Liposome-based drug co-delivery systems in cancer cells

Materials Science and Engineering C 71 (2017) 1327–1341

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Materials Science and Engineering C journal homepage: www.elsevier.com/locate/msec

Review

Liposome-based drug co-delivery systems in cancer cells Sepideh Zununi Vahed a, Roya Salehi a,b, Soodabeh Davaran a,b, Simin Sharifi b,c,⁎ a b c

Chronic Kidney Disease Research Center, Tabriz University of Medical Sciences, Tabriz, Iran Drug Applied Research Center, Tabriz University of Medical Science, Tabriz, Iran Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran

a r t i c l e

i n f o

Article history: Received 28 May 2016 Received in revised form 10 November 2016 Accepted 21 November 2016 Available online 23 November 2016 Keywords: Liposome Co-delivery Combination therapy Chemotherapy Cancer treatment

a b s t r a c t Combination therapy and nanotechnology offer a promising therapeutic method in cancer treatment. By improving drug's pharmacokinetics, nanoparticulate systems increase the drug's therapeutic effects while decreasing its adverse side effects related to high dosage. Liposomes are extensively used as drug delivery systems and several liposomal nanomedicines have been approved for clinical applications. In this regard, liposome-based combination chemotherapy (LCC) opens a novel avenue in drug delivery research and has increasingly become a significant approach in clinical cancer treatment. This review paper focuses on LCC strategies including co-delivery of: two chemotherapeutic drugs, chemotherapeutic agent with anti-cancer metals, and chemotherapeutic agent with gene agents and ligand-targeted liposome for co-delivery of chemotherapeutic agents. Definitely, the multidisciplinary method may help improve the efficacy of cancer therapy. An extensive literature review was performed mainly using PubMed. © 2016 Elsevier B.V. All rights reserved.

Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Classification of liposomal drug delivery systems. . . . . . . . . . . . . . . . . . . . . . . 2.1. Liposome composition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Liposomal co-delivery of chemotherapeutic agents . . . . . . . . . . . . . . . . . . . . . . 3.1. Liposomal co-delivery of two drugs . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Liposomal co-delivery of chemotherapeutic agent with anti-cancer metals . . . . . . . . 3.2.1. Liposomal co-delivery of chemotherapeutic agent with platinum . . . . . . . . 3.2.2. Liposomal co-delivery of chemotherapeutic agent with copper . . . . . . . . . 3.2.3. Liposomal co-delivery of chemotherapeutic agent with gold . . . . . . . . . . 3.3. Liposomal co-delivery of chemotherapeutic and gene agents . . . . . . . . . . . . . . 3.3.1. Liposomal co-delivery of chemotherapeutic drug and siRNA . . . . . . . . . . 3.3.2. Liposomal co-delivery of chemotherapeutic drug and shRNA . . . . . . . . . . 3.3.3. Liposomal co-delivery of chemotherapeutic drug and antagomirs. . . . . . . . 3.3.4. Liposomal co-delivery of chemotherapeutic agent and DNA . . . . . . . . . . 3.3.5. Liposomal co-delivery of chemotherapeutic drug and viral vector expressing gene 4. Targeted liposome for co-delivery of chemotherapeutic agents . . . . . . . . . . . . . . . . 4.1. Passive targeted liposome for co-delivery of chemotherapeutic agents. . . . . . . . . . 4.2. Active targeted liposome for co-delivery of chemotherapeutic agents . . . . . . . . . . 4.2.1. Transferrin targeted liposome for co-delivery of chemotherapeutic agents . . . . 4.2.2. Folate targeted liposome for co-delivery of chemotherapeutic agents . . . . . . 4.2.3. Hyaluronic acid targeted liposome for co-delivery of chemotherapeutic agents. . 4.2.4. Antibody targeted liposome for co-delivery of chemotherapeutic agents. . . . . 4.2.5. Peptide targeted liposome for co-delivery of chemotherapeutic agents . . . . . 4.3. pH sensitive liposome for co-delivery of chemotherapeutic agents . . . . . . . . . . . 4.4. Temperature sensitive liposome for co-delivery of chemotherapeutic agents . . . . . . . 5. Liposomal drug delivery challenges . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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⁎ Corresponding author at: Faculty of Pharmacy, Tabriz University of Medical Sciences, Golgasht Street, Daneshgah Ave., Tabriz, Iran. E-mail address: sharifi[email protected] (S. Sharifi).

http://dx.doi.org/10.1016/j.msec.2016.11.073 0928-4931/© 2016 Elsevier B.V. All rights reserved.

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6. Conclusions and future directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Cancer, a leading cause of worldwide death, is considered as a biocomplex phenomenon since different factors affect the outbreak of the disease. Various strategies including surgery, chemotherapy, radiotherapy, targeted therapy, immunotherapy, hyperthermia, hormone therapy, stem cell therapy, and mixtures of these methods have been developed for cancer treatment [1–7]. Chemotherapy is the ultimate treatment choice for several types of cancers; however, it presents critical limitations such as a lack of specificity, toxic side effects and development of drug resistance [8–13]. Most of the anticancer agents currently administered by confirmed therapeutic protocols are systemically circulated without special localization to cancer tissue. This widespread biodistribution of drugs results in both anticancer activities and off-target adverse activities. Combination therapy, using several different anti-cancer agents, is also developed as an optimistic method for the treatment of cancer. Combinatorial drug treatments have proven to be feasible because they activate the inhibition of several mechanisms or multiple connection points of a single mechanism. The advantages of combination therapy are supported by clinical studies showing synergistic effects that are greater to the sum of the therapeutic outcomes of each drug [14–18]. Although co-delivery (simultaneous delivery) of chemotherapeutic systems facilitate improvement in cancer therapy, their achievement is mainly hindered as a result of the inadequate accessibility of anticancer agents to tumor tissue, requiring high doses, rapid abolition, poor solubility and inappropriate bioavailability. Therefore, to mitigate the difficulties associated with traditional and combinational chemotherapies, there is a call for developing an ideal drug delivery system that could improve the therapeutic effect of drugs while decreasing their toxic side effects [19]. Nanomedicine presents a novel direction and a potent form of drug therapy that can enhance drug performance and overcome aforementioned limitations. Given that most of nanomedicines approved by the US Food and Drug Administration (FDA) were not specifically considered to have selectivity toward biological targets, they are first-generation of nanomedicines [20–26]. Application of nanotechnology in cancer treatment is widely expected to produce novel therapeutics for successful cancer treatment while reducing side effects to normal tissues. Nanotechnology has a critical role in cancer therapy regarding the application of different nanovectors such as liposomes, micelles, dendrimers, metal nanoparticles (NPs), carbon nanotubes (CNTs), natural and synthetic polymer NPs, and polymer–drug conjugates [27–36]. Among the various investigated delivery systems, liposomes hold great promise in the realm of drug delivery. Liposomes are spherical structures that are formed by one or several concentric lipid bilayers surrounding discrete aqueous spaces. Liposomes present several distinctive characteristics compared with other drug delivery systems including biocompatibility, no immunogenicity, ability for self-assembly, ability to load both hydrophilic and hydrophobic agents and improve their solubility, ability to carry large drug payloads and protect the encapsulated agents from the external media [37–40], ability to reduce the toxicity of the encapsulated agent and the exposure of sensitive tissues to toxic drugs coupled with the ability of site-specific targeting and improving penetration into tissues. Certainly, for drug formulation, liposomes are the most versatile and sophisticated nanoparticle type since they have the capacity to deliver several biologically active compounds and macromolecules (e.g. DNA, peptides, proteins and imaging agents) (Fig. 1.A), both in their lipid bilayer (i.e., hydrophobic molecules) and in their lumen (i.e., hydrophilic molecules) [41,42]. Therefore, they not

