690 new case and 29, 430 deaths are estimated in the US alone [95]. Taxane drugs and platinum
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compounds first line for chemotherapy against prostate cancer. Although due to severe adverse effects due to MDR, they are not as effective with monotherapy [142]. To overcome this adverse
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effect, Saralkar et al. used hydrophobic phytochemicals Curcumin and resveratrol and formulated calcium alginate NPs to encapsulate them. The drug-loaded nanoparticles had a cytotoxic effect in DU145 prostate cancer cells with no hemolytic effects [143].
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4.10. Cervical cancer Cervical cancer is one of the most common causes of cancer-related deaths in females. The first line of therapy for cervical cancer is Cisplatin (DDP) as monotherapy, or it’s combination with
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paclitaxel [144, 145]. Serious adverse effects related to DPP are nephrotoxicity, hepatotoxicity, and drug resistance [146-148], which could be overcome by nano-carrier-based delivery of DDP to the tumor sites and combination chemotherapy [149-151]. Li et al. combined both techniques and constructed lipid-polymer hybrid nanoparticles (LPNs) for DDP and Cur co-delivery. Moreover, they compared the LPN formulation with the most common NPs delivery formulation
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such as Polymeric Nanoparticles (PNPs). HeLa cells and HUVEC cells used for in-vitro
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cytotoxicity assay. Highest in vitro tumor activity was exhibited by DDP/CUR/LPNs as
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indicated by lowest IC50 value among the groups. CI of DPP/CUR/LPNs was significant at 0.61
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as compared to DPP/CUR/PNPs, and DPP/CUR solution with CI value of 0.96 and 1.40, respectively. Investigated the in vivo antitumor efficacy of LPNs in cervical cancer-bearing
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BALB/c mice model DPP/CUR/LPNs treated group showed the most significant reduction in
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4.11. Leukemia
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tumor size compared to other groups [152].
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According to the American cancer society report, in 2018 nearly 60,300 new cases and 24,370 deaths are expected due to leukemia [95]. Silver nanoparticles (AgNPs) have antimicrobial
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activity and anti-cancer effect [153]. The generation of reactive oxygen species due to the release of silver ions is the reason behind AgNPs mediated cytotoxicity [154]. Petrov et al. utilized this property of AgNPs and evaluated the effect of a combination of AgNPs and curcumin in a multilayer polymeric micelle of poly (ethylene oxide)-b-poly (n-butyl acrylate)-b-poly (acrylic acid) (PEO-b-PnBA-b-PAA) triblock terpolymer micelles, in acute myeloid leukemia. This 27
formulation specifically presented a pronounced cytotoxic effect on acute myeloid leukemia (HL-60), and it's multidrug-resistant subline HL-60/DOX, as compared to an individually loaded carrier [155].
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4.12. Lung cancer
Lung cancer has one of the highest incidence among all forms of cancer. Suboptimal therapy due to lack of targeted effects and severe side effects are some disadvantages of conventional therapy against lung cancer. The advent of using siRNA for cancer therapy has attracted more attention, as RNA interference is more specific to the target gene and can knock down some oncogene
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expression for cancer therapy [156]. Zhang et al. demonstrated the effect of epidermal growth
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factor (EGF) modified monomethoxy (polyethylene glycol)-poly (D, L-lactide-co-glycolide)-
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poly(L-lysine) (mPEG-PLGA-PLL, PEAL) NPs (EGF-PEAL), loaded with Dox and Bcl-2-
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siRNA NPs on lung cancer. The blank EGF-PEAL NPs showed minimal cytotoxicity in the
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H1299 cell lines, indicating a useful drug delivery carrier. The co-delivery of siRNA and Dox in
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EGF-PEAL also reported higher cytotoxicity. Annexin V/PI staining assay showed maximum apoptosis in H1299 cells was induced by the combination of early and late apoptosis rates of
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61.56% and 11.37 % respectively. In vivo studies demonstrated tumor volume to be the smallest
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(2-3 fold) with the co-delivery of Dox and Bcl-2-siRNA group [157].
Tang et al. designed SLNs for the co-delivery of CUR and piperine in paclitaxel-resistant human
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ovarian carcinoma cell line A2780/Taxol. The purpose of the study was to evaluate whether the presence of Cur could reverse MDR associate resistance in this cell line. The in vitro cytotoxicity studies showed significantly higher cell growth inhibition with (Cur + Pip)-SLN (59.90±8.40%), as compared to Cur (25.85±5.74%) and Pip (6.87±4.52%) alone [158].
28
Boron Neutron Capture Therapy (BNCT) radiotherapy combines a boron-containing compound with low energy neutron irradiation to target cancer cells.10B captures the neutrons and disintegrates into alpha particles and lithium nuclei, which induce site-specific damage to tumor
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cells after accumulation [159]. Diego et al. exploited this target for anticancer effects by formulating Rubro-curcumin (stable adduct of boric acid, curcumin, and oxalic acid) [160] in PLGA NPS. Prepared folate specific PLGA NPs, to provide tumor-specific accumulationlate specific PLGA NPs were prepared. In vitro cytotoxicity assays showed enhanced inhibition rate
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with the formulation compared to individual drugs [161].
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5. Clinical trials involving curcumin
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Curcumin both in its free form and as nano-particulate formulations have been under
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investigation in human clinical trials for many years. It has shown clinical benefits in patients with colorectal cancer, pancreatic cancer, breast cancer and multiple myeloma. Searching for
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summarized in Table 2 [162].
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Curcumin as a treatment for cancer in www.clincaltrials.gov shows 22 recent trials which are
Table 2: Recent clinical trials involving curcumin NCT number
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Serial No. 1.
Phase
Trial Status Active, not recruiting
Cancer type Advanced colorectal cancer
Description
Phase 1
2.
NCT01333917
Phase 1
Completed
Colorectal cancer
Curcumin Biomarkers
2016
3.
NCT01294072
Phase 1
Active, not recruiting
Colorectal cancer
Study Investigating the Ability of Plant Exosomes to Deliver
2020
A
NCT01859858
29
Effect of Cur on Dose Limiting Toxicity and Pharmacokinetics of Irinotecan in Patients with Solid Tumors
Completion date 2018
Curcumin to Normal and Colon Cancer Tissue Phase 1/2
Active, not recruiting
Colorectal cancer
Combining Curcumin with FOLFOX Chemotherapy in Patients with Inoperable Colorectal Cancer
2019
5.
NCT02598726
Phase 1
Recruiting
Malignant Neoplasm
Curcumin and Piperine in Reducing Inflammation for Ureteral StentInduced Symptoms in Patients with Cancer
2021
6.
NCT02138955
Phase1/ 2
Active, not recruiting
Advanced Cancer/Faile d standard therapy
A Phase IB Dose Escalation Study of Lipocurc in Patients with Cancer
2017
7.
NCT02336087
Phase 1
Recruiting
Pancreatic cancer
Gemcitabine Hydrochloride, Paclitaxel AlbuminStabilized Nanoparticle Formulation, Metformin Hydrochloride, and a Standardized Dietary Supplement in Treating Patients with Pancreatic Cancer That Cannot be Removed by Surgery
2018
8.
NCT02439385
N
A
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Enrolling by invitation
Colorectal cancer
Avastin/FOLFIRI in Combination with Curcumin in Colorectal Cancer Patients with Unresectable Metastasis
2019
Phase 2
Recruiting
Breast cancer
"Curcumin" in Combination with Chemotherapy in Advanced Breast Cancer
2018
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Phase 2
A 9.
NCT03072992
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NCT01490996
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4.
30
NCT00745134
Phase 2
Active, not recruiting
Rectal cancer
Curcumin with Preoperative Capecitabine and Radiation Therapy Followed by Surgery for Rectal Cancer
2019
11.
NCT02724618
Phase 2
Active, not recruiting
Prostate cancer
Nanocurcumin for Prostate Cancer Patients Undergoing Radiotherapy (RT)
2022
12.
NCT02095717
Phase 2
Active, not recruiting
Prostate cancer
2018
13.
NCT00852332
Phase 2
Recruiting
N
Multicenter Study Comparing Taxotere Plus Curcumin Versus Taxotere Plus Placebo Combination in First-line Treatment of Prostate Cancer Metastatic Castration-Resistant (CURTAXEL)
Breast cancer
Docetaxel with or Without a Phytochemical in Treating Patients with Breast Cancer
2017
14.
NCT02944578
Phase 2
Recruiting
Cervical cancer
Topical Curcumin for Precancer Cervical Lesions
2021
15.
NCT02138955
16.
NCT02556632
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10.
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Phase 2
A Phase IB Dose Escalation Study of Lipo-cur in Patients with Cancer Completed
Breast cancer
Prophylactic Topical Agents in Reducing Radiation-Induced Dermatitis in Patients with NonInflammatory Breast Cancer
2016
Phase 2
Recruiting
Cervical, Endometrial , and Uterine cancer
Study of Pembrolizumab, Radiation and Immune Modulatory Cocktail in Cervical/Uterine
2022
A
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Phase 2
17.
NCT03192059
31
Cancer Phase 2
Completed
Endometrial cancer
Effect of Curcumin Addition to Standard Treatment on Tumour-induced Inflammation in Endometrial Carcinoma
2016
19.
NCT02782949
Phase 2
Recruiting
Gastric cancer
Curcumin in Preventing Gastric Cancer in Patients with Chronic Atrophic Gastritis or Gastric Intestinal Metaplasia
2019
20.
NCT00641147
Phase 2
Completed
Familial Adenomato us Polyposis
Curcumin in Treating Patients with Familial Adenomatous Polyposis
2016
21.
NCT03061591
Phase 2
Not yet recruiting
Familial Adenomato us Polyposis
Turmeric Supplementation on Polyp Number and Size in Patients with Familial Adenomatous Polyposis.
2020
22.
NCT02064673
Phase 3
Prostate cancer
Adjuvant Curcumin to Assess Recurrence-Free Survival in Patients Who Have Had a Radical Prostatectomy
2020
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NCT02017353
Recruiting
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N
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18.
