Functionalized mesoporous silica nanoparticles in anticancer therapeutics

Functionalized mesoporous silica nanoparticles in anticancer therapeutics

Journal Pre-proof Functionalized Mesoporous Silica Nanoparticles in Anticancer Therapeutics Abul Barkat, Sarwar Beg, Sunil K Panda, Khalid S Alharbi, ...

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Journal Pre-proof Functionalized Mesoporous Silica Nanoparticles in Anticancer Therapeutics Abul Barkat, Sarwar Beg, Sunil K Panda, Khalid S Alharbi, Mahfoozur Rahman, Farhan J Ahmed

PII:

S1044-579X(19)30104-X

DOI:

https://doi.org/10.1016/j.semcancer.2019.08.022

Reference:

YSCBI 1651

To appear in:

Seminars in Cancer Biology

Received Date:

8 August 2019

Revised Date:

15 August 2019

Accepted Date:

20 August 2019

Please cite this article as: Barkat A, Beg S, Panda SK, S Alharbi K, Rahman M, Ahmed FJ, Functionalized Mesoporous Silica Nanoparticles in Anticancer Therapeutics, Seminars in Cancer Biology (2019), doi: https://doi.org/10.1016/j.semcancer.2019.08.022

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Functionalized Mesoporous Silica Nanoparticles in Anticancer Therapeutics

Md. Abul Barkat1*#, Sarwar Beg2*#, Mahfoozur Rahman5, Farhan J Ahmed2

Sunil

K

Panda3,

Khalid

S

Alharbi4,

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Department of Pharmaceutics, School of Medical & Allied Sciences, KR Mangalam University, Gurgaon, Sohna, Haryana, India 2 Department of Pharmaceutics, School of Pharmaceutical Education & Research, Jamia Hamdard (Hamdard University), New Delhi, India 3 Research Director, Menovo Pharmaceuticals Research Lab, Ningbo, People Republic of China 4 Department of Pharmacology, College of Pharmacy, Jouf University, Sakakah, Kingdom of Saudi Arabia 5 Department of Pharmaceutical Sciences, SIHAS, Sam Higginbottom University of Agriculture, Technology & Sciences, Allahabad, U.P., India

#

The authors have equally contributed for compilation of the manuscript.

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Address for correspondence: Dr. Sarwar Beg Assistant Professor, Department of Pharmaceutics, School of Pharmaceutical Education & Research, Jamia Hamdard (Hamdard University), Hamdard Nagar, New Delhi, India - 110062 Phone: +91-8447120434, +91-9315791422 E-mail: [email protected] [email protected]

Abstract

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The application of nanomedicines in tumor targeting and attaining meaningful therapeutic benefits for the treatment of cancers has been going on for almost two decades. Beyond the lipidic and polymeric nanomedicines-based passive and active targeting, the quest for inventing the new generation of carriers has no end. This has lead to the evolution of some of the unique carrier systems with supramolecular assembly structures. Mesoporous nanoparticulate systems (MSNPs) are the recently explored substances with favorable potential for drug delivery and drug targeting applications especially in cancer chemotherapeutics. Notwithstanding their

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physical properties that makes them a suitable carrier for cancer treatment, but their outstanding ability towards chemical functionalization helps in delivering the imaging agents for diagnostic applications. MSNPs can improve the dissolution rate and systemic availability of the poorly

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water soluble drugs due to their mesoporous structures. Besides, guest molecules including targeting ligands, biomimetic agents, fluorescent dyes, and biocompatible polymers can be

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efficiently encapsulated in their tunable porous structure for targeting purpose. Some special features of the MSNPs which make them one of the highly effective nanocarrier systems include

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their ability to encapsulate non-crystalline drugs in their mesopores, high dispersion ability as a function of large surface area and wetting properties. For anticancer drug delivery, MSNPs are

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worthful to provide excellent drug loading capacity and endocytotic behavior. Moreover, the external surface of MSNPs can be precisely modified for tumor-recognition and developing sensitivity of the antitumor agents towards the cancer cells. Owing to the innumerable

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applications of MSNPs till now in cancer treatment, the present article particularly focuses to provide an overview account with complete details on the topic to make the readers abreast with details on physiochemical and material properties of MSNPs, their applications and current innovations for the purpose.