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only present a variety of benefits, but can enlarge their scope of drugs to get their optimized pharmacological effects [43,44]. However, unmodified liposomes are rapidly cleared by phagocytic cells of the reticuloendothelial system (RES) in blood circulation. To overcome this challenge, surface of liposomes are coated with a biocompatible and inert polymer such as polyethylene glycol (PEG). The polymer layer surrounding the outer of liposome prevents them from rapid clearance by the RES [45,46]. The goal of liposome-based cancer treatment is to improve drug efficacy, reduce toxicity, specify their targeting and minimize other limitations. In pursuit of this goal, different platforms have been extensively developed including modifications in liposomes (changes in lipid composition, charge, surface coatings and ligands) and drug formulations, one of which is LCC. Liposome-based combinatorial drug delivery can be highly beneficial for cancer therapy and overcome most of the current challenges each technique faces with [47–51]. By understanding the current developments in liposomal-based drug co-delivery systems and their challenges, future research will improve the existing systems and address the limitations. In this Review, we provide an overview of the developed combination drug delivery systems based on liposomes in cancer treatment and include most of in vitro, in vivo and clinical studies. 2. Classification of liposomal drug delivery systems Liposomes may have one or bilayer membranes. Vesicle size is a critical parameter in defining the half-life circulation of liposomes, and both number and size of bilayers affect the amount of drug loading in the liposomes. Size of liposome can differ from very small (25 nm) to large (2.5 μm) vesicles (Fig. 1.B). Additionally, On the basis of their size and number of bilayers, liposomes are grouped into two types: (1) unilamellar vesicles and (2) multilamellar vesicles (MLV). Unilamellar vesicles can also be classified into two subgroups: (1) small unilamellar vesicles (SUV) and (2) large unilamellar vesicles (LUV). In unilamellar liposomes, the vesicle has a single phospholipid bilayer sphere surrounding the aqueous solution. In multilamellar liposomes, vesicles have an onion-like structure. Classically, several unilamellar vesicles will be formed inside of the other vesicle, forming a multilamellar structure of concentric phospholipid spheres separated by water molecules, (Fig. 1.B) [52]. 2.1. Liposome composition Different composition of liposome can affect the drug delivery system including liposomes, binding ability, distribution and the way their contents are released (Tables 1, 2). Liposomes need a positive charge using cationic lipids in their composition, in order to bind to the nucleic acids [53]. For example, for the treatment of multidrug resistance (MDR)/cancer immunotherapy, mixtures of small interfering RNA (siRNA)/plasmid DNA (pDNA) and hydrophobic drug can be used [54]. Additionally, by controlling the composition of liposome membrane, the physicochemical characteristics of the liposome surface, including fluidity, charge and permeability may be changed. It is reported that by optimizing the formulation of liposomes, decrease of Pgp-mediated MDR may be achieved [55]. Since liposome-based drug delivery systems are administered systematically, their interaction with cells should be also taken into account. It is supposed that the inside surface of blood vessels, endothelial cells as well as cancer cells and tumor endothelial cells contain negatively charged components like glycosaminoglycans that may affect the liposomes distribution and their uptake by these

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A

1329

B

pH responsive polymer cage

SUV <100 nm

Conjugated drug Passive targeting with PEG

LUV 100-1000 nm

GUV >1 µm

Surface conjugated drug Active targeting ligand (

)

Antibody

DNA/siRNA

Multilamellar

Hydrophilic drug

Protein

Hydrophobic drug Peptide

Viral vector Aptamer Carbohydrate Small molecule

Multivesicular

Fig. 1. Liposomal structure, vesicle size and lamellarity classification systems. A: Structural and design considerations for liposomal drug delivery. Liposomes can be passive targeted through PEG and to promote receptor-mediated endocytosis by using active targeting ligands such as antibodies, peptides, proteins, carbohydrates, and various other small molecules and also drug loaded pH-responsive polymer-caged liposome. Chemotherapeutics or diagnostics agents can be encapsulated into the aqueous lumen, incorporated into the lipid bilayer, or conjugated to the liposome surface. B: The common vesicle size and lamellarity classification system. Small unilamellar vesicles (SUV) are less than 100 nm in diameter; large unilamellar vesicles (LUV) are between 100 and 1000 nm; and giant unilamellar vesicles (GUV) are larger than 1 μm. Multilamellar vesicles have many membrane layers, and multivesicular vesicles encapsulate smaller vesicles.

cells. Therefore, it is challenging to determine which type of charge is helpful for nanoparticle delivery systems since contradicting results are available. However, it is recommended that the use of slightly negatively/positively charged nanoparticles can minimize their self to self and self to non-self interactions; therefore, they may present optimal results [53]. 3. Liposomal co-delivery of chemotherapeutic agents Different strategies have been developed to achieve liposomal codelivery of chemotherapeutic agents. Increasing evidences indicate that the liposome-based combinational formulations increase the drug's anticancer effects, antiproliferative activity, tumor cell apoptosis and cytotoxicity and the potency of combinational drug regimen; while decreasing the systemic toxicity. Furthermore, liposomal co-delivery of chemotherapeutic agents can destroy the cancer cell's drug resistance. Besides these advantages, a liposomal co-delivery system is reported to eliminate invasive cancer cells and their vasculogenic mimicry (VM) channels [56–58]. However, no appreciable survival enhancement is generally reported [59–62]. Some examples of liposomal systems for co-delivery of chemotherapeutics agents are listed in Tables 1 and 2. 3.1. Liposomal co-delivery of two drugs Nanoliposomes play a critical role in cancer treatment. Liposomes allow synchronizing and controlling of the pharmacokinetics and biodistribution of the drugs, along with uniform time and spatial co-delivery of two chemotherapeutics agents [63]. Salinomycin (SAL), a polyether antibiotic, has been displayed to selectively inhibit cancer stem cells; however, its clinical use has been limited by hydrophobility. Wang et al. designed a cross linked MLV (cMLV)

for the combination delivery of SAL and Doxorubicin (DOX) to eradicate both cancer stem cells and breast carcinoma cells. SAL and DOX were released from the liposomes in sustained release kinetics, demonstrating the cMLVs stability. Furthermore, the inhibition effect of cMLV (DOX + SAL) against breast cancer cells was more effective than either single-drug treatment. The effective targeting of cMLV (DOX + SAL) to cancer stem cells validated via breast cancer stem cell markers in vitro. In vitro and in vivo breast cancer suppression by cMLV (DOX + SAL) was more effective than single-drug cMLV treatment or with the combination treatment of cMLV (DOX) and cMLV (SAL) (Fig. 2). Their study showed that cMLVs is a drug delivery system that can act as a potential system for combination cancer therapy, allowing co-delivery of an chemotherapeutic agent and a cancer stem cell inhibitor for the eradication of both cells [64]. In preformed liposomes, proton gradient has been the most frequently utilized drug loading system, and could be produced via citrate buffers or ammonium sulfate [65,66]. Alternatively, the proton gradient could be obtained via ionophores such as A23187 and nigericin (electroneutral agents) that change internal divalent and monovalent metal ions, respectively, with external protons to provide a transmembrane proton gradient [67]. Interestingly, drug loading could also be developed in lack of A23187 ionophore when the intraliposomal core involve a transition metal ion such as Mn2+ which is capable of making complexes with anti-neoplastic drugs such as DOX [68,69]. Chiu et al. study showed the therapeutic effect of a formulation of DOX and irinotecan coencapsulated liposome whereby the drug content of liposome could be fine-tuned by concentration of intraliposomal Mn2 +. With the potential of loading drug compounds via two different mechanisms (coordination complexation and pH gradient), the Mn2 +/ A23817 based remote drug loading technique could have wide applicability in expanding multi-functional liposomal systems, which are

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Table 1 Liposomal co-delivery of two chemotherapeutic agents. Formulation

Liposome preparation technique/composition

Therapeutics

Indication

Status

Results

Ref

PEG-Liposome

Thin-film hydration/DPPC, DSPE-PEG-2000, cholesterol, DDAB

Docetaxel + Gemcitabine

Osteosarcoma

In vivo In vitro

[86]