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6. Challenges with curcumin combination therapy Effective combination therapy for anticancer treatment requires dealing with an investigation of multiple hurdles. Initial studies demand precise tuning of an optimal mass ratio (ratio-metric dosing) of each drug in a combination, based on individual drug efficacy and pharmacokinetic profile [163]. Due to low bioavailability and poor absorption, the formulation of combination 32
becomes more challenging with curcumin [4]. One of the major challenges of non-site-specific combination nanoparticulate formulation is off-site effects due to action on healthy cells. Although, recently several chemotherapeutic nano-formulations combine folate or other specific
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antigens, to enhance site specificity for the delivery of cytotoxic drugs to tumor cells. Delivery system could be further extended into combination chemotherapy for achieving maximum treatment efficacy as described in Figure 7 via a potential delivery system of curcumin combination nanoparticles with paclitaxel. (Insert Figure 10 here). Also, some of the materials used for fabricating nano-formulations are toxic, so each formulation should be thoroughly tested
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for short and long-term toxicity. As the intravenous route is the most popular route of
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administration of nano-formulation, toxicity related to the interaction between endothelial cells
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of blood vessels and nanocarrier should be considered [164]. For nanocarrier-based combination
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therapy, other critical aspects to be considered are Quality by design parameters, rationally based
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on size and surface physicochemical property of materials to be fabricated. [165].
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7. Conclusion and future directions
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Delivery of nano-encapsulated anticancer drugs with curcumin as an adjunct, is emerging
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globally as an improvement to monotherapy. Along with the chemo-sensitizing synergism and tissue specificity imparted by this approach, the combinatorial therapy is now being
A
acknowledged for fighting back multidrug resistance and providing effective treatment strategies. The present in-vitro and in-vivo work pose a promising picture, but a lot must be done before transition of this therapy could be made from lab-scale to safe human dosage forms. The biggest challenge from pharmaceutical point is alteration of curcumin from its natural form to a formulation relevant derivative, which is more stable and bio-pharmaceutically possess more 33
“drug like properties”. In one such attempt, poly (curcumin-dithiodipropionic acid) PCDA coating on nanoparticles was used. This coating was made up of disulfide bond linked monocurcumin, which degrades at a significantly higher concentration of glutathione (GSH) in the
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cytoplasm than in the extracellular environment, leading to GSH-responsive release of curcumin; thus, altering curcumin’s original form to a more practically viable form for formulation. Other intense fabrications like prodrug approach, polymer coating, complexation, co-crystallization of curcumin etc. would require time and cost inputs, both of which are general offsets for pharmaceutical industries. More research thus needs to be put into incorporation of curcumin in a
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delivery system, which could be optimized to its best possible usage, counterbalancing the
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monetary input. Other major barriers to human usage of this approach lie in lack of its target
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specific properties. Methods like ligand attachment, PEGylation of NPs, tissue specific coating,
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or upcoming external means like electrophoresis and iontophoresis etc. could be possible solutions to such hindrances. Human dose optimization for curcumin alone or with the
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combination drugs needs to be further investigated. With no commercial drugs in the market so
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far, dosing would be a major rate limiting step here. In vitro dose-response studies and possible
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FDA approval with preclinical or clinical data backups must be set in place to even start those conversations. Further, a complete pharmacokinetic (PK) profiling and in vitro-in vivo
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correlation (IVIVC) for the drug combinations, needs to be drawn to further move up the ladder. Also, upon dosage designing, antitumor activity of the combination NPs needs to be tested in
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actual cancer settings. Effectivity of these formulations is often determined by altered vasculature, characteristic to cancer masses. Toxicity studies for many developmental doses discussed in the work above have been performed, but extensive toxicologic profiling and
34
percentage damage to healthy tissue is required to weight in the risk to benefit ratio of this chemotherapeutic approach and justify their incorporation. Switching the course of present chemotherapy to nano-particulate curcumin combination therapy
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is a translational attempt which requires work from basic molecular aspects to pharmaceutical and then to preclinical and clinical trials. Extensive efforts are required from current prospects that curcumin combination NPs possess, to ultimately make this approach a potential future treatment improvement in cancer chemotherapy
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Funding
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This research did not receive any specific grant from funding agencies in the public, commercial,
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or not-for-profit sectors.
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Conflict of interest
References
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Cancer
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The authors declare that there are no conflicts of interest.
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[4] G. Sa, T. Das, Anti cancer effects of curcumin: cycle of life and death, Cell division 3(1) (2008) 14. [5] B.B. Aggarwal, I.D. Bhatt, H. Ichikawa, K.S. Ahn, G. Sethi, S.K. Sandur, C. Natarajan, N.
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Seeram, S. Shishodia, 10 Curcumin—Biological and Medicinal Properties, (2006). [6] Y. Liu, X. Hong, Effect of three different curcumin pigmens on the prdiferation of vascular smooth muscle cells by ox-LDL and the expression of LDL-R, Zhongguo Zhong yao za zhi= Zhongguo zhongyao zazhi= China journal of Chinese materia medica 31(6) (2006) 500-503.
[7] D.S. Kim, S.-Y. Park, J.-Y. Kim, Curcuminoids from Curcuma longa L.(Zingiberaceae) that
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(1–42) insult, Neuroscience Letters 303(1) (2001) 57-61.
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protect PC12 rat pheochromocytoma and normal human umbilical vein endothelial cells from βA
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Figure legends Figure 1: Different type of cancers that curcumin is found to manage.
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Figure 2: The anti-cancer mechanism of curcumin. It is characterized by decrease in angiogenesis, metastasis and proliferation and increase in apoptosis with associated factors.
Figure 3: Different types of possible curcumin nano-formulation with their major advantages. Figure 4: In vivo antitumor efficacy of LPNs as compared to other groups. Tail injection of
different formulation groups of equivalent doses was administered in mice. Co-administration by
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reproduced with copyright permissions from [166])
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DTX and CUR LPN's showed most efficient suppression on tumor growth (p < 0.05). (Figure
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Figure 5: NanoDoxCurc (NDC) surmounts DOX resistance (a) Tumor sections from Dox
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xenografts examined by fluorescence microscopy; accumulation of DOX nanoparticles observed (b) NDC significantly inhibits the growth of subcutaneous DOX-resistant cancer xenografts.
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Excised tumors presented significant reduction in tumor growth with NDC group as compared to
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other treatment groups (N=5, *p<0.005). (c) Post treatment levels of MDR1 expression measured
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by immunofluorescence and (d) western blot in Dox xenografts. (e) Mice with DOX-resistant ascites with different treatment groups; more than 50% increase in survival was observed in
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NDC treated mice compared to others (N=8, *p<0.005). (Figure reproduced from open access unrestricted use article [167])
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Figure 6: Schematic representation of delivery of nanocarrier combination therapy. (A) An anticancer drug in free form and curcumin as nanocarrier (Free drug + Nano), (B) Separate nanocarrier delivery of both drugs (Nano + Nano), C) Co-encapsulation of both drugs in the same nanocarrier (co-encapsulation)
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Figure 7: (a-d) Combination Index Plots of Folate-BSA-difluorinated curcumin (T C) and Folate-BSA-Paclitaxel (T P) using MTT assay in SKOV3 Cell line (left) and HeLa cell lines (right). The data demonstrates synergistic cell killing effect (e) depicts the Fa-CI plot
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demonstrating synergistic combination efficiency as compare to fraction effected. Average synergism reported at Fa < 0.5. (f) Graph showing the enhance cell killing compared to paclitaxel. (Figures reproduced with copyright permissions from [168]).
Figure 8: Combination Nanocarrier possible dosing and effects. The in-vitro and then in-vivo fixed molar ratio (synergistic effect) can be translated from in vitro assay to in vivo assay using
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nanoparticle approach strategy.
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Figure 9: In-vitro cytotoxicity depicting chemotherapy efficacy (chemo-sensitizing effect) and
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drug resistance reversal of synthesized doxorubicin with curcumin coated mesoporous carbon
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nanoparticles (PEG-PCDA/MCNs) was tested by MTT assay against drug resistant of MCF7/ADR cells. (A) DOX dose-dependent in vitro cytotoxicity of different DOX formulations
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against the drug resistant MCF-7/ADR cells after 48 h incubation; Free DOX shows lowest
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inhibition concentrations (IC50) vs significantly enhanced IC50 with the designed nanoparticles,
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(B) Viability rate of MCF-7/ADR cells after 48 h incubation with MCNs and PEGPCDA/MCNs; a significantly decreased viability of cells is seen with the drug incorporated
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nanoparticles vs the controls, (significant difference, *: p < 0.05; **: p < 0.01). (figure reproduced with permission from Li et al. [112])
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Figure 10: A mechanism of action display for a possible paclitaxel (PTX) and curcumin (CUR) nanoparticle. Their interaction with Folate receptor and subsequent Endocytosis of the PLGAFA-PTX Lipid Nanocarrier has been depicted.
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S1043-6618(18)30436-5 https://doi.org/10.1016/j.phrs.2018.11.005 YPHRS 4054
To appear in:
Pharmacological Research
Received date: Revised date: Accepted date:
28 March 2018 31 October 2018 4 November 2018
Please cite this article as: Batra H, Pawar S, Bahl D, Curcumin in Combination with Anti-Cancer Drugs: A Nanomedicine Review, Pharmacological Research (2018), https://doi.org/10.1016/j.phrs.2018.11.005 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Curcumin in Combination with Anti-Cancer Drugs: A Nanomedicine Review
1
2
Neuroscience Institute & Center for Behavioral Neuroscience, Georgia State University, 789 Petit Science Center, Atlanta, GA, 30303
Department of Computer Science, Georgia State University, 34 Peachtree Street, Atlanta, GA, 30303. 3
Department of Biology, Georgia State University, 34 Peachtree Street, Atlanta, GA, 30303.
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Division of Pharmaceutics and Translational Therapeutics, University of Iowa, Iowa City, Iowa 52242
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Harshul Batra1, Shrikant Pawar2, 3, and Dherya Bahl4
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Article Type: Review.
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*Correspondence author:
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Dr. Harshul. Batra, Neuroscience Institute & Center for Behavioral Neuroscience, Georgia State University, 789 Petit Science Center Atlanta, GA, 30303.