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Keywords: Nanoparticles; Mesoporous carriers; Cancer; Drug delivery; Multimodal targeting

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1. INTRODUCTION The use of nanotechnology-based interventions in medicines (also very popularly known as nanomedicines) for the treatment and management of cancers (including both diagnosis and treatment) has very profoundly increased the expectations of millions of cancer patients due to their improved efficacy and safety, marked with reasonable cost over the existing therapeutic products available in the market. Despite rapid advancement in the field of cancer biology and cancer chemotherapy, which has lead to the development of several newer therapeutic products,

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yet the real-time need of cancer therapy to become highly effective system in clinical setup are far from the expectations [1-3]. Indeed the therapeutic outcomes of the chemotherapeutic agents

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delivered using conventional drug delivery strategies remains quite poor due to limited sitespecific drug targeting ability to the cancer cells, along with faster blood clearance, severe side-

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effects and drug resistance like problems. On the contrary, a promising drug delivery approach to deal with these drawbacks include the application of multifunctional nanotechnology-driven drug delivery systems, where micelles, drug conjugates, nanoparticles (NPs) and nanomaterials have

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proven immense worth. Several literature reports have been published from researchers all over the world on cancer nanomedicines in the last two decades has further triggered many

pharmaceutical products [4-6].

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pharmaceutical companies to invest capital in this direction to bring the innovative

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In this context, mesoporous silica nanoparticles (MSNPs) with structural size < 500 nm offers exceptional qualities for multipurpose drug delivery applications. MSNPs include a bunch of tiny hollow nanocapsular structures and provide opportunity for conjugation of drug molecules and/or therapeutic agents through the open functional groups. These are highly robust in nature and exist in surface with modular symmetry, which can be further modified by chemical

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functionalization. Moreover, MSNPs offers high aspect ratio, which allows enhanced surface functionalization ability with better porosity to host molecular cargos without any disturbance in the silica framework [3]. Besides, large Brunauer, Emmet and Teller (BET) surface area (700– 1000 m2/g) and pore volume (0.6–1 cm3/g) of MSNPs also provides high drug loading capacity (up to 50% w/w) by adsorption of a variety of drug molecules [7, 8]. Facile silane chemistry offers easy surface functionalization of MSNPs with many different types of functional groups which makes them highly eligible for multifaceted therapeutic applications. Conjugation of magnetic/luminescent agents can be possible with MSNPs for multimodal delivery of the drugs 3

as well as the imaging agents [9]. Worth mentioning, mesoporous silica based carriers have given the status of “Generally Recognized as Safe (GRAS)” by the United States Food and Drug Administration (USFDA), thus they are considered as the best suited nanoplatforms of current era for clinical translation of potential therapeutics for the treatment of diseases [10]. Figure 1 illustrates the diverse benefits, abilities, applications and biological fate of the MSNPs in drug delivery research. MSNPs platform endures lot of flexibility and functionalization ability for targeted and controlled release drug delivery. Further, surface tailoring strategy permits

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engineering of these nanocarriers to achieve sufficient systemic bioavailability, efficient biological interactions, cellular uptake, and immune-surveillance. As a whole, this imparts in

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achieving the tailored pharmacokinetic drug release profile with improved targeted delivery and enhanced therapeutic activity. Hence, comprehensive understanding of the MSNP’s

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physiochemical and biological properties is required for in-depth understanding of the bioperformance during pre-clinical examination to push the technology towards clinical application. Very recently, USFDA has approved first silica-based nanoparticulate diagnostic

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system named as “C-dots” (Cornell dots) for Phase-I clinical trial. This constitutes a significant step towards clinical viability of silica-based nanoparticulate systems and provides a boost

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towards further research in this direction [11, 12]. On the heels of tremendous ongoing research in the domain of MSNPs applications in drug delivery research, the present article particularly draws attention to the usefulness and latest progresses related to MSNPs use in cancer

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chemotherapy.