PEG-Liposome

ePC, cholesterol, CHEMS, DOPE, PEG2000-DSPE, Tf-PEG3400-DOPE

Ncl-240 (inhibitor of the PI3K/mTOR pathway) + Cobimetinib (a MEK/ERK pathway inhibitor)

Colon carcinoma

In vitro

Liposome

Thin film hydration/SPC, cholesterol

Vincristine + Quinine (a multidrug resistance inhibitor)

Breast cancer Colorectal cancer Lung carcinoma

In vivo In vitro

PEG-Liposome

Thin film hydration/SPC, cholesterol, DSPE-PEG (2000)

Paclitaxel + Rapamycin (with anti-tumor and immunosuppressant properties and an inhibitor of mTOR protein kinase)

Breast cancer

In vivo In vitro

Multilamellar liposome

Dehydration-rehydration/DOPC, Doxorubicin + Paclitaxel DOPG, MPB-PE

Breast cancer

In vivo In vitro

PEG-Liposome

Brain cancer

In vivo

CPX-351 liposome

Phospholipon 100H, cholesterol, Topotecan (topoisomerase PEG-DSPE inhibitor drug) + Vincristine DSPC, DSPG, cholesterol Cytarabine + Daunorubicin

- The system delivered the anti-tumor drugs in the interstitial spaces of osteosarcoma tumor by EPR effect. ↑ Cytotoxic activity ↑ Apoptosis - Predominant G2/M phase arrest ↑ Potency of combinational drug regimen ↓ Tumor burden comparing to that of free combination mixture ↑ Cytotoxic effect due to a synergistic effect of the agents - Combined prevention of the PI3K and MEK pathways leads to a antiproliferative activity, due to cell-cycle regulation leading to the trigger of apoptosis pathway - The system overcomes the VCR resistance - It could be a promising liposomal therapeutic formulation to overcome multidrug resistance, and may have critical medical applications for the treatment of cancer - Liposomes released in a slow and sustained fashion ↑ Cell line cytotoxicity ↑ In vivo therapeutic effects - The system controlled the tumor growth ↑ Loading efficiency and sustained release pattern of the drugs ↑ Co-delivery therapeutic activity ↓ Systemic toxicity ↑ Therapeutic efficacy

Acute myeloid leukemia

Phase II

[93]

CPX-1 liposome

DSPC, DSPG, cholesterol

Irinotecan + Floxuridine

Phase I Phase II

Liposome

Film hydration/Cardiolipin, PC, Cholesterol

6-Mercaptopurine + Daunorubicin

Advanced solid tumors Colorectal cancer Acute myeloid leukemia

- The study showed the maximum degree of synergy and minimum antagonism effects ↑ Efficacy and therapeutic index ↑ Efficacy

[230]

PEG-liposome modified with HIV-1 peptide

EPC, cholesterol, DSPE-PEG2000

Epirubicin + Celecoxib

Invasive breast cancer

In vitro In vivo

The cytotoxicity was dose dependent and had shown a synergistic effect when double drug liposome was used - The liposomes transport across cell and nuclei membranes ↑ Anticancer efficacy by inducing apoptosis through caspase cleavages ↑ Prolonged circulation in blood

In vitro

[225]

[226]

[227]

[228]

[229]

[94]

[231]

DPPC: 1.2-dipalmitoyl-sn-96 glycero-3-phosphocholine, DSPE–PEG2000: 1.2-distearoyl-sn-glyc-97 ero-3-phosphoethanolamine-N-methoxy (polyethylene glycol), DDAB: Dimethyl-99 dioctadecyl-ammonium bromide, DOPE: Dioleoyl-sn-glycero-phosphoethanolamine, CHEMS: Cholesteryl hemisuccinate, Tf: Human holo-transferrin,SPC: Soy phosphatidylcholine, DOPC: 1.2-dioleoyl-sn-glycero-3-phosphocholine, DOPG: 1.2-dioleoyl-snglycero-3-phospho-(10-rac-glycerol), MPB-PE: 1.2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-[4-(pmaleimidophenyl) butyramide, DSPC: Distearoylphosphocholine, DSPG: Distearylphosphatidylglycerol, PC: Phosphatidylcholine,

amenable to the delivery of therapeutic and diagnostic agents. The DOX and irinotecan co-loaded liposomal delivery system were further evaluated in an intraperitoneally grown human ovarian tumor xenograft model and displayed to remarkably improve the survival of the tumor-bearing animals. This breakthrough in therapeutic efficacy was possible due to enhancement in systemic drug exposure, with the maintenance of the synergistic molar drug ratio in circulation [70]. Matrix metalloproteinases (MMPs) have been studied as a potential target for treating invasive breast cancers [71]. Madhan et al. developed combination of MMP inhibitor, Epigallocatechin gallate (EGCG) along with Paclitaxel (PTX) in the form of a liposomal co-delivery system. The in vitro activity of the liposomes was evaluated by their ability to stimulate apoptosis and limit cell invasion. Their results revealed the synergistic effect of PTX/EGCG combination and the suitability of

PTX/EGCG co-delivery for the treatment of invasive breast carcinoma [72]. Vitamin C is a strong reducing agent that plays a role in various physiological functions [73–75]. Vitamin C not only displays cytotoxicity toward cancer cells but also improves the anti-neoplastic effect of some anti-cancer agents, in particular anthracyclines, because one of their cytotoxic effects is related to free radical production [76–80]. It was revealed that DOX and vitamin C have synergistic activity toward the breast carcinoma cells over a wide range of vitamin C concentrations [81]. Lipka and coworkers developed a new liposomal system of active anthracycline encapsulation based on an ascorbic acid gradient. Improved Epirubicin anticancer effect observed as a result of the synergistic anticancer effect of anthracyclines along with ascorbic acid. Suitable solubility of Epirubicin in the ascorbic acid gradient was another reason

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Table 2 Liposomal co-delivery of chemotherapeutic and gene agents. Formulation

Liposome composition

Chemotherapeutics Gene agent

Indication

Status

Results

Ref

siRNA-loaded Layer-by-layer films atop a drug-loaded liposome

DSPC, cholesterol, POPG

Doxorubicin

MDR1 siRNA

Breast cancer

In vivo In vitro

[232]

Cationic liposome

DC-cholesterol, DOPE, OQCMC

Paclitaxel

MRP1 siRNA

Breast cancer

In vitro

Trilysinoyl oleylamide based liposomes

Cationic oligolysinoyl lipids, DOPE, cholesterol

Mcl1 siRNA

MGluPG, EYPC, DOPE, DLPC

Human nasopharynx carcinoma Lymphoma

In vivo

pH sensitive liposome (lipoplex)

Suberoylanilide Hydroxamic Acid (SAHA) Ovalbumin

- An effective combination therapy ↑ DOX efficacy ↓ Tumor mass - No detected toxicity - Silences the expression of MRP1 - Suppress the pump resistance ↑ Concentration of intracellular PTX ↑ Anti-tumor effect - It is a useful carrier for MDR cancer therapy ↑ Synergistic anti-tumor effect

[235]

Hyaluronic acid and folate modified cationic liposome

ePC, DOPE, cholesterol, DSPE, PEG2000, FA, HA, (PTX/PEI/DNA complex)

Paclitaxel

DNA

Human hepatocellular carcinoma

In vitro

Angiopep-2 modified cationic liposome

DC- cholesterol, DOPE, and DSPE-PEG2000-COOH

Paclitaxel

pEGFP-hTRAIL Glioma

- Efficient tumor-specific immune responses - It may be a promising approach for efficient cancer immunotherapy This system presented promising potentials for combination therapy since it targeted cancer cells and promoted transfection efficiency ↑ Uptake and gene expression in both cells and glioma-bearing mice

IFN-γ encoding plasmid DNA

In vivo In vitro

In vitro In vivo

[233]

[234]

[236]

[237]