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Graphical abstract
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Email address: [email protected]
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Abstract
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A huge surge of research is being conducted on combination therapy with anticancer compounds formulated in the form of nanoparticles (NPs). Numerous advantages like dose minimalization and synergism, reversal of multi drug resistance (MDRs), enhanced efficacy have emerged with
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nanoencapsulation of chemotherapeutic agents with chemo-sensitizing agent like curcumin. Within last couple of years various nano-sized formulations have been designed and tested both in vitro with cell lines for different types of cancers and in vivo with cancer types and drug resistance models. Despite the combinatorial models being advanced, translation to human trials has not been as smooth as one would have hoped, with as few as twenty ongoing clinical trials
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with curcumin combination, with less than 1/10th being nano-particulate formulations. Mass
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production of nano-formulation based on their physico-chemical and pharmacokinetics deficits
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poses as major hurdle up the ladder. Combination of these nano-sized dosage with poorly
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bioavailable drugs, unspecific target binding ability and naturally unstable curcumin further complicates the formulation aspects. Emphasis is now therefore being laid on altering natural
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forms of curcumin and usage of formulations like prodrug or coating of curcumin to overcome
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stability issues and focus more on enhancing the pharmaceutical and therapeutic ability of the
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nano-composites. Current studies and futuristic outlook in this direction are discussed in the review, which can serve as the basis for upcoming research which could boost commercial
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translational of improved nano-sized curcumin combination chemotherapy.
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Abbreviations
MDR, multi drug resistance; NPs, nanoparticles; PTX, paclitaxel, Dox, doxorubicin; P-gp, pglycoprotein; PEG, polyethylene glycol; PLGA, poly(lactic-co-glycolic acid); PLA, polylactic acid; BTZ, Bortezomib; PLACL, poly L-lactic acid-co-ε-caprolactone; DDP, cisplatin Keywords: Curcumin, Nano-formulations, combination therapy, Cancer, Drug Delivery
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1. Introduction One-fifth of the deaths worldwide annually are caused by various type of cancers [1]. Cancer is a
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result of successive genetic and epigenetic alterations resulting in apoptosis, uncontrolled cell proliferation, metastasis, and angiogenesis [2, 3]. Several strategies have been employed in recent years to combat cancer evasion, including surgery, hormonal therapy, chemotherapy, and radiation therapy. Chemotherapy which involves usage of cytotoxic antineoplastic drugs (alkylating agents and antimetabolites), although effective in most cases, has immense side-
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effects and lead to drug resistance (intrinsic and acquired). Acquired resistance is considered
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more severe and is caused by mutations induced by over-expression of therapeutic targets or
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stimulation of cancer-promoting pathway. Also, tumors contain a high degree of molecular
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heterogeneity leading to enhanced drug resistance [4].
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Curcumin is a natural phenolic antioxidant [5]. At high concentrations, it functions as
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cardioprotective, neuroprotective and antidiabetic agent [6-8]. It has shown pharmacological effects against diseases like type II diabetes, Alzheimer's disease, atherosclerosis and human
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immunodeficiency virus (HIV) replication [6-8]. Anti-cancer activity of curcumin has been
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extensively investigated recently, and significant improvements in gastrointestinal, melanoma, genito-urinary, breast, and lung cancers have been seen [9-12] (Insert Figure 1 here). It has
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pleiotropic properties, due to which it is seen to be most effective against single pathway targeted cancers [13, 14] (Insert Figure 2 here). It has also shown anti-inflammatory activity with a tolerance dose of at 12 g/day [15, 16]. The significance of curcumin to be considered as a possible drug lies in its free passage through cellular membranes due to its high lipophilicity. However, it does have low aqueous solubility making it susceptible to alkaline degradation. This 4
could be a probable reason for its low bioavailability and an increased dose for reaching therapeutic optimal blood concentrations [17-20]. Almost half a century ago, nanomedicine emerged as a specific niche for drug delivery, within
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the multidisciplinary field of nanotechnology. A principal focus for the last 20 years has been on the development of nano-formulation driven drug delivery of nanocarriers [21, 22]. Various nanocarriers that have been investigated for drug delivery [21, 22] include polymeric micelles, liposomes,
magnetic
nanoparticles,
conjugates,
and
peptide
carriers.
Integration
of
Nanotechnology within cancer research has proved to be advantageous in several ways,
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including (a) cancer treatment and detection (diagnostics and imaging agents); (b) biomarker
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identification for disease prediction; and (c) mechanism of cancer progression [23-25]. A narrow
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therapeutic window of drugs however is one of the major challenges with anticancer drugs and is
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the reason for serious side effects due to non-specific drug uptake by healthy cells. The efficacy
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of cancer drugs is also restrained due to multidrug resistance (MDR), often associated with
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chemotherapy. To overcome these issues the primary strategy of combination chemotherapy along with drug delivery systems using nanoparticles (NPs) is being actively explored [26].
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Curcumin could be a potential elementary candidate to be used for combination chemotherapy as
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it could overcome the issues associated with anti-cancer therapeutics. This article tries to summarize current research on combination of curcumin with several anticancer compounds
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with different mechanisms, as a possible target for treating various cancers. We provide a global overview of the role of nanoparticles (NPs) in oncology and different NPs currently used in cancer clinically. We briefly describe advantages of combination therapy in nanomedicine and summarize the current data on curcumin nano-formulations with an emphasis on its effect in invitro and in-vivo studies. Finally, we discuss futuristic clinical outlook, challenges, and 5
perspectives of developing nanoparticle-based curcumin combination therapy in cancer. This work envisions to serve as an up to date comprehensive literature basis, which could be utilized to build upon any future studies for better understanding of mechanism and ADME of curcumin
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along with a selection of proper combinational drug and fabrication of appropriate delivery technology. This review could be used as the go-to reference, to begin with in-vitro and in-vivo studies for successful development and in-clinic adaptation of nano-sized curcumin combination therapy.
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2. Nanoparticles in oncology
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Nanomedicine today is an entire field of research and development, with oncology as one of its
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major application. Lack of specificity is a primary drawback of cancer therapeutics for which
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nano-strategies based designing of personalized cancer treatment could be a solution. Recent decades have noticed emergence and approval of several nanoparticulate dosage forms by U.S.
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Food and Drug Administration (FDA). They overpower traditional delivery techniques with
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improved drug delivery, reduced toxicity, better safety profile, targeted therapy and extended
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product life-cycles [27].
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2.1. Type of Nanoparticles in Cancer therapy There are two categories of therapeutic and diagnostic nanoparticles: (a) organic (e.g., polymeric,
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liposomes, micelles, etc. (b) inorganic (e.g., gold, silica, iron oxide, etc.). Natural or synthetic organic molecules are the template for the formation of organic NPs. Organic and inorganic NPs differ in their technique of fabrication. For organic NPs, the encapsulation technique of biodegradable materials used are relatively simple and require several self-organizing or chemical binding organic molecules. Whereas, inorganic NPs involve precipitation of inorganic 6
salts in which atoms are often linked by covalent/metallic/magnetic bonding leading to formation of a three-dimensional array. Broad applications involving organic NPs in the clinic include formulations for hemostasis, vaccination, long-lasting depot delivery systems, and topical agents
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for systemic delivery through the skin [28-30]. Whereas inorganic nanoparticles are typically used in developing formulations for thermal ablation of tumors, intraoperative sentinel lymph node imaging, imaging applications, and anemia treatment [31, 32]. Intravenous organic NP formulations are characterized into two categories: (a) gene therapy applications [33, 34], or (b) small molecule drug delivery for cancer treatment (e.g., head and neck, melanoma, breast,
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metastatic, etc.) [35, 36]. Nanoparticle technologies defeat free drug counterparts as a drug-
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delivery system with an extended circulation of a drug, improved targeting to disease tissues,
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enhanced drug protection, and controlled release [37, 38]. These advantages make the
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nanoparticulate delivery system a potential model to dramatically change clinical care by
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improving current therapies or avail new treatment options (Insert Figure 3 here).
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3. Combination chemotherapy in cancer
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The interconnected pathways in cancer physiology reduce effectivity of monotherapy strategy. Drug resistance and chances of tumor recurrence due to pathway overlapping [39], cross-talk
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[40] and neutralizing response [41, 42] could be various complications hindering full potential of independent drugs. The easiest approach to overcome this issue could involve utilization of
A
combination chemotherapy strategy, which has shown to be successful in preliminary clinical trials. Combination chemotherapy design involves an understanding of several principles like non-overlapping toxicity, non-cross resistance, and enhanced tumor cell killing efficacy [43]. Synergistically acting drugs in vitro are governed by molar ratios, vs. Maximal Tolerated Dose
7
(MTD) govern drug ratios in-vivo [44, 45]. Nanocarriers like liposomes and polymeric micelles could further help to overcome mono-therapeutic complications. A previous generation of cancer combination chemotherapy comprised of traditional drug combinations including anthracycline,
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methotrexate, and paclitaxel (PTX)-based combinations [46]. A study on one such combination displayed an effective reversal of chemotherapeutic drug resistance with Dox and rapamycin codelivery. This combination leads to complete tumor remission, as compared to dox and rapamycin alone [47]. In another such study, in vivo effects of curcumin combination with antitumor drug was studied and displayed effectively. Docetaxel (DTX) and Curcumin (CUR)
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co-encapsulated lipid nanoparticles (LPN’s) were evaluated on PC3 tumor xenografts in mice
N
(human prostate cancer-bearing Balb/c nude mice model). These potent nanoparticles inhibited
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tumor volume growth significantly, when compared to other groups, with no visible side effects.
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It was concluded that this combination could prove to be an effective prostate cancer treatment [166] (insert Figure 4 here). Additionally, nanoparticulate delivery for combination
D
chemotherapy could benefit hydrophobic and hydrophilic drug codelivery [48], spatiotemporal
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control release behavior, and ratio-metric drug loading adjustments [49, 50]. The focus of this
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therapy lies in exploring new combinations to provide better insight into molecular and cellular
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mechanisms of cancer treatment.