2. MSNPs BASED MULTIFUNCTIONAL CARRIERS 2.1 Origin of mesoporous silica materials The inception of research efforts for developing the mesoscopic materials was started way back

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in 1970s. For the first time in 1992, Mobil Research and Development Corporation (MRDC), New Jersey (US) synthesized the hollow mesoporous solids structures from the aluminosilicate gels with the help of liquid crystal template mechanism. The developed substance was referred as “Mobil Crystalline Materials” or “Mobil Composition of Matter” (MCM-41). Later in 2001, Vallet-Regí and coworkers first time investigated the utility of MCM-41 in drug delivery applications, which further triggered the attention of researchers for exploration of them in drug delivery applications. Hence, significant research efforts have been given for designing versatile 4

MSNPs for treating diverse pathological conditions with special emphasis for exploring their applications in cancer treatment [11]. 2.2 Chemistry of mesoporous materials As per the IUPAC, the structural and/or functional materials with pore size in the range of 2–50 nm are considered as the mesoporous materials consisting of repetitive arrangement with pores arranged in an ordered fashion [15-17]. The pore size can be easily tuned by incorporating suitable surfactants. In general, MCM-41 is having pore size of 2.5 to 6 nm and hexagonal in

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shape, where cationic surface active agents are employed as templates. MCM-41 is widely used mesoscopic material for drug delivery applications. Besides this, several other mesoporous

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materials have been fabricated by changing the starting materials and reaction conditions. These materials have their unique structural orientation, pore diameter and physiochemical properties.

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For example, the materials like MCM-48 exist in cubic structural orientation while MCM-50 exists in a lamellar structure [18]. Nonionic triblock copolymers such as alkyl poly(ethylene

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oxide) oligomeric surfactants and poly(alkyleneoxide) block copolymers are used to produce the material SBA-11 (cubical orientation; Santa Barbara Amorphous-11), SBA-12 (3D hexagonal; Santa Barbara Amorphous-12), SBA-15 (hexagonal; Santa Barbara Amorphous-15) and SBA-16

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(cubic cage like structure; Santa Barbara Amorphous-16) on the basis of triblock polymers used and symmetry of the mesoscopic structure produced.

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Of late, researchers have revealed the highly mechanized mesoporous structure of SBA-15 which has extensive applications in biomedical engineering. SBA is quite different from MCM as it has larger pore diameter of around 4.6-30 nm and thick silica walls [19]. Another material, FSM-16 (folding sheet materials containing C16 surfactant) also posses mesoporous structure that are fabricated by the use of quaternary ammonium surface active agent as a template and layered

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polysilicate kanemite. Tozuka et al. confirmed the pharmaceutical usefulness of FSM-16, apart from its application as an adsorbent and for chemical catalysis [20]. Other MSNPs available with good pore symmetry and shape includes Technical Delft University (TUD-1), Hiroshima Mesoporous Material (HMM-33) and Centre for Research Chemistry and Catalysis (COK-12) [18]. Figure 2 pictorially illustrates the schematic classification of the MSNPs with their structural view and dimensions. Among the several variants of MSNP materials, MCM-41, MCM-48, 5

SBA-15, SBA-16 are some of the materials, which have been extensively investigated in drug delivery applications. Furthermore, these mesoporous materials have been explored as biosensors. Specifically, MCM-50, SBA-11 and SBA-12 are the important examples of materials with profound applications in chemical catalysis and biosensing devices. 2.2 Silica hybrid host carrier system MSNPs act as a host system for drugs and offer high therapeutic load within the porous system. It provides protection of the foreign compounds from degradation as well as also hides its

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detection by the immune system [21]. In recent years, the synthesis of mechanized mesoporous silica based materials have been widely studied, [22-25], such as sol−gel methods employed to

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synthesize MCM-41 [26] and SBA-15 [27], among several types of mesoporous structure [28, 29]. There are various factors like concentrations, pH value, chemical nature of the surfactants,

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temperature, and time which directly or indirectly affects the size, morphology, pore size and structure of the silica based mesoporous material. The application of conventional mesoporous

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materials like MCM-41 is restricted in drug delivery because of its bigger particles diameter in m range. In the cellular uptake examination for endocytic uptake, NPs with the particle size

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120 nm are considered [30]. Hence, studies have been conducted to get spherical MSNPs in the above size range [21, 31]. As by various researchers employed a standard production procedure, subsequent addition of surface active agent template, silica source, and organo trialkoxysilanes to

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a extremely basic aqueous solution at high temperatures to develop MCM-41-like NPs [21, 32]. Argyo et al. developed an adaptable approach for the synthesis of MSNPs with good stability and high yields. In this synthesis, triethanolamine is used as base and complexing ligand for silica synthesizer and is employed to adjust the particle size (80 nm) [21]. Its worm-like pore fabrication with pores developing process from the midpoint to the outside edge refers a seed-