DSPC: Distearoylphosphocholine, DC: 3-β-[N-(N′’,N′-Dimethylaminoethane)-carbamoyl], DOPE: Dioleoylphosphatidylethanolamine, OQCMC: octadecyl quaternized carboxymethyl chitosan, DG: N,Ń́ -́ dioleylglutamide, EYPC: egg yolk phosphatidylcholine, MGluPG: 3-Methylglutarylated poly(glycidol), DLPC: Dilauroyl phosphatidyl Choline, ePC: Egg phosphatidylcholine, DSPE-PEG2000-FA: 1.2-Distearoyl-sn-glycero-3-phosphoethanolamine-N-folate poly-(ethylene glycol)2000, PEI: polyethylenimine, FA: folate, HA: hyaluronic acid, PTX: Paclitaxel, DSPE: distearoylphosphoethanolamine, PEG: polyethylene glycol.

contributing to high anti-tumor effect of this system. It may cause higher bioavailability and improved dissolution rate of the drug from liposomes. High anticancer effect of this liposom (Epirubicin loaded with an ascorbic acid gradient) was observed toward murine mammary cancer in the in vivo study [82]. Hormone and trastuzumab resistant breast carcinoma are unsuccessful clinical treatment cases. Wong et al. developed a liposomal system containing a synergistic combination of vincristine (VCR) and

quercetin (a plant flavonoid with potent antioxidant and chemopreventive action) with sustained drug circulation times and coordinated drug release in vivo, to improve effective treatments against trastuzumab resistant breast cancer. Additionally, the co-loaded liposomal delivery system has proved to be the most effective tumor growth prevention in the human breast tumor xenograft compared with free quercetin, free VCR, free VCR/quercetin mixtures and vehicle control. Specifically, only the co-loaded liposomal system showed significant anticancer effect at

Primary Tumor

cMLV(Dox)

cMLV(Dox+Sal)

Cancer Cell Cancer Stem Cell Recurring Tumor

Complete Response

Fig. 2. Liposomal co-delivery of an anticancer agent and a CSC inhibitor for the elimination of both breast cancer cells and cancer stem cells. antagomirs (adapted from ref. [64] with permission). In vitro and in vivo breast cancer suppression by cMLV (DOX + SAL) was more effective than single-drug cMLV treatment or with the combination treatment of cMLV (DOX) and cMLV (SAL).

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Liposomal co-delivery of two drugs

B

A

Docetaxel-HP-cyclodextrin

Curcumin Albumin-PTX nanoparticle

Gemcitabine PEG

PEG

C

D

MTX Doxorubicin

Cytarabine

PEG-PLD

Daunorubicin

Poly-l-lysin

Liposomal co-delivery of chemotherapeutic agent with anti-cancer matals

E

Pt

Pt

Pt Pt

Pt

Pt Pt Pt

Pt

Pt

Cisplatin

Pt

Pt

Doxorubicin Pt

Pt

Pt Pt

Pt Pt

Pt Pt Pt

Liposomal co-delivery of chemotherapeutic drug and gene agents

F

G

siRNA Adenovirus encoding IL-12 gene

Paclitaxel

Paclitaxel PEG

PEG

Targeted liposomes for co-delivery of chemotherapeutic agents

I

H Hyaluronic acid Lonidamine Paclitaxel TPGS

vapreotide Paclitaxel Complex of siRNA, chondroitin and protamin

Fig. 3. Structure and design considerations of some liposomal co-edelivery systems. A: Pegylated liposome encapsulated Curcumin and albumin-PTX nanoparticle B: Gemcitabine/ Docetaxel-HP-γ-cyclodextrin-loaded Pegylated liposome, C: doxorubicin and mitoxantrone loaded Layer-by-Layer Liposome, D: CPX-351; bilamellar liposomal nanoparticle formulation of cytarabine and daunorubicin in a fixed 5:1 M ratio, E: polymer-caged nanobin (PCN) comprising a doxorubicin-encapsulated liposomal core that is protected by a pHresponsive cisplatin prodrug-loaded polymer shell, F: Pegylated cationic solid lipid nanoparticles (cSLN) encapsulating PTX and complexed them with human MCL1-specific siRNA (siMCL1), G: Pegylated anionic liposome loaded with Paclitaxel and adenovirus encoding for murine interleukin-12, H: Paclitaxel/lonidamine loaded-TPGS and hyaluronic acid dualfunctionalized liposome, I: liposome co-loaded VEGF-targeted siRNA (siVEGF) and paclitaxel. VAP utilized as a ligand for targeting drug delivery based on its high affinity to SSTRs.

two-thirds of the most tolerated dose of VCR, without any significant weight loss of body in the animals [83]. Ko et al. established PEGylated hybrid polymer-lipid liposomes coloaded with curcumin (CUR, chemopreventive and cancer chemotherapeutic agent and an effective NF-ĸB inhibitor) and PTX to study the therapeutic property of a simultaneous drug regimen. For this purpose, PTX-loaded albumin nanoparticles were organized and encapsulated in PEGylated hybrid liposomes comprising CUR by a thin-film hydration method (Fig. 3.A). PTX and CUR release was sustained and occurred in a sequential kinetics, wherein CUR was expected to downregulate the nuclear factor NF-ĸB and Akt pathways and enhance the therapeutic effect of PTX. The ratiometric combination of PTX and CUR was remarkably more cytotoxic than the single drugs. Importantly, dual-drug-

loaded liposomes showed a more cytotoxic activity than a mixture combination at a lower dose. PTX-loaded albumin nanoparticles (APN) activated significantly early and late apoptosis pathways, triggered a stronger G2/M arrest, and enhanced the subG1 cell population. By coloading CUR with PTX in a polymer-lipid hybrid liposomal formulation, they could increase the therapeutic effect in cancer treatments. Their results revealed that such co-delivery formulations could serve as a promising therapeutic method to advance clinical outcomes against various cancers [84]. In another study, Narayanan and coworkers co-loaded CUR and resveratrol (RES) and showed reduced prostate cancer incidence in PTEN knockout mice [85]. Moreover, Liu et al. formulated a docetaxel (DTX) and gemcitabine (GEM) co-encapsulated PEGylated liposome (DTX/GEM-L). 2-hydroxypropyl-g-cyclodextrin/DTX