One of the most challenging approaches towards treating cancers is overcoming MDR. The
A
major mechanism of resistance of cancer cells to drugs includes altered apoptosis pathway and overexpression of multidrug transporters [50, 51]. A powerful approach to disrupt MDR and to overcome the negative impact of the anticancer drugs is by co-delivery of chemo-sensitizing and chemotherapeutic agents. One of the major player involved in MDR is efflux of a variety of anticancer drugs by efflux transporter p-glycoprotein (P-gp), which is the adenosine triphosphate 8
(ATP)-binding cassette transporters, encoded by the MDR-1 gene [52]. In liver, pancreatic, gastrointestinal, and ovarian cancer, overexpression of P-gp leads to the reduction in the efficacy of drugs such as vinblastine, doxorubicin, vinblastine, paclitaxel, etc. [53].
In apoptotic
of nuclear factor kappa B (NF-kB) or BCL-2 [54].
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pathway-dependent MDR, the apoptotic response to anticancer drugs dampens by deregulation To combat MDR in cancer, several
nanoparticle formulations are designed to include the combination of drugs with chemosensitizers, MDR cytotoxic, and modulating agents. A Doxorubicin (DOX)-curcumin composite nanoparticle formulation called NanoDoxCurc (NDC) for overcoming DOX
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resistance was developed by Pramanik et al. [168]. Its effectivity in the form of inhibited MDR
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phenotype, is tested in athymic nude mice (DOX resistant) for several models of DOX resistant
A
cancers (multiple myeloma, acute leukemia, prostate and ovarian cancers). Additionally, reduced
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cardiac toxicity and bone marrow suppression was further indicated with this course of
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treatment, which was subjected to reduction in DOX induced oxidative stress (Figure 5).
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In the last decade, NPs with multiple chemotherapeutic agents, each with a different mechanism of action forms a basis of combination drug therapy. This approach helps in reducing unwanted
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side effects. Specific interactions with a target sites for a different type of cancer is the main
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advantage of nanomedicine combination therapy. Previously, most combination NPs contained drugs with similar water solubility. Polymeric nanoparticles in their hydrophobic core carry poor
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water-soluble drugs and liposomes contain hydrophilic drugs. Whereas in recent times development of more sophisticated NP drug delivery system has made it possible to deliver hydrophobic and hydrophilic drugs in one system. Several challenges in delivering drugs with different physiochemical attributes remain to be addressed warranting future studies.
9
3.1. Advantages of combination therapy For a rational design to achieve optimal efficacy, a proper understanding of specific mechanisms of parent drug and combination strategies used are essential. Combination of two drugs can
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generate a combinatorial effect with lower, equal or higher than the total effects of the individual partner drugs. Combination effects could be synergistic, antagonistic or potentiation. The synergistic combinatorial effect is when the effect produced is larger than the summed effect of the drugs individually, with no cross-reactivity and different acting target sites or pathways. When the effect is greater than or equal to the summed effect of the individual drugs with a final
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target as same site or pathway, the effect is additive. In potentiation effects, alteration of
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activity/effect of one drug by the other is seen. With enhanced activity, a reduction in side effect
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via regulation of ADME properties is also seen [46, 55, 56]. A nanoparticulate combination has
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explored all these effects to achieve a variety of favorable outcomes, including reduction of
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unwanted side effects, drug-resistance prevention, a decrease in dose of individual drugs, and
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enhanced efficacy (Insert Figure 6 here)
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3.2. Formulas used for determining combinatorial effects
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Combination Index (CI) = D1/Dm1 + D2/Dm2
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Where D1 and D2 represent the dose of a drug in combined administration, Dm1 and Dm2 represent the dose required to produce the same effect when used alone. When CI < 1, synergism is indicated; CI = 1, additive nature is indicated; CI > 1, mean antagonism [57].
Reversal fold (RF) =
IC50 anticancer drug alone 10
IC50 anticancer drug + modulator
RF > 1 indicates a synergistic effect, RF = 1 indicates no effect, and RF < 1 indicates an
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antagonistic effect [58]. (IC50 anticancer drug alone in MDR cells - IC50 anticancer drug + modulator in MDR cells) Relative Reversal Rate
(IC50 anticancer drug alone in MDR cells - IC50 anticancer (RRR %) [59]
=
* 100
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drug alone in parental cells)
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In a recent study by Gwade et al [167], synergistic anticancer activity of paclitaxel (PTX) and
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curcumin (CUR) combination was noted against ovarian and cervical cancers. The authors
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performed encapsulation of BSA (bovine serum albumin) nanoparticles which encapsulated PTX and CUR along with a folate receptor ligand conjugation on the nanoparticles. This formulation
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is reported to possess a synergistic cell killing effect and combination effectivity compared to
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control groups, when studied in HeLa and SKOV3 Cell lines. The CI values were reported to be
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less than 0.5 indicating an average synergism, as indicated in Figure 7. High potency of the drugs and different anticancer targeting pathways, make these two drugs apt candidates for
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combination, which then results in lowered dose levels and synergism in their combined
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therapeutics. Other such studies have also been indicated elsewhere [169]
4. Curcumin combination nanomedicine Curcumin has shown to be successful in several types of cancer lines, mainly because of its ubiquitous action on different modulator of anti-cancer effects (Insert Figure 8 here). Curcumin
11
alone or in combination is nontoxic and is proposed to accentuate the therapeutic efficiency of chemotherapeutics by inhibiting ABC efflux transporter. Curcumin inhibits tumor growth by arresting cell cycle progression, inducing apoptosis, inhibiting the expression of antiapoptotic
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proteins, inhibiting multiple cell survival signaling pathways and their cross-communication, and modulating immune responses [4, 60, 61]. All these properties make curcumin a promising drug for mono or combination therapy. Table 1 summarizes a few examples of curcumin monotherapy. Although its pharmacokinetic profile is not as appealing as pharmacological profile, nano-based formulations could be a savior and balance this out. Its modulating effects on
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P-gp efflux transporters, which are a major cause of MDR in the first place, makes it a perfect
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adjunct for a combination [62]. Curcumin combination nanoparticulate therapeutic doses tested
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in-vitro and in-vivo for several types of cancers are listed in Table 1.
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Table 1: Selected examples of Curcumin nano-particulate delivery system’s monotherapy in
Nanoparticle platform Hyaluronic Acid linked Nanomicelles
2.
PEG-PLGA NPs
Cancer type
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Serial no. 1.
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cancers
Pancreatic cancer
89.5±2.8
Breast cancer
70-300 nm
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Size
Polymeric micelles
Colon cancer
27.6± 0.7nm
4.
pH-chitosan
Glioblastoma
Not reported
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3.
mesoporous
12
Status of investigation In vitro
Observations
Ref
Improved cell killing and internalization in MiaPaca-2 (IC50= 140±2.42 nM ) and AsPc-1(160±2.96 nM) cell line.
[63]
In vitro
Improved cell growth inhibition in MCF-7 (17.86±1.08 µM) cell lines with the formulation.
[64]
In vitro/in vivo
The cytotoxic activity of the nanoformulation was higher than free curcumin. (5.50μg/mL). 70% inhibition of tumor growth in mice inoculated with MCF-7 cells. MTT assay for the formulation showed a higher IC50 value of 5.21 µg/mL for
[65]
In vitro
[66]
silica nanoparticles
the formulation as compared to non-pH and free drug group.
PLGA-PEGFe3O4 NPs
Lung cancer
Not reported
In vitro
Enhanced cytotoxicity observed in A549 with the formulation (IC50=7.3 µM). hTERT downregulated.
[67]
6.
folate-BSA-CDF NPs
Ovarian cancer
279 nm
In vitro
High cell viability (IC50=0.25µM) and cellular uptake compared to free drug and non-targeted nanoformulation.
[68]
7.
Cholesterol-PLA polymeric micelles
Breast cancer
Nearly 1.87 fold higher tumor growth inhibition in B16F10-xenografted tumorbearing mice with the polymeric micelles formulation (627.72 ± 0.9 mm3) as compared to free CUR (1174.68 ± 1.64 mm3).
[69]
8.
Nanoemulsions
Prostate cancer
The results showed that the cell update and cytotoxicity considerably increased with Cur nanoemulsions compared to free Cur. Cur nanoemulsions exhibited a significantly prolonged biological activity and demonstrated better therapeutic efficacy than free Cur.
[70]
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N
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In vitro/in vivo
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5.
In vitro
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D
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34.54±2. 2 nm
4.1. Liver cancer
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Liver cancer is the second most common cause of cancer death among men and the sixth leading cause of cancer death among women. Globally, Hepatocellular Carcinoma (HCC) accounts for 75-80 % of the cancer deaths. Due to metastasis and recurrence, a 5-year survival rate of patients with HCC is at 15 % [71]. Hu et al. investigated the combined effect of nanoparticulate delivery of curcumin (Cur) with a kinase inhibitor, sorafenib, in the treatment of HCC. The combination 13
down-regulated expression of MMP9 via NF-κB/p65 signaling pathway. Furthermore, the population of cancer-initiating cells CD133-positive significantly decreased in both MHCCLM3 (4.82 ± 1.22%) and Huh7 (5.46 ± 0.68%) cells with this combination therapy. In vivo outcomes
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demonstrated lung metastatic tumors to be significantly reduced compared with control treatment (16.7% vs. 100%; P = 0.015) [72]. Combining chemotherapeutic agent and chemosensitizer in nanocarriers to overcome MDR in HCC was a focus of Zhao et al. research. Synthesized DOX/Cur-NPs increased Caspase-3 and Bax/Bcl-2 ratio, and decreased C-myc, PCNA and VEGF as seen in liver tissue. With DOX treatment there was a 46.44-fold increase in Resistance
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Index (RI) of BEL 7402/5-FU cells in comparison with the BEL 7402 cells, significantly
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decreased by DOX/Cur-NPs (2.07). This indicates a modulatory effect of DOX/Cur-NPs on
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MDR. The modulation effect calculated by the reversal fold (RF) value in which IC50 of DOX-
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NPs in BEL 7402/5-FU cells divided by that of DOX/Cur-NPs. The DOX/Cur-NPs showed an
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RF value of 1.94, indicative of a synergistic effect [73].