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growth method. Increasing interest in the delivery of larger drugs or other molecules like enzymes or oligonucleotides causes the stunning development in the field of MSNPs synthesis with large pore sizes (10−20 nm) [33, 34]. So as to get admittance to the pores, the templating surface active agents have to be eliminated and it can be done by two processes namely, calcination and extraction. To circumvent hindrance like reduced pore size, NPs agglomeration, exclusion of organic moieties, or poor condensation rate of the silica set-up, Cauda et al. developed a novel synthesis approach in which it amalgamates the significant benefits of both 6

aforesaid approaches for template exclusion [21]. In this approach, a liquid-phase high temperature “calcination” of MSNPs is executed with the use of organic solvent (high boiling point) causing an improved silica condensation as keeping the colloidal character of the NPs. 2.3 Modification of MSNPs with a functional shell 2.3.1 Functionalization approach To facilitate the utilization of the total potential of MSNPs for drug delivery purposes, it is necessary to put functionality to the silica platform. Molecular functionality added to the surfaces

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of silica scaffold can radically alter the characteristics of the acquired material that is vital in host−guest interactions with the cargo. The inclusion of organic moieties at particular places is

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proposed to get fine-tune surface of the materials [35, 36]. The structurally selective adjustment of the in-house pore system and the peripheral particle surface by organic and inorganic moieties

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is often an important requisite for such substances to work as multifunctional nanocarriers for the delivery of drug showing the necessary features. Peripheral surface functionalization play an

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important role in the colloidal and chemical stability, and cell targeting by changing the nature of the particles via interactions with the surroundings as well as incorporating bigger molecules

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for pore gating to enhance the biocompatibility [37, 38]. In contrast, in-house organic moieties can helps to improve the interaction via covalent bonding for drugs or proteins molecules that offers the power over transport (diffusion), delivery kinetics, and stability of the therapeutics [21,

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39].

On the whole, there are numerous ways suggested to accomplish functionalization of silica materials but two approaches are most widely employed for the functionalization purpose namely postsynthetic grafting and co-condensation, apart from periodic mesoporous organosilica synthesis and use of metal organic reagents [21, 26]. So as to get command over functional

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groups position in MSNPs, Bein and co-researchers developed a site-selective delayed cocondensation strategy [40, 41]. Such approach opens new ways for design and synthesis of variety of highly functionalized MSNPs for the purpose of controlled drug release. Mesoporous silica based materials have capability to encapsulate a variety of molecules inside their pore channels makes them promising for drug delivery purposes. Encapsulation of different cargo molecules is important because it offers protection from enzymatic degradation. The therapeutic agents are loaded by the particles via adsorption. The interactions of drug molecules 7

with the particle generally take place via hydrogen bonding as well as electrostatic interactions [42]. Cargo loading and delivery potentials of the mesoporous silca particles are also got affected due to electrostatic interactions among the drug molecules and silica surface. While such functional changes applied on the MSNPs, the payloads are delivered in a controllable fashion at the targeted sites, with no premature delivery throughout its circulation in the blood. Such events can considerably decrease the side effects the drug molecules and enhances the overall therapeutic potential [42].

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2.3.2 Gating approach Another important functionality in this perspective is facilitated delivery of the drug via

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especially fabricated gating concepts. Generally, gatekeepers are categorized into three different groups (Figure 3). Pore gating systems are comprised of bulky molecular classes or NPs, for

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example proteins, superparamagnetic iron oxide NPs, or gold NPs that blocks the pore access for effective locking of the internal mesoporous setting [43-47]. Such macromolecules are either

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degraded or appended to the particles of silica surface through linkers which are scissile when it went in contact with certain stimuli [48, 21]. Excellent pore locking can be accomplished by the

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surface coating of MSNPs. For example, polymers, oligonucleotides, or supported lipid bilayers have been used for sealing because it efficiently blocks the premature drug release [49, 50]. Generally, phase transitions and competitive displacement reactions facilitate the pore opening

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and proficient cargo delivery [18]. The third approach for controlled drug release involves incorporation of the therapeutic agents in the MSNPs. Both coordinative and covalent bonds can be disrupted by means of certain stimuli like competitive binders or reductants to trigger the cargo delivery [18]. Zink and colleague researchers have demonstrated various nanocarriers with on-demand controllable delivery processes which include nanoimpellers comprising of

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azobenzene groups which have been illustrated to prompt UV-light-activated delivery of a cell membrane-impermeable dye [51]. 3. MSNPs application in cancer treatment 3.1 Tumor targeting applications A