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inclusion complex was made to enhance DTX aqueous solubility, (Table 1 and Fig. 3.B) [86]. Layer-by-layer (LbL)-designed nanoparticles are a group of therapeutic nanovectors utilized in an increasing number of biomedical uses. Kim et al. investigated the in vivo pharmacokinetic profile and stability of nanoparticles used for systemic drug delivery by combining the advantages of the LbL method with those of liposomes. LbL assembly is prepared by sequential deposition of PEG-block-poly (L-aspartic acid) (PEG-b-PLD) and poly-L-lysine (PLL) on liposomal nanoparticles (LbLLNPs). Using a modular design, DOX was loaded into the liposome core and mitoxantrone (MTO) was loaded onto the surrounding layers of shell (Fig. 3.C). Their study revealed the mechanistic basis for assembly of LbL-LNPs, and their physicochemical characterization. In vivo studies presented 3-layered and 11-layered LbL-LNPs prolonged drug plasma half-life. In addition, cytotoxicity investigation of drug loaded LbL-LNPs and blank were exanimated in MCF-7 cells. Overall, this work presented the value of the LbL system as a good multi-therapeutic formulation with potential for in vivo cancer drug targeting [87]. Another promising approach to overcome the limitations of conventional cancer therapy is combination of anti-cancer drugs with modulators. Fanciullino et al. have developed a triple liposomal system of 5Fluorouracil (5-FU), LipoFufol, combined with folinic acid and 2′deoxyinosine to show strong antiproliferative effect, even against chemoresistant colorectal models, while being less toxic than 5-FU. Pharmacokinetic studies on animals in administration of LipoFufol showed that sustained release and higher drug exposure can be achieved compared with single 5-FU. However, when exanimated to rats with temporary partial deficiency of DPD (dihydropyrimidine dehydrogenase), LipoFufol showed to be less toxic than single 5-FU, probably because of decreased liver uptake that makes DPD activity less critical for its disposition. LipoFufol proved to enhance the pharmacokinetic profile of 5-FU, prolonging its circulation time due to the PEGylated materials which affect tumor accumulation as confirmed by biodistribution study in mice bearing tumor. Overall, LipoFufol showed a safer and greater alternative to standard 5-FU in experimental treatment of colorectal cancer, both in vitro and in vivo [88]. MDR is an important barrier in cancer treatment. A promising strategy for treating MDR is the co-delivery of anticancer agents mixture to cancer cells in a single nanocarrier [89,90]. Meng et al. co-encapsulated RES along with PTX in a PEGylated liposome to construct a liposomal form of combination therapy for drug-resistant tumors. Their study showed that the composite liposome could generate potent cytotoxicity against drug-resistant breast cancer cells in vitro and improve the bioavailability and the tumor-retention of the drugs in vivo without any notable increase in the toxicity. Results suggested that the co-delivery of RES and PTX in a liposomal system may potentially improve the treatment of MDR cancers [91]. As with any carrier-mediated co-delivery formulation, determination of the optimum dose as the relative ratio of various drugs is a complex aspect in liposome-based simultaneous drug delivery formulation. Mayer et al. reported accurate control over combinatorial drug dosing in liposomes [92]. The mixture of drugs encapsulated into liposomes at appropriate ratios could be achieved by controlling liposome synthesis and drug loading procedure. Various liposomes based on this formulation such as CPX-1 and CPX-351 are currently studied in clinical trials, Table 1 [93,94]. CPX-351 is a 100 nm bilamellar liposomal formulation of cytarabine and daunorubicin mixture in a fixed 5:1 M ratio (Fig. 3.D). Some other examples of liposomal systems for co-delivery of chemotherapeutics agents are listed in Table 1.

narrow spectrum of activity and dose-dependent toxicity remain drawbacks of cisplatin which limit its clinical applications [98,99]. The problem has been addressed by the platinum-based compounds displaying lower toxicity, higher selectivity, and a broader spectrum of activity [100,101]. Moreover, metal ion (e.g. zinc (II), copper (II), gold, and copper chelating agents) contained complexes have held promise as anticancer agents [102–105]. The study of ruthenium containing complexes in clinical trials showed more application on the applying non-platinum metal-based complexes in cancer treatment [106,107].

3.2. Liposomal co-delivery of chemotherapeutic agent with anti-cancer metals

3.2.3. Liposomal co-delivery of chemotherapeutic agent with gold To explore the performance of organic/inorganic nanomaterialbased chemodrug delivery systems, combined liposomes and gold nanoparticles were employed as hybrid liposome model systems [126]. Ding et al. developed a hybrid system with PTX for an in vivo study. As a direct carrier, PTX is conjugated on the surface of gold

The field of medical inorganic chemistry has gained great attention in the anti-tumor agents' formulation and diagnostic fields in biomedicine since the discovery of cisplatin [95–97]. However, resistance, a

3.2.1. Liposomal co-delivery of chemotherapeutic agent with platinum Cisplatin was a member of platinum-containing anti-cancer agents, now also including oxaliplatin and carboplatin. In in vivo, platinum complexes, bind to DNA and lead to its crosslinking and finally induce cell apoptosis [108,109]. Irinotecan is one of the established antineoplastic drugs, which along with cisplatin, presents an effective combination for small-cell lung cancer treatment. Tardi et al. studied the efficacy of this combination by drug ratios controlling following in vivo administration. Maximum anticancer effect was detected for the liposome-encapsulated irinotecan/cisplatin (7:1 M ratio), designated as CPX-571, compared with the free-drug mixture in all studied models. Their results confirmed the ability of drug delivery technology to improve the therapeutic effect. Moreover, the study showed that CPX-571 is a promising candidate for clinical development [110]. Another liposomal formulation is a polymer-caged nanobin (PCN) established by Lee et al., which employs different methods to incorporate several drugs into the same liposome. Pt-PCN (DXR) formulation (PCN comprising a DOX-encapsulated liposomal core that is protected by a pH-responsive cisplatin prodrug-loaded polymer shell with tunable drug ratios) reduced the doses and improved the efficacy and cytotoxicity of each drug against breast and ovarian carcinoma cells (Fig. 3.E). The results demonstrated that PCN presents different strategies for building synergistic effect into combination chemotherapy regimens [111]. 3.2.2. Liposomal co-delivery of chemotherapeutic agent with copper Based on different metabolism and response of cancer cells to copper with respect to normal cells, copper-based complexes have been developed in cancer therapy, provided with antineoplastic characteristics. Moreover, more attention has been conducted on copper's absorption, metabolism, distribution and excretion mechanisms besides the development of different diseases [112–122]. Patankar et al. have developed a MLVs formulation of a complex between topotecan and copper; topotecan encapsulated into copper sulfate and the divalent metal ionophore A23187 containing liposomes. The formulation's stability, pharmacokinetics, efficiency, plasma drug levels and the peritoneal cavity were assessed in vitro and in vivo. Liposomal formulation showed significant anti-cancer activity compared to free topotecan at doses with no noticeable toxic effects; however, it was 2-to 3-fold more toxic [123]. A copper-DOX complex within the liposomal core has been developed and applied in multi-dose therapy by Ferrara and co-workers. Their results revealed that this complex kept the anti-tumor efficacy of DOX and decreased its toxicity; moreover, the formulation facilitated a multidose strategy producing regression or tumor eradication [124]. Likewise, in order to preserve the blood circulating stability of DOX and trigger its release in the tumor site, Li et al. produced a pH and temperature sensitive copper ion mediated DOX liposomes (Cu-DOX-TSLs). The efficient intracellular DOX release from the complex in the tumor cells revealed the complex's anti-tumor effect in vivo [125].

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nanoparticles, covalently. The complex then is encapsulated in the bilayer of liposomes, as the second carrier to protect the system. The results confirm the improved solubility, stability, circulation longevity, liver targetability and anticancer efficacy of the hybrid liposomes and afford a great possibility of the hybrid systems to develop super long-acting anti-neoplastic drug delivery systems [127]. 3.3. Liposomal co-delivery of chemotherapeutic and gene agents The aim of gene therapy is to eliminate tumor cells, block the transduction of cancer cells or prevent the disease-induced proteins without any harm to the normal cells, via specific genetic materials against cancer [128–131]. PDNA and siRNA containing cancer genes are also utilized for the treatment of cancer in the clinical trials [54]. It has been shown that a proper combination of anti-cancer drugs and gene agents can enhance the therapeutic effect and patient compliance due to the decreased drug dosage and reduced development of drug resistance [132–134]. The main challenge in combination delivery of drugs and gene agents is to select appropriate carriers, since gene agents have negatively charged surface and higher molecular weight, while most frequently utilized anti-cancer drugs are hydrophobic molecules [135]. For the development of nucleic acid therapeutics via cationic liposomes, one prerequisite is that the nucleic acids must be appropriately transported to target cells and reach the suitable subcellular compartment (e.g., the cytoplasm or nucleus). The transfection efficiencies of cationic liposomes affected by the types of helper and cationic lipids, as well as their compositions [136]. Similar to the comparison among siRNA, small/short hairpin RNA (shRNA), antagomirs and DNA, it is also difficult to rank the transfection efficiency of them as part of co-delivery system from published data, partly because of different results from different experimental systems. From the standpoint of delivery and transfection efficiency, siRNA poses advantages over shRNA. For delivery, siRNA acts in the cytosol and does not require transport into the nucleus, whereas shRNA acts in the nucleus. For transfection, the activity of siRNA does not need interaction with chromosomal DNA, whereas shRNA-expressing pDNA needs appropriately designed promoters. The latter poses an additional challenge, particularly for quiescent cells that have low permeability across the nuclear envelope. For example, shRNA has lower transfection efficiency compared to siRNA in cells with low proliferating activity. The 100 times lower molecular weight of siRNA (∼ 19–30 bp), compared to shRNA, moreover presents less problems for delivery and improves the ease of chemical modifications [137,138].Under in vitro conditions, siRNA-mediated gene silencing is relatively transient, permanent for only few days and generally of shorter duration compared to shRNA-expressing pDNA [138]. Under in vivo conditions, shRNA and siRNA were similarly effective in luciferase knockdown from 3 h to 3 days, although shRNA was significantly more potent on a molar basis [139]. Recently, there has been an extraordinary improvement in a co-delivery system. The objective of this section is to review liposomal nanocarriers that have been investigated for the co-delivery of anti-cancer drugs and gene agents for cancer therapy, and to invent more systems in the co-delivery formulation (Table 2). 3.3.1. Liposomal co-delivery of chemotherapeutic drug and siRNA RNA interference (RNAi) is a special mechanism which happens normally in most of the eukaryotic cells. RNAi that mediated by microRNA (miRNA) and siRNA have emerged as the most promising systems for anti-cancer therapy, since both can induce gene-specific cleavage, resulting in degradation of mRNA through their complementary pairing with mRNA. For example, siRNA targeting of MDR1 gene can decrease the formation of efflux transporters in cell membrane, causing in a rise in cellular drug concentration [140]. Survivin siRNA can sensitize the drug resistance cells by preventing cell survival pathway [141]. Hence, gene silencing will open a window of time in which the chemoresistant