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Yan et al. developed glycyrrhetinic acid (GA)-modified chitosan-cystamine-poly(є-caprolactone) copolymer (PCL -SS-CTS-GA) micelle for co-delivery of DOX and curcumin to HCC. GA aided
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in target specificity to hepatocytes due to its affinity to the liver membrane [74, 75]. In HepG2
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and HUVEC cell lines, PCL-SS-CTS-GA/DOX/CCM at a DOX-CCM molar ratio of 1:1, 2:1, and 3:1 were used in-vitro. CI value of less than 1 indicated a strong synergistic effect at all
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molar ratios [76]. A PH sensitive prodrug conjugate was produced by conjugation mechanism, with self-assembling property in water at pH 7.4 into nanoparticles (PEG-DOX NPs). Cur being hydrophobic encapsulates into the core through hydrophobic interaction (PEG-DOX-Cur NPs). After internalization of these NPs in tumor cells due to an acidic environment (PH 5.4) inside the tumors, PEG and DOX holding Schiff base breaks open and lead to releasing of both parent 14
drugs CUR and DOX into the tumor cells. HeG 2 and Hela cells used for in vitro cytotoxicity studies. The studies showed higher cytotoxicity values compared to individual drugs. NP formulation for the PEG-DOX-Cur NPs in both the cell lines reported an IC50 value of 1.700
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µg/mL (DOX) and 0.680 µg/mL (Cur) in HEG 2 cells and 1.741 µg/mL (DOX) and 0.697 µg/mL (Cur) in Hela cells respectively. The primary reason for higher toxicity observed was due to internalization and rapid release of drug in tumor cells. Moreover in vivo studies using xenograft mice with hepatic tumors also showed a significant reduction in the tumor volume with the PEG-DOX-Cur NPs [77].
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Recently, Peng et al. designed novel PEGylated lipid/PAA/CaCO3 ternary system encapsulating
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Cur and Dox (LPCCD) with a goal of increasing cancer cell toxicity and reduction of cardiotoxic
A
side effect. An in vitro cytotoxicity study in HepG2 cells demonstrated better IC50 with LPCCD
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as compared to free Dox & Cur formulation. Also, cardiotoxicity which is a major side effect of
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DOX treatment was also evaluated in mice cardiac sections by histology. LPCCD group reported
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no inflammatory and hypertrophic cardiac cells [78]. Zhang et al. developed pH-sensitive NPs for co-delivery of DOX and CUR. MTT assay in SMMC 7721 cell line established an increase in
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cell growth inhibition with D+C/NP formulation. Additionally, as noted by flow cytometry, the
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apoptotic rate for the formulation was nearly 1.99-fold higher than that of the free drug treatment. To investigate the anti-tumor efficacy and potential toxicity of Dox & Cur co-loaded
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NPs, in vivo studies were conducted. A significant increase in tumor weight inhibition by formulation compared to a combined free drug (73.37 % and 32.6% and 73.37%, respectively) was observed [79].
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4.2. Colon cancer As the third-most common malignant tumor, colon cancer accounts for more than 1.4 million new cases and over half a million deaths worldwide annually [71]. Surgery, chemotherapy, and
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radiotherapy are the go-to therapeutic approaches against colon cancer with chemotherapy as the first line of treatment [80]. MDR as well as the heterogeneous nature of cancer cells leads to resistance and increase in adverse effects and subsequently results in an increase of effective doses [81]. Like other cancers, combination therapy with NPs drug delivery system helps to overcome issues associated with monotherapy in colon cancer [82]. Xiao et al. developed
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cationic polymeric NPs for co-delivery of camptothecin (CPT) and curcumin. Combination
N
index (CI) value of 0.46 indicated a strong synergism with the CPT/CUR at a molar ratio of 4: 1
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after 24 h of incubation [83].
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Overexpression of CD44, a single-chain glycoprotein, has been reported in a variety of colon
D
cancer [84-86]. Hyaluronic Acid (HA) is shown to have a high affinity for CD-44 receptors [87].
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So, the addition of HA provided a colon cancer-targeting capability due to more efficient internalization of HA-functionalized NPs in cells through an HA receptor-mediated endocytosis
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pathway by interacting with CD44 receptors [85]. Xia et al. capitalized this property for
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formulating HA-CPT/CUR-NPs. Ex vivo studies in AOM/DSS-induced colon cancer mouse model with the developed NPs showed higher permeation and accumulation of HA-
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functionalized NPs in colon tumor region. Strong synergistic effects observed between CPT and Cur in this formulation, depicted by an IC50 value of 0.7 μM in Colon-26 cells at both 24 and 48 hours [88]. Chrysin (Chr), a naturally occurring flavone, is found in plant extracts. It is one of the most broadly used herbal medicine. Chr has been reported to have several effects such as anti16
inflammatory, antioxidant, antidiabetic, anti-allergic, antibacterial, antiestrogenic, and anticancer [89, 90]. As seen in in-vitro and in-vivo studies, anticancer effect of Chr is mainly due to arresting of the cell cycle, induction of apoptosis, inhibition of angiogenesis, and metastasis with
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no toxicity on normal cells [91]. Lotfi-Attari et al. formulated PLGA/PEG NPs, encapsulating a combination of Cur and Chr for the first time. In vitro studies in Caco-2 cell lines with Cur–Chr– PLGA/PEG NPs demonstrated significant growth arrest of cancer cells and high intracellular concentrations. The CIs value for the formulation was <1 which is indicative of a synergistic effect of the combination [92].
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Anirudhan et al. designed a transdermal drug delivery system (TDDS) to encapsulate 5-
N
fluorouracil (5-FU) and curcumin (CUR). Polymer β-Cyclodextrin and aminated nano dextran
A
used to entrap CUR and 5-FU respectively which provides flexible kinetics for the release of
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drugs after treatment with specific solvents. Polysaccharides ALG and CS were used to coat the
D
surfaces of NP's with opposite charges in the final product. In vitro studies on human carcinoma
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cell lines, HCT-116 depicted a reduction in cell viability from 71.1 to 48.7 % at increasing
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concentrations, when treated with solvent dipped final formulation [93]. Bagheri et al. showed the synergistic effect of co-delivery of Chrysin and CUR nanoparticulate
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delivery in SW480 colon cancer cell line. MTT assay favored the combination depicted by twice the decrease in cell growth inhibition rate as compared to free CUR and chrysin. These effects
A
were attributed to downregulation of hTERT by the combinatorial therapy [94].
4.3. Breast cancer Breast cancer is one of the most common types of cancer with more than 508,000 deaths till 2011. In 2012, nearly 1.7 million women diagnosed with breast cancer [71]. In the US alone, 17
246,660 cases of breast cancer are expected to register in 2018 [95]. Doxorubicin is the first line of therapy for several types of cancers including breast cancer [96]. Doxorubicin functions by DNA intercalation leading to disruption of DNA damage repair, causing the release of reactive
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oxygen species and eventually programmed cell death [97]. Like other anti-cancer drugs, drug resistance is a major issue associated with doxorubicin. To overcome MDR associated resistance with DOX, Wang et al. fabricated polymeric micelles and incorporated DOX with CUR to function as P-gp and apoptosis inhibitor. In the MCF-7/Adr (DOX-resistant) breast cancer cell lines, the formulation (DOX/Cur)-PMs compared with DOX-treated cells lead to the 18.29-fold
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increase of apoptotic cells and enhanced invitro toxicity. In vivo studies in 4T1 bearing Balb/c
N
mice model for breast cancer showed a significant reduction in tumor weight as compared to
A
control and free drugs [98].
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Ruttala et al. designed CUR and albumin-PTX hybrid encapsulation liposomes (CL-APN) and
D
performed in vitro cytotoxicity assay in MCF-7 and B16F10 carcinoma cell lines. 1:1 molar ratio
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of the PTX and CUR in formulation showed enhanced cytotoxicity. In cell migration assay CL-
drugs [99].
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APN demonstrated the highest inhibition in both cell lines compared to control and individual
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To target breast cancer, Cui et al. co-delivered CUR and DOX in a pH-sensitive prodrug using transferrin Tf-PEG-CUR. Several malignant tumors overexpress Tf. This property makes it a
A
perfect candidate for target-specific delivery to these type of cancers [100-102]. Both drugs being hydrophobic were entrapped in the core of Tf-PEG-CUR/DOX NPs. Mildly acidic pH release of CUR was significantly increased from 33.6% at pH 7.4 to 72.4 % at pH 5. A similar trendas observed for DOX release. In vitro cytotoxicity assay in MCF-7 cell lines showed the highest inhibition by the Tf-PEG-CUR/DOX NPs with IC50 of 2.5 μM. The concentration of 18
DOX and CUR in tumor, lung, and liver, major target areas in breast cancer, was the highest. The preparation also presented fewer adverse effects. Its concentration in heart and kidney was lower than others in the group. This formulation showed a high inhibition rate of tumor growth
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(IRT) (83.5%) [103].
Using curcumin as a theranostic agent (diagnostic + therapeutic) was studied by Nguyen et al. by fabricating Cur-PLA-TPGS NPs (curcumin + paclitaxel) co-loaded with PLA-TPGS NPs (Cur+PTX)- PLA-TPGS NPs. Fluorescence of CUR in MCF7 cell and MCF7 spheroid monitored by confocal fluorescence microscopy. This concluded that the monitoring of the
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delivery and bio-distribution of the drug delivery system, curcumin acted as a potential
A
N
fluorescent probe [104].
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Sahu et al. utilized nanosuspensions technique to co-deliver CUR and DOX. In vitro cytotoxicity in MCF7 cell line with CUR-DOX co-loaded nanosuspension showed the
D
highest inhibition rate, compared to individual drug nanosuspensions of 83.31% and 81.65% at
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0.5 and 1.0μg/mL respectively. Moreover, in vivo studies showed a highest tumor inhibition
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ratio (TIR) of 70% compared to groups treated with CUR nanosuspension (34%) and DOX
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nanosuspension (15%) [105]. In vivo stability and increased drug loading capacity are a few advantages of coating super-
A
magnetic iron oxide nanoparticles (SPIOs) with albumin. However, synthesis of SPIOs system is complicated and time-consuming. To overcome this limitation, Chen et al. used a one-step synthesis strategy of in situ co-precipitation, to synthesize albumin-stabilized SPIOs (BSASPIOs). Further to test for the effectiveness of this system in-vitro and in vivo, they encapsulated two cytotoxic drugs CUR and Sunitinib in BSA-SPIOs. Values for the free drug Sun and Cur in 19
MCF-7 were 6.15 μM and 23.8 μM respectively. The IC50 values of BSA-SPIOs enclosed CUR and Sunitinib were enhanced to 2.43 μM (for Sun) and 6.79 μM (for Cur). Moreover, an increase in inhibition noted with the application of external magnetic field with IC50 values of 2.03 μM
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(for Sun) and 5.67 μM (for CUR), respectively. In vivo studies showed the highest inhibition of tumor growth with nearly 2.3-fold tumor weight reduction by the BSA-SPIOs SunCUR combination, compared to free SunCUR therapy [106].