cells transiently become sensitized to the anti-tumor drug, thereby overcoming multi-drug resistance [142–145]. On the other hand, since tumor suppressor protein gene, such as p53, can trigger apoptosis or cell growth arrest, DNA plasmid encoding p53 can also be delivered for cancer therapy. All the DNA plasmid and RNA interference agents are known as gene agents [146]. Zhang et al. developed pH-sensitive cationic liposome for co-delivery of sorafenib (a kinase inhibitor agent for the treatment of primary kidney cancer) and siRNA to tumor tissue. The findings showed that carboxymethyl chitosan-modified sorafenib and siRNA co-delivery cationic liposome (CMCS-SiSf-CL) could protect siRNA against serum and RNase. CMCS-SiSf-CL exhibited an enhanced sorafenib release and significantly increased cellular uptake at pH 6.5 compared to that at pH 7.4, which confirmed the pH-sensitivity of carboxymethyl chitosan shell. In addition, CMCS-SiSf-CL showed more siRNA tumor accumulation compared to single siRNA due to passively target through EPR effect and protection of siRNA by CMCS-SiSf-CL [147]. Lu et al. evaluated the effectiveness of siRNA therapy using newly developed pegylated cationic liposome carrier (PPCat). Liposome carrier utilized a fusogenic lipid which destabilizes the endosomal membrane system. PPCat carrier contained PTX to enhance the transfection of survivin siRNA (siSurvivin) and in vivo delivery. In vitro anticancer effect was evaluated using short and long term cytotoxicity assays. In vivo intravenous therapy was evaluated in mice bearing subcutaneous tumors. Treatment of cultured cells with single agent mitomycin C (MMC) at 50% cytotoxic concentration increased mRNA and protein levels of survivin; addition of PPCat containing siSurvivin reversed the survivin induction and enhanced the MMC activity. In tumor-bearing mice, MMC delayed tumor growth and nearly tripled the survivin protein level in residual tumors, whereas addition of PPCat-siSurvivin, which by itself yielded a minor survivin reduction, completely reversed the MMC-induced survivin and enhanced the MMC effect. Their results showed effective in vivo survivin silencing and synergism between PPCat-siSurvivin and MMC. This combination represents a potentially useful chemo-gene therapy for bladder cancer [148]. Oh et al. formulated cationic solid lipid nanoparticles (cSLN) encapsulating PTX and complexed them with human MCL1-specific siRNA (siMCL1), (Fig. 3.F). They report that the co-delivery of siMCL1 and PTX using cSLN enhanced anticancer efficacy in vivo and in vitro compared to either single agent [149]. Different liposomal-based siRNA (targeted to MRP1 and Bcl-2 mRNA respectively suppressors of pump and nonpump cellular resistance) approaches have been developed to target cancer cell death and drug resistance. For instance, Long et al. studied the possibility of co-delivery of Bcl-2 siRNA and DTX in a PEGylated liposomal system to improve the chemotherapeutic efficacy in MDR cancer cell lines. The lipo-DTX/ siRNA showed a prolonged blood circulation time of DTX and a tumor regression profile with 100% survival rate. The synergistic effect of DTX and MDR reversing ability of siRNA in the tumor mass was the promising features of the developed system in tumor inhibition [150]. Moreover, Oh and coworkers conjugated the MTO to palmitoleic acid and described an efficient combination therapy with co-delivery of anticancer siRNA. Administration of the palmitoleyl MTO liposomes remarkably blocked tumor growth and tumor size compared to untreated controls [151]. Likewise, in order to target lung cancer cells death and suppress their drug resistance in MDR, Saad and colleagues developed an effective cationic liposome-based co-delivery formulation including cationic lipids, siRNA and DOX targeted to Bcl-2 mRNA and MRP1 [152]. 3.3.2. Liposomal co-delivery of chemotherapeutic drug and shRNA A shRNA is an artificial structure with a hairpin turn that is expressed in cells via plasmids or vectors (viral or bacterial) to silence a desired gene [153,154]. Some challenges confront shRNA-based therapeutics. shRNA is typically delivered through use of a vector, and although they are generally effective, they pose significant safety concerns.

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Specifically, viral based gene therapy methods have proved dangerous in past clinical trials [155]. The promoter-based shRNA method needs multiple enzymatic and/or transport steps before interaction with RNA-induced silencing complex (RISC) that results in cleavage of the targeted mRNA. Saturation of transport or enzymes systems by viral vectors expressing high levels of shRNA may interfere with endogenous microRNA processing, leading to toxicity [156,157]. Another challenge is the possibility that the patient might show an immune response against the therapy. Finally, there might be off-target effects and the shRNA could silence other unintended genes. In improving successful new shRNA-based therapeutics, all of these challenges must be taken into account [158]. A thermosensitive magnetic liposomal delivery system established co-delivery of gene silencing shRNA vector and antitumor drug (DOX) into gastric cancer. The in vitro and in vivo experiments on the formulation's release activity, targeted cancer cell uptake and gene silencing, cytotoxicity and anticancer effects demonstrated that the system could inhibit cancer cells growth comparing to single delivery [159]. 3.3.3. Liposomal co-delivery of chemotherapeutic drug and antagomirs Antagomirs, also known as anti-miRNAs or blockmirs, are another class of chemically engineered oligonucleotides that are employed for silencing miRNAs. They prevent the binding of other molecules to a target site on an mRNA (Fig. 4) [160–163]. A novel modified liposomal system with an anti-microbial peptide and co-delivery of PTX along with antagomir-10b could trigger cell death in the meantime besides hindering of T cells migration [164]. 3.3.4. Liposomal co-delivery of chemotherapeutic agent and DNA More recent strategy to improve cancer treatment is cationic liposome–DNA complexes (lipoplexes) that are extensively utilized in gene therapy due to their potential advantages (e.g. safety, versatility and low immunogenicity) over viral vectors [166]. In spite of the recent clinical successes, the optimization of these systems proceeds on trialand-error; therefore, deep understanding of the physico-chemical and biological features of both liposomes and lipoplexes can enhance the clinical performances of these formulations [167]. Yang et al. assessed the potential of gene therapy via IL-15, a potentially immunotherapeutic cancer agent, and Caspy2, an active zebra caspase for triggering apoptosis and immune response in murine tumors,