Increased sensitivity of MDR tumor cells by addition of small-molecule compounds known as chemosensitizers, which lead to an improvement of the efficacy of chemotherapeutic drugs [107-
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109]. As a novel chemo/photo- co-therapeutic nanomaterial, mesoporous carbon along with a
N
chemosensitizer (CUR) can be used to develop mesoporous carbon nanoparticles (MCNs). Some
A
advantage of MCNs comprises high pore volume ratio, larger surface area, and efficient drug
M
loading capability [110]. The PCDA backbone, which is made up of disulfide bond linked mono-
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curcumin, degrades at a significantly higher concentration of glutathione (GSH) in the cytoplasm
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than in the extracellular environment, leading to a GSH-responsive release of curcumin (CUR) [111]. Li et al. designed PEG-PCDA coated MCN (chemo/photo chemotherapy activity) to
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deliver DOX to drug-resistant MCF-7/ADR cells. In vitro studies on MCF-7/Adr cell lines
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showed the maximum inhibition (IC50= 17.41 mg/mL) with the formulated PEGPCDA/DOX@MCNs. Additionally, the IC50 value reduced to 11.16 mg/mL after NIR laser
A
irradiation [112]. Results of this study are illustrated in Figure 6. (Insert Figure 9 here)
Another approach against MDR resistant MCF-7/Adr cells is through Folate conjugation on the surface of nanoparticles. It could become a useful approach to develop target-specific NPs due to its affinity to folate receptors which are overexpressed in several cancers. Baek et al. fabricated
20
2-hydroxypropyl-β-cyclodextrin (HPCD) conjugated with folate for co-delivery of curcumin with paclitaxel (FPCHN-30). The formulation showed enhanced absorption of paclitaxel as compared to that of free drug, which was due to P-gp inhibition of curcumin. In vitro studies in
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MCF-7/Adr cells revealed that FPCHN-30 with folic acid showed the highest cytotoxicity and cellular uptake [113].
Medel et al. tested the efficiency of a biodegradable and biocompatible block copolymer (PEGb-PLA) in co-delivery of the curcumin-bortezomib system to treat breast cancer. NP formulation in MCF-7 and MDAMB-231 breast cancer cells caused significant cytotoxicity with an IC50
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values of 18.8 nM and 122.4 nM respectively [114].
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value of 7.5 nM and 59.2 nM respectively as compared to free Cur-BTZ combination with IC50
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HA can interact with the CD44 receptor. Tumor-specific nano-formulations involve HA conjugation in the final design. Yang et al. designed nanoparticles to directly target breast cancer
D
stem cells (bCSCs). They prepared and evaluated targeting co-delivery system of Hyaluronic
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Acid (HA-Hybrid NPs) to the surface of hydrophobic PLGA NPs to co-deliver PTX and CUR. In
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the MCF-7 cells, the formulation exhibited the lowest IC50 values of 0.751×10-3 μg/mL and 0.4318 μg/mL for PTX and CUR respectively. Compared to free PTX+CUR CI (0.77), the CI of
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HA-Hybrid NPs/PTX+CUR was significantly lower at 0.32. In vivo studies pointed out improved tumor growth inhibition (TGI) at 67.5% as compared to other groups. Additionally,
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average tumor volume for HA-Hybrid NP/PTX+CUR group was found to be 2.5 times smaller than control. [115]. Lin et al. used silica-based materials, mesoporous silica with the PEG (PLMSNs) for co-delivery of Tax and Cur. The in-vitro activity in canine breast cancer line showed enhanced IC50 values for the formulation [116].
21
Sudakaran et al. exploited a new synthetic biodegradable/ biocompatible copolymer poly L-lactic acid-co-ε-caprolactone (PLACL) with Aloe Vera (AV) MGO for co-delivery of CUR/β-CD in breast cancer cell lines. In vitro studies on MCF-7 cells showed 52.19% cell growth inhibition by
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PLACL/AV/MgO/CUR/β-CD compared to PLACL/AV/MgO [117].
Yuan et al. designed and fabricated pH-sensitive NPs to co-deliver DOX and CUR to MDR resistance breast cancer cells. In-vitro cytotoxicity assay on MCF-7/ADR cells showed 2.2 and 7.2 times lower IC50 value for CURDOX-NPs as compared to DOX-NPs and DOX solution respectively. In vivo studies revealed the slowest tumor growth and maximum growth inhibition
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rate by CURDOX-NPs. Moreover, the formulation demonstrated a lower percentage of cancer
A
N
stem cells as compared to CUR-NPs formulation alone (15.0% vs. 6.82%) [118].
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4.4. Brain cancer
The most common and aggressive brain tumors in human are malignant glioma with a 5-year
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survival rate of only 5% [119]. Blood-Brain Barrier (BBB) is the principal obstruction for
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delivery for limited glioma chemotherapy (e.g., temozolomide, carmustine). Cui et al. fabricated
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T7-modified magnetic PLGA nanoparticulate system (MNP/T7-PLGA NPs), consisting of hydrophobic magnetic nanoparticles (MNPs), to co-deliver PTX and CUR. In vitro cytotoxicity
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effects were examined in U87 cells. IC50 for the MNP/T7-PLGA NPs loaded with PTX+CUR was reported to significantly improve at 3.06 μg/mL, compared to other groups. In vivo tumor
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studies also revealed superior anti-glioma efficacy for the formulation [120]. Due to a continuous requirement of glucose supply in cancer cells, GLUT-1 is significantly overexpressed [121]. BBB in glioblastoma contains significantly overexpressed GLUT-1 [122, 123]. This could be a good target for the anticancer drug delivery to glioblastoma cells. 22
Sarisozen et al. developed polymeric micelles coated with a single chain fragment variable (scFv) against GLUT-1 to co-deliver CUR and DOX. In vitro cytotoxicity assay was tested in U87MG glioblastoma cells. The CI for polymeric micelles at 0.63 further reduced to 0.46 with
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GLUT1 targeting strategy. Moreover, the formulation leads to a 3-fold increase in nuclear localization of DOX in U87MG cells, which was the apparent reason for enhanced cytotoxicity [124].
4.5. Skin cancer
Every year nearly two million new cases of skin cancer are diagnosed in the United States alone
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[95]. 5-fluorouracil, imiquimod, bleomycin, and interferon alpha are the most widely used
N
chemotherapeutic agents against skin cancer [125]. Recently, small interference (siRNA) has
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shown effectivity in preclinical and clinical trials against cancer [126]. Jose et al. fabricated and
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evaluated liposomes for co-delivery of curcumin and STAT3 siRNA, combined with anodal
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iontophoresis technique. Iontophoresis application enhances skin penetration of positively
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charged lipoplexes (liposome-siRNA complexes) by electro-repulsion and electro-osmosis technique [127]. In vitro cytotoxicity assay in A431 cells with the formulation, demonstrated
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higher inhibition of cell growth (72.9±2.3%), compared to individual treatments. Anodal
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iontophoresis applied to reach the target depth of 100 μm inside the skin and for better penetration of the compounds in the ski[128].
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Effect of curcumin in combination with the paclitaxel in folic acid conjugated PLGA-PEG NPs was studied by Kumar et al. In in vivo studies, CUR-PLGA-PEG-FA formulation demonstrated enhanced bioavailability and retention time of curcumin with no effect on toxicity profile. Further, in combination with Paclitaxel on cervical cancer xenograft model revealed enhanced
23
tumor growth inhibition. A nearly 2-fold decrease in tumor volume compared to individual drug treatment groups [129].
Jose et al. exploited the effect of Iontophoresis on a liposomal formulation of CUR and STAT
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siRNA on a melanoma tumor mouse model. In vitro cytotoxicity studies with B16F10 cell lines showed higher growth inhibition (76.3 ± 4.0%) compared to curcumin-loaded cationic liposomes (46.0 ± 3.4%) and cationic liposome-STAT3 siRNA group (58.4 ± 3.0%). In vivo studies on melanoma tumor model also supported the in vitro results with maximum nearly three-fold increase in inhibition on tumor growth and volume by the curcumin-loaded liposome-STAT3
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siRNA complex compared to other groups [130].
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Combination of chemotherapy with phototherapy for the treatment of skin cancer exploited by
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Singh et al. They designed gold coated Hydrogenated Soya Phosphatidyl Choline (HSPC) liposomes encapsulating CUR. In vitro studies on B16F10 cell lines showed the 9-fold increase
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in cell growth inhibition by Au-Lipos Cur NPs compare with free curcumin after laser irradiation
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and ~8 fold compared to non-gold coated/non-irradiated formulation of lipos-Cur NPs [131].
4.6. Pancreatic cancer
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Pancreatic cancer is the second most common cause of cancer-related deaths. It is estimated to account for 55,440 new cases and 44,330 deaths in 2018 in the US alone [95]. New therapeutic
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avenues are essential to overcome an abysmal 5-year survival rate of pancreatic cancerare essential. Kim et al. utilized nanoparticle albumin-bound (NabTM) technology using highpressure homogenization, to co-deliver PTX and Cur. Efficient internalization into MiaPaca-2 cells observed with PTX/CCM Alb-NPs. Moreover in vitro cytotoxicity studies revealed 71%
24
increase in IC50 with this formulation in MiaPaca-2 cells [132]. Toxicological study of the formulation containing chitosan-SLNs (c-SLNs) in combination with sulforaphane (ACS combination) on co-delivery of Aspirin and Cur studied by Thakkar et al. for pancreatic cancer.
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This formulation has been previously shown to be effective against pancreatic cancer in in-vitro studies, but the toxicity profile of the c-SLNs and ACS is not studied before. The formulation was found to be safe for long-term oral administration against pancreatic cancer with no signs of toxicity in acute, subacute, and sub-chronic studies. Future direction points in the utilization of cSLNs and ACS technique for formulating other anti-cancer drug combinations [133].
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4.7. Osteosarcoma
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In kids and young adults, Osteosarcoma (OS) accounts for 60% of primary bone cancers [134].
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Currently approved treatments for OS include surgery and chemotherapy [95]. Combination of
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surgery with chemotherapy increases the cure rate of patients with OS from 20 % to 70 % [135].
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The commonly used chemotherapeutics to treat OS include DOX, cisplatin, and methotrexate.
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Even with the combination of chemotherapy and surgery, failure in nearly 30% of stage IV patients due to drug resistance is observed [136]. Polymeric nanoparticles coated with lipid-PEG
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or (LPNs) were constructed to overcome the resistance issues and to inhibit the rapid clearance
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effect of the reticuloendothelial system. Constructed LPNs utilized to co-deliver DOX, and CUR (DOX+CUR LPNs) and tested the formulation for in-vitro and in-vivo effects in OS. In vitro
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cytotoxicity assay was performed in Human osteosarcoma cell lines (KHOS cells). The IC50 of DOX+CUR LPNs was found to be lowest at 0.6 μM as compared to other groups. In-vivo efficacy was observed in BALB/c mice injected with KHOS cell model. On 21-day posttreatment, OX+CUR LPNs group treated mice, the tumor volume was lowest at about 182 mm3,
25
compared to the saline-treated group (973 mm3). Moreover, with DOX+CUR LPNs, the Tumor Growth Inhibition (TGI) was significantly higher at 81.3% compared to other groups [137].
4.8. Gastrointestinal cancer
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Gastrointestinal cancers are the third leading cause of cancer-related deaths worldwide [138]. Intravenous (IV) administration is the most common route of chemotherapeutic delivery in GI cancer patients. IV route has several disadvantages like discomfort, stress to patients, multiple hospitalizations trip, high cost, and high risk of hospital-acquired infections [139, 140]. To overcome this problem, Bar-Zeev et al. developed a novel oral delivery nano-delivery system
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using self-assembling β-casein (CN) enclosing hydrophobic chemotherapeutic drugs (PTX) and
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MDR (TQD) chemosensitizers. In vitro cytotoxicity assays were performed in EPG85-257RDB
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(P-gp overexpressing) and EPG85-257P gastric carcinoma cell lines. The β-CM formulation with
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combination showed significantly lower IC50 value with MDR resistance EPG85-257RDB cell
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4.9. Prostate cancer
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line (111 nM) compared to EPG85-257P cell line (2185 nM) [141].
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Prostate cancer is the second most common cause of cancer-related deaths. In 2018, nearly 164, 690 new case and 29, 430 deaths are estimated in the US alone [95]. Taxane drugs and platinum
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compounds first line for chemotherapy against prostate cancer. Although due to severe adverse effects due to MDR, they are not as effective with monotherapy [142]. To overcome this adverse
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effect, Saralkar et al. used hydrophobic phytochemicals Curcumin and resveratrol and formulated calcium alginate NPs to encapsulate them. The drug-loaded nanoparticles had a cytotoxic effect in DU145 prostate cancer cells with no hemolytic effects [143].
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4.10. Cervical cancer Cervical cancer is one of the most common causes of cancer-related deaths in females. The first line of therapy for cervical cancer is Cisplatin (DDP) as monotherapy, or it’s combination with
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paclitaxel [144, 145]. Serious adverse effects related to DPP are nephrotoxicity, hepatotoxicity, and drug resistance [146-148], which could be overcome by nano-carrier-based delivery of DDP to the tumor sites and combination chemotherapy [149-151]. Li et al. combined both techniques and constructed lipid-polymer hybrid nanoparticles (LPNs) for DDP and Cur co-delivery. Moreover, they compared the LPN formulation with the most common NPs delivery formulation
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such as Polymeric Nanoparticles (PNPs). HeLa cells and HUVEC cells used for in-vitro
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cytotoxicity assay. Highest in vitro tumor activity was exhibited by DDP/CUR/LPNs as
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indicated by lowest IC50 value among the groups. CI of DPP/CUR/LPNs was significant at 0.61
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as compared to DPP/CUR/PNPs, and DPP/CUR solution with CI value of 0.96 and 1.40, respectively. Investigated the in vivo antitumor efficacy of LPNs in cervical cancer-bearing
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BALB/c mice model DPP/CUR/LPNs treated group showed the most significant reduction in
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4.11. Leukemia
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tumor size compared to other groups [152].
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According to the American cancer society report, in 2018 nearly 60,300 new cases and 24,370 deaths are expected due to leukemia [95]. Silver nanoparticles (AgNPs) have antimicrobial
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activity and anti-cancer effect [153]. The generation of reactive oxygen species due to the release of silver ions is the reason behind AgNPs mediated cytotoxicity [154]. Petrov et al. utilized this property of AgNPs and evaluated the effect of a combination of AgNPs and curcumin in a multilayer polymeric micelle of poly (ethylene oxide)-b-poly (n-butyl acrylate)-b-poly (acrylic acid) (PEO-b-PnBA-b-PAA) triblock terpolymer micelles, in acute myeloid leukemia. This 27
formulation specifically presented a pronounced cytotoxic effect on acute myeloid leukemia (HL-60), and it's multidrug-resistant subline HL-60/DOX, as compared to an individually loaded carrier [155].
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4.12. Lung cancer
Lung cancer has one of the highest incidence among all forms of cancer. Suboptimal therapy due to lack of targeted effects and severe side effects are some disadvantages of conventional therapy against lung cancer. The advent of using siRNA for cancer therapy has attracted more attention, as RNA interference is more specific to the target gene and can knock down some oncogene
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expression for cancer therapy [156]. Zhang et al. demonstrated the effect of epidermal growth
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factor (EGF) modified monomethoxy (polyethylene glycol)-poly (D, L-lactide-co-glycolide)-
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poly(L-lysine) (mPEG-PLGA-PLL, PEAL) NPs (EGF-PEAL), loaded with Dox and Bcl-2-
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siRNA NPs on lung cancer. The blank EGF-PEAL NPs showed minimal cytotoxicity in the
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H1299 cell lines, indicating a useful drug delivery carrier. The co-delivery of siRNA and Dox in
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EGF-PEAL also reported higher cytotoxicity. Annexin V/PI staining assay showed maximum apoptosis in H1299 cells was induced by the combination of early and late apoptosis rates of
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61.56% and 11.37 % respectively. In vivo studies demonstrated tumor volume to be the smallest
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(2-3 fold) with the co-delivery of Dox and Bcl-2-siRNA group [157].
Tang et al. designed SLNs for the co-delivery of CUR and piperine in paclitaxel-resistant human
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ovarian carcinoma cell line A2780/Taxol. The purpose of the study was to evaluate whether the presence of Cur could reverse MDR associate resistance in this cell line. The in vitro cytotoxicity studies showed significantly higher cell growth inhibition with (Cur + Pip)-SLN (59.90±8.40%), as compared to Cur (25.85±5.74%) and Pip (6.87±4.52%) alone [158].
28
Boron Neutron Capture Therapy (BNCT) radiotherapy combines a boron-containing compound with low energy neutron irradiation to target cancer cells.10B captures the neutrons and disintegrates into alpha particles and lithium nuclei, which induce site-specific damage to tumor
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cells after accumulation [159]. Diego et al. exploited this target for anticancer effects by formulating Rubro-curcumin (stable adduct of boric acid, curcumin, and oxalic acid) [160] in PLGA NPS. Prepared folate specific PLGA NPs, to provide tumor-specific accumulationlate specific PLGA NPs were prepared. In vitro cytotoxicity assays showed enhanced inhibition rate
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with the formulation compared to individual drugs [161].
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5. Clinical trials involving curcumin
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Curcumin both in its free form and as nano-particulate formulations have been under
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investigation in human clinical trials for many years. It has shown clinical benefits in patients with colorectal cancer, pancreatic cancer, breast cancer and multiple myeloma. Searching for
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summarized in Table 2 [162].
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Curcumin as a treatment for cancer in www.clincaltrials.gov shows 22 recent trials which are
Table 2: Recent clinical trials involving curcumin NCT number
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Serial No. 1.
Phase
Trial Status Active, not recruiting
Cancer type Advanced colorectal cancer
Description
Phase 1
2.
NCT01333917
Phase 1
Completed
Colorectal cancer
Curcumin Biomarkers
2016
3.
NCT01294072
Phase 1
Active, not recruiting
Colorectal cancer
Study Investigating the Ability of Plant Exosomes to Deliver
2020
A
NCT01859858
29
Effect of Cur on Dose Limiting Toxicity and Pharmacokinetics of Irinotecan in Patients with Solid Tumors
Completion date 2018
Curcumin to Normal and Colon Cancer Tissue Phase 1/2
Active, not recruiting
Colorectal cancer
Combining Curcumin with FOLFOX Chemotherapy in Patients with Inoperable Colorectal Cancer
2019
5.
NCT02598726
Phase 1
Recruiting
Malignant Neoplasm
Curcumin and Piperine in Reducing Inflammation for Ureteral StentInduced Symptoms in Patients with Cancer
2021
6.
NCT02138955
Phase1/ 2
Active, not recruiting
Advanced Cancer/Faile d standard therapy
A Phase IB Dose Escalation Study of Lipocurc in Patients with Cancer
2017
7.
NCT02336087
Phase 1
Recruiting
Pancreatic cancer
Gemcitabine Hydrochloride, Paclitaxel AlbuminStabilized Nanoparticle Formulation, Metformin Hydrochloride, and a Standardized Dietary Supplement in Treating Patients with Pancreatic Cancer That Cannot be Removed by Surgery
2018
8.
NCT02439385
N
A
M D TE EP
Enrolling by invitation
Colorectal cancer
Avastin/FOLFIRI in Combination with Curcumin in Colorectal Cancer Patients with Unresectable Metastasis
2019
Phase 2
Recruiting
Breast cancer
"Curcumin" in Combination with Chemotherapy in Advanced Breast Cancer
2018
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Phase 2
A 9.
NCT03072992
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NCT01490996
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4.
30
NCT00745134
Phase 2
Active, not recruiting
Rectal cancer
Curcumin with Preoperative Capecitabine and Radiation Therapy Followed by Surgery for Rectal Cancer
2019
11.