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toward the murine tumors. Constructed plasmid containing Caspy2 and IL-15 genes is loaded in DOTAP/cholesterol cationic liposomal system and injected intratumorally into the mice bearing melanoma, breast and colon carcinoma. This coexpression prevented tumor growth and caused prolonged survival of the mice bearing melanoma or colon cancer, significantly. Moreover, a decrease in spontaneous lung metastasis and a long-time protective immunity toward the parental cancer cell re-challenge were observed in breast and colon cancer models, respectively [168]. 3.3.5. Liposomal co-delivery of chemotherapeutic drug and viral vector expressing gene Adenovirus vectors (Ads), double-stranded DNA and nonenveloped viruses, have had dominant potential to be used in gene delivery vector and anticancer vaccination [169]. It is suggested that Ads expressing mouse IL-12 are effective in treatment of cancer [170,171]. Sun et al. designed an antimelanoma delivery formulation (AL/Ad5/PTX) that incorporate PTX and adenovirus encoding for murine interleukin-12 into anionic liposomes (Fig. 3.G). This co-delivery formulation prolongs the survival time of mice bearing melanoma in a synerstic way [172]. 4. Targeted liposome for co-delivery of chemotherapeutic agents In order to improve the therapeutic potency of liposomal co-delivery systems in cancer therapy, the development of both active targeting and responsive delivery vectors hold great promise. Targeted drug delivery, or smart drug delivery, has tackled the challenges of conventional drug delivery in a way that drugs loaded with nanoparticles are targeted to a special tissue for prolonging, localization and specific targeting of drug. The conventional drug delivery system is the drug absorption across a biological membrane, while the targeted delivery system releases the drug in a dosage form [173]. The advantages of the targeted drug delivery is a decrease in the frequency of the drug dosages, having a more uniform effect of the drug, reduced fluctuation in circulating drug levels and decrease of drug side-effects. Furthermore, targeted drug delivery systems preserve the required plasma and tissue drug levels in the body, thus blocking any drug-mediated damage to the healthy tissue [174–176]. These systems have been developed to optimize regenerative techniques [177]. In the following section passive, active, pH sensitive and temperature sensitive liposomes for co-delivery of chemotherapeutic agents are discussed.

miRNA mRNA

gene

miRNA target

Translation off Antagomir

Antagomir blocking the miRNA

gene

miRNA target Translation on

Fig. 4. Regulation of gene expression through control of miRNAs antagomirs (adapted from ref. [165] with permission). As shown in Scheme 1, a miRNA recognizes a complementary target sequence of a gene and inhibits its expression. The antagomir binds to the miRNA and blocks its function, leading to the activation of gene expression. The gene of interest can be any endogenous gene or genetic circuit that is under control of a particular miRNA; or it can be an exogenous reporter gene, engineered to respond to a specific cellular miRNA.

4.1. Passive targeted liposome for co-delivery of chemotherapeutic agents The drug's triumph in passive targeting is directly associated with circulation time that is accomplished by cloaking the nanoparticle with some sort of coating substances such as PEG. Nanoparticle pegilation allows water molecules to bind to the oxygen molecules on PEG. These hydrogen bonds form a hydration film around the nanoparticle that makes the substance antiphagocytic. These particles are natural to the RES, leading to longer circulation time [178–180]. Nanoparticles between 10 and 100 nM in size systemically circulate for longer periods of time with this mechanism of passive targeting [181]. Passive targeting of liposomal systems solely depends on improved permeability and retention effect (EPR). 4.2. Active targeted liposome for co-delivery of chemotherapeutic agents Long circulating liposomal formulations, through the EPR, have demonstrated to accumulate at some tumor sites passively [182]. Nevertheless, due to poor drug bioavailability, their clinical therapeutic efficacy has not essentially been amended [183]. Two strategies, based on active targeting and externally triggered content release, have been developed to improve the efficacy of liposomal anti-cancer agents. In contrast to liposomal passive targeting, in active targeting, the liposome surface is manipulated with ligands that bind to the overexpressed

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receptors at tumor site specifically [184,185]. Despite significant efforts made for the development of actively targeted liposomes, their translation in the clinic needs to be improved. One of them is that their tumor accumulation is limited by numerous barriers that inhibit them from reaching their target cells [25,186,187]. Targeted ligands for actively targeting nanomedicines can improve cellular internalization through endocytosis-prone surface receptors, for instance folate [188], galactosamine [189], Hyaluronic acid [190], EGF, transferrin (Tf) [191,192], antibodies and peptides [193]. 4.2.1. Transferrin targeted liposome for co-delivery of chemotherapeutic agents Accessibility to cell surface, overexpression on tumor cells, and constitutive endocytosis make the transferrin receptor (TfR) a target to deliver liposomes into cancer cells [194–197]. Wu et al. synthesized and assessed a transferrin conjugated liposomes that were co-encapsulated with both DOX and verapamil (VER) via a transmembrane pH gradient because of their weakly basic nature. The system demonstrated an increase in anti-tumor effect (3 times) compared to liposomal DOX alone and a significant decrease in VER-related side effects (e.g. cardiotoxicity) [198]. Furthermore, the combination of TfR targeting along with DOX and VER co-loading could overcome the MDR in DOX resistant cells. Therefore, bypassing Pgp-mediated efflux and chemoresistance mechanisms present a crucial role in improving receptor mediated endocytosis of the drug delivery nanovector. 4.2.2. Folate targeted liposome for co-delivery of chemotherapeutic agents Folate receptor (FR), a membrane-associated folate binding protein, is overexpressed in over 90% of ovarian cancer and other epithelial cancers [199–201]. Xu et al. developed a FR targeted co-delivery formulation by folate-DOX/Bmi1 siRNA liposome (FA-DOX/siRNA-L). The FADOX/siRNA-L system demonstrated great tumor targeting effect and prevented tumor growth in vitro and in vivo experiments [202].

method, liposomal contents are released at or near the cell surface over time, and then enter the cell through passive diffusion or normal transport mechanisms. However, the rate of diffusion and redistribution of the released drug away from the cell would be more than the rate the drug enters the cell in the dynamic in vivo study [185,207–210]. Guo and co-workers designed a targeted immunoliposomal complex conjugated with anti-EGFR (epidermal growth factor receptor) Fab’ co-delivering DOX and ribonucleotide reductase M2 (RRM2) siRNA (DOXRRM2-TLPD), to achieve combined therapeutic effects. In vitro and in vivo investigations showed an improved therapeutic activity including cytotoxicity, apoptosis and senescence-inducing effect of DOX-RRM2TLPD compared with free drug treated or non-targeted controls. DOXRRM2-TLPD offers the possibility of co-delivering DOX and siRNA specifically and efficiently to EGFR overexpressing Hepatocellular carcinoma, and represents a potential therapeutic system toward chemotherapy combined with gene therapy in Hepatocellular carcinoma [211]. 4.2.5. Peptide targeted liposome for co-delivery of chemotherapeutic agents A somatostatin analog, vapreotide (VAP), can be used as a ligand for active targeting in drug delivery approach on its great affinity to somatostatin receptors (SSTRs), which is overexpressed in several cancer cells [212]. Feng and colleagues built a vapreotide targeted core-shell type liposome co-encapsulating VEGF-targeted siRNA (siVEGF) and PTX (Fig. 3.I). VAP utilized as a ligand for targeting drug delivery based on its high affinity to SSTRs. The nanoparticle core was a negatively charged ternary complex that was composed of protamine, chondroitin sulfate and siRNA, and could be covered with cationic lipid shell. As a result, the mixed liposome had remarkably stronger drug delivery in cancer cells via receptor-mediated targeting delivery, accompanied by substantial prevention of neovascularization induced by siVEGF silencing [213]. 4.3. pH sensitive liposome for co-delivery of chemotherapeutic agents