NCT02724618
Phase 2
Active, not recruiting
Prostate cancer
Nanocurcumin for Prostate Cancer Patients Undergoing Radiotherapy (RT)
2022
12.
NCT02095717
Phase 2
Active, not recruiting
Prostate cancer
2018
13.
NCT00852332
Phase 2
Recruiting
N
Multicenter Study Comparing Taxotere Plus Curcumin Versus Taxotere Plus Placebo Combination in First-line Treatment of Prostate Cancer Metastatic Castration-Resistant (CURTAXEL)
Breast cancer
Docetaxel with or Without a Phytochemical in Treating Patients with Breast Cancer
2017
14.
NCT02944578
Phase 2
Recruiting
Cervical cancer
Topical Curcumin for Precancer Cervical Lesions
2021
15.
NCT02138955
16.
NCT02556632
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A
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10.
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Phase 2
A Phase IB Dose Escalation Study of Lipo-cur in Patients with Cancer Completed
Breast cancer
Prophylactic Topical Agents in Reducing Radiation-Induced Dermatitis in Patients with NonInflammatory Breast Cancer
2016
Phase 2
Recruiting
Cervical, Endometrial , and Uterine cancer
Study of Pembrolizumab, Radiation and Immune Modulatory Cocktail in Cervical/Uterine
2022
A
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Phase 2
17.
NCT03192059
31
Cancer Phase 2
Completed
Endometrial cancer
Effect of Curcumin Addition to Standard Treatment on Tumour-induced Inflammation in Endometrial Carcinoma
2016
19.
NCT02782949
Phase 2
Recruiting
Gastric cancer
Curcumin in Preventing Gastric Cancer in Patients with Chronic Atrophic Gastritis or Gastric Intestinal Metaplasia
2019
20.
NCT00641147
Phase 2
Completed
Familial Adenomato us Polyposis
Curcumin in Treating Patients with Familial Adenomatous Polyposis
2016
21.
NCT03061591
Phase 2
Not yet recruiting
Familial Adenomato us Polyposis
Turmeric Supplementation on Polyp Number and Size in Patients with Familial Adenomatous Polyposis.
2020
22.
NCT02064673
Phase 3
Prostate cancer
Adjuvant Curcumin to Assess Recurrence-Free Survival in Patients Who Have Had a Radical Prostatectomy
2020
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NCT02017353
Recruiting
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A
N
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18.
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6. Challenges with curcumin combination therapy Effective combination therapy for anticancer treatment requires dealing with an investigation of multiple hurdles. Initial studies demand precise tuning of an optimal mass ratio (ratio-metric dosing) of each drug in a combination, based on individual drug efficacy and pharmacokinetic profile [163]. Due to low bioavailability and poor absorption, the formulation of combination 32
becomes more challenging with curcumin [4]. One of the major challenges of non-site-specific combination nanoparticulate formulation is off-site effects due to action on healthy cells. Although, recently several chemotherapeutic nano-formulations combine folate or other specific
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antigens, to enhance site specificity for the delivery of cytotoxic drugs to tumor cells. Delivery system could be further extended into combination chemotherapy for achieving maximum treatment efficacy as described in Figure 7 via a potential delivery system of curcumin combination nanoparticles with paclitaxel. (Insert Figure 10 here). Also, some of the materials used for fabricating nano-formulations are toxic, so each formulation should be thoroughly tested
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for short and long-term toxicity. As the intravenous route is the most popular route of
N
administration of nano-formulation, toxicity related to the interaction between endothelial cells
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of blood vessels and nanocarrier should be considered [164]. For nanocarrier-based combination
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therapy, other critical aspects to be considered are Quality by design parameters, rationally based
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on size and surface physicochemical property of materials to be fabricated. [165].
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7. Conclusion and future directions
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Delivery of nano-encapsulated anticancer drugs with curcumin as an adjunct, is emerging
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globally as an improvement to monotherapy. Along with the chemo-sensitizing synergism and tissue specificity imparted by this approach, the combinatorial therapy is now being
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acknowledged for fighting back multidrug resistance and providing effective treatment strategies. The present in-vitro and in-vivo work pose a promising picture, but a lot must be done before transition of this therapy could be made from lab-scale to safe human dosage forms. The biggest challenge from pharmaceutical point is alteration of curcumin from its natural form to a formulation relevant derivative, which is more stable and bio-pharmaceutically possess more 33
“drug like properties”. In one such attempt, poly (curcumin-dithiodipropionic acid) PCDA coating on nanoparticles was used. This coating was made up of disulfide bond linked monocurcumin, which degrades at a significantly higher concentration of glutathione (GSH) in the
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cytoplasm than in the extracellular environment, leading to GSH-responsive release of curcumin; thus, altering curcumin’s original form to a more practically viable form for formulation. Other intense fabrications like prodrug approach, polymer coating, complexation, co-crystallization of curcumin etc. would require time and cost inputs, both of which are general offsets for pharmaceutical industries. More research thus needs to be put into incorporation of curcumin in a
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delivery system, which could be optimized to its best possible usage, counterbalancing the
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monetary input. Other major barriers to human usage of this approach lie in lack of its target
A
specific properties. Methods like ligand attachment, PEGylation of NPs, tissue specific coating,
M
or upcoming external means like electrophoresis and iontophoresis etc. could be possible solutions to such hindrances. Human dose optimization for curcumin alone or with the
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combination drugs needs to be further investigated. With no commercial drugs in the market so
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far, dosing would be a major rate limiting step here. In vitro dose-response studies and possible
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FDA approval with preclinical or clinical data backups must be set in place to even start those conversations. Further, a complete pharmacokinetic (PK) profiling and in vitro-in vivo
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correlation (IVIVC) for the drug combinations, needs to be drawn to further move up the ladder. Also, upon dosage designing, antitumor activity of the combination NPs needs to be tested in
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actual cancer settings. Effectivity of these formulations is often determined by altered vasculature, characteristic to cancer masses. Toxicity studies for many developmental doses discussed in the work above have been performed, but extensive toxicologic profiling and
34
percentage damage to healthy tissue is required to weight in the risk to benefit ratio of this chemotherapeutic approach and justify their incorporation. Switching the course of present chemotherapy to nano-particulate curcumin combination therapy
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is a translational attempt which requires work from basic molecular aspects to pharmaceutical and then to preclinical and clinical trials. Extensive efforts are required from current prospects that curcumin combination NPs possess, to ultimately make this approach a potential future treatment improvement in cancer chemotherapy
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Funding
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This research did not receive any specific grant from funding agencies in the public, commercial,
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or not-for-profit sectors.
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Conflict of interest
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Figure legends Figure 1: Different type of cancers that curcumin is found to manage.
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Figure 2: The anti-cancer mechanism of curcumin. It is characterized by decrease in angiogenesis, metastasis and proliferation and increase in apoptosis with associated factors.
Figure 3: Different types of possible curcumin nano-formulation with their major advantages. Figure 4: In vivo antitumor efficacy of LPNs as compared to other groups. Tail injection of
different formulation groups of equivalent doses was administered in mice. Co-administration by
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reproduced with copyright permissions from [166])
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DTX and CUR LPN's showed most efficient suppression on tumor growth (p < 0.05). (Figure
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Figure 5: NanoDoxCurc (NDC) surmounts DOX resistance (a) Tumor sections from Dox
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xenografts examined by fluorescence microscopy; accumulation of DOX nanoparticles observed (b) NDC significantly inhibits the growth of subcutaneous DOX-resistant cancer xenografts.
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Excised tumors presented significant reduction in tumor growth with NDC group as compared to
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other treatment groups (N=5, *p<0.005). (c) Post treatment levels of MDR1 expression measured
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by immunofluorescence and (d) western blot in Dox xenografts. (e) Mice with DOX-resistant ascites with different treatment groups; more than 50% increase in survival was observed in
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NDC treated mice compared to others (N=8, *p<0.005). (Figure reproduced from open access unrestricted use article [167])
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Figure 6: Schematic representation of delivery of nanocarrier combination therapy. (A) An anticancer drug in free form and curcumin as nanocarrier (Free drug + Nano), (B) Separate nanocarrier delivery of both drugs (Nano + Nano), C) Co-encapsulation of both drugs in the same nanocarrier (co-encapsulation)
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Figure 7: (a-d) Combination Index Plots of Folate-BSA-difluorinated curcumin (T C) and Folate-BSA-Paclitaxel (T P) using MTT assay in SKOV3 Cell line (left) and HeLa cell lines (right). The data demonstrates synergistic cell killing effect (e) depicts the Fa-CI plot
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demonstrating synergistic combination efficiency as compare to fraction effected. Average synergism reported at Fa < 0.5. (f) Graph showing the enhance cell killing compared to paclitaxel. (Figures reproduced with copyright permissions from [168]).
Figure 8: Combination Nanocarrier possible dosing and effects. The in-vitro and then in-vivo fixed molar ratio (synergistic effect) can be translated from in vitro assay to in vivo assay using
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nanoparticle approach strategy.
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Figure 9: In-vitro cytotoxicity depicting chemotherapy efficacy (chemo-sensitizing effect) and
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drug resistance reversal of synthesized doxorubicin with curcumin coated mesoporous carbon
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nanoparticles (PEG-PCDA/MCNs) was tested by MTT assay against drug resistant of MCF7/ADR cells. (A) DOX dose-dependent in vitro cytotoxicity of different DOX formulations
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against the drug resistant MCF-7/ADR cells after 48 h incubation; Free DOX shows lowest
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inhibition concentrations (IC50) vs significantly enhanced IC50 with the designed nanoparticles,
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(B) Viability rate of MCF-7/ADR cells after 48 h incubation with MCNs and PEGPCDA/MCNs; a significantly decreased viability of cells is seen with the drug incorporated
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nanoparticles vs the controls, (significant difference, *: p < 0.05; **: p < 0.01). (figure reproduced with permission from Li et al. [112])
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Figure 10: A mechanism of action display for a possible paclitaxel (PTX) and curcumin (CUR) nanoparticle. Their interaction with Folate receptor and subsequent Endocytosis of the PLGAFA-PTX Lipid Nanocarrier has been depicted.
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