4.2.3. Hyaluronic acid targeted liposome for co-delivery of chemotherapeutic agents The overexpression of the HA cell surface receptor; CD44, on a different cancer type such as epithelial, ovarian, colon, stomach, and acute leukemia makes it a vector for active targeting process toward these tumors [203–205]. Zhang et al. developed a HA and D-alpha-tocopheryl poly (ethylene glycol) succinate (TPGS) dual-modified cationic liposome containing a synthetic cationic lipid, 1.5-dioctadecyl-N-histidylL-glutamate (HG2C18) for co-delivery of lonidamine (LND), a chemosensitizing agent, along with PTX against MDR breast cancer (Fig. 3.H). It was shown that the HG2C18 lipid contributes to the endolysosomal release of the liposome following internalization for effective intracellular delivery. The TPGS component was confirmed to be able to increase the intracellular accumulation of PTX by preventing the P-gp efflux, and to facilitate the targeting of mitochondria. The intracellularly released LND inhibited the intracellular ATP production by interfering with the mitochondrial activity for increased P-gp inhibition, also sensitized the MDR breast cancer (MCF-7/MDR) cells to PTX for promoted activation of apoptosis pathway through a synergistic effect. With the outer hyaluronic acid shell, the liposome was particularly accumulated at the tumor site and displayed a superior anticancer efficacy in the xenograft MCF-7/MDR tumor mice models. These results suggest that this liposome for co-delivery of an anti-cancer drug and an MDR modulator establishes a promising strategy for the destruction of MDR in cancer treatment [206]. 4.2.4. Antibody targeted liposome for co-delivery of chemotherapeutic agents Liposomal anticancer drugs targeting the epitopes that expressed at the surface of cancer cells (immunoliposomes) can enhance the sitespecific delivery of drug to cancer cells. Targeted liposomal drugs can bind to either noninternalizing or internalizing epitopes. In the first

Lower pH range of tumors (~ 6.8) compared to normal cells (pH 7.4) allows pH sensitive nanocarriers to depredate their structures and release the drug only within acidic tumor environments [214–216]. A pH-sensitive cationic liposome was developed for co-delivery of sorafenib and siRNA to the tumor tissue. The formulated liposomes displayed enhanced sorafenib release and increased cellular uptake at pH 6.5 that verified the pH-sensitivity of carboxymethyl chitosan shell [147]. 4.4. Temperature sensitive liposome for co-delivery of chemotherapeutic agents At certain temperatures, some nanocarriers can deliver drugs successfully. The higher temperature gradient of tumor, around 40 °C, makes it possible for tumor-specific site delivery [216]. Li and coworkers produced a pH sensitive copper–DOX combined load in core of temperature-sensitive liposomes in order to keep its circulating stability and targeted release of DOX in the tumor site. The efficient intracellular DOX release from Cu-DOX-TSLs against the tumor cells further confirmed the great anti-tumor effect in vivo [125]. 5. Liposomal drug delivery challenges Currently, there are quite a few drugs in the market that are used only in direst situations, often because of severe side-effects and toxicity. Many of these drugs have exceptional antimicrobial effect, but the poor pharmacokinetic and pharmacodynamic properties that limit their use. Drug encapsulation in a liposome can improve the abovementioned problems to such an extent that the drugs can be brought into regular use as the pharmacokinetic and pharmacodynamic properties can be controlled [187,217,218]. The advantages of liposomes as a drug delivery system are listed in Table 1.

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No drug delivery system is fault-free; this is the case with liposomal system as well. As liposomes are used to enhance and to increase the efficacy of a drug, the cost as well as all other implications thereof must be taken into account. Cost is important when it comes to lipid drug delivery systems, as these systems are costly to produce. High costs of these systems associated with the raw materials used in lipid excipients and expensive equipment are needed to increase manufacturing. In most cases liposomal formulations are non-toxic, but certain formulations such as cationic formulations tend to be cytotoxic. This is especially true when liposomal doses are very high [43,44,52]. Problems of liposomal drug delivery systems are listed in Table 1. Stability of liposomal drug delivery should be big challenge besides its cost. Stability studies should address the chemical, physical, and microbiological stability of the liposome drug product. The physical stability of drug loaded liposome can be affected by some of factors including the integrity of liposome, the size distribution of liposomes and unsaturated fatty acid groups. Some liposomes are susceptible to fusion (irreversible coalition of smaller liposomes to form larger liposomes), aggregation (reversible conglomeration or assembling of two or more liposomes without fusion), and leakage of the loaded drug during storage of liposomes. Fusion, aggregation, or leakage can be affected by the loaded drug substance or by the lipid components in the liposome. Stability testing should include tests to evaluate liposome integrity and size distribution. It should be assessed the chemical stability of the lipid components in the liposome as well as the chemical stability of the loaded drug substance. Lipids with unsaturated fatty acids are exposed to oxidative degradation, while both unsaturated and saturated lipids are subject to hydrolysis to form lysolipids and free fatty acids. It may be proper to conduct stress testing of unloaded liposomes to evaluate possible degradeation or other reaction procedures unique to the liposomes. When designing stress and accelerated stability testing studies, it should be recognized that liposome drug products behave differently near or above the phase transition temperature(s) [219]. Commercialization of liposomal drug systems needs an extensive shelf life studies. The expiration dating period or shelf-life of a drug is distinct as the time at which the average drug characteristic (e.g., potency) remains within an approved specification after manufacture. According to the literature, many methods have been investigated for the stabilization of liposomes, such as freezing, lyophilization, and spraying drying. In general, freeze-drying increases the shelf-life of liposomal systems and conserves them in dried form as lyophilized cakes to be reconstituted with water for injection prior to administration. Furthermore, cryoprotectants need to be added to maintain particle size distribution of liposomes after the freeze-drying-rehydration cycle. Several types and concentrations of sugars have been studied for their ability to protect liposomes against leakage and fusion during lyophilization processes [220]. In commercial liposome lyophilized products, lactose and sucrose has been used as a cryoprotectant in the formulations of liposomes to increase stability during lyophilization. Interestingly, these commercial products showed similar shelf-life in comparison with other liposome products (e.g., emulsions and suspension) and hence lyophilization may not have the expected effect on liposome stability [221]. lyophilization may not extend the shelf-life of products but may increase therapeutic efficacy in vivo [222,223]. Although therapeutic efficiency of liposome-based drugs may vary depending on the preparation technique, the choice of lipids, physico-chemical characteristics of the bioactive materials, and overall charge of the liposome, lyophilization is suitable for the long-term storage of liposome-based drugs [224]. 6. Conclusions and future directions Clinical applications of liposomal nanocarriers have been proven to be the most beneficial for their ability to “passively” gather at sites of enhanced vasculature permeability and for their ability to decrease the side effects of the loaded drugs relative to free drugs. The combination of two or more therapeutic agents on a single carrier system offers

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new therapeutic potentials but at the same time poses several new challenges. In order to detect a proper drug mixture, it is required to perform thorough biological assessment which must be supported by a deep understanding of the related molecular mechanisms. Another important aspect is the determination of the best mass ratio of each agent within a simultaneous drug delivery system. This needs systematic research investigating the effect of different drug ratios on the biological efficacy of the co-delivery systems. Recently, a systematic approach to evaluate different drug ratios loaded in liposomal technology resulting in the progress of different liposomal systems that are now being evaluated in phase II clinical trials include CPX-351 (cytarabine: daunorubicin) and CPX-1 (irinotecan: floxuridine) has been developed. Determination of the kinetics of release of each agent in a multidrug simultaneous formulation will also be required to determine the optimal ratio as one drug may affect the release pattern of the other therapeutic agent and thereby affect activity of them. Lastly clinical development of these codelivery systems is particularly challenging due to costs of designing such complex formulations. However, drug co-delivery liposomal therapeutics are probably to be appreciated by pharmaceutical companies as novel chances to develop the patient lives compared to current blockbuster therapeutic agents. Liposomal co-delivery system has become a promising technology for successful cancer treatment. We can look forward to many more clinical co-delivery system products based on liposome in future.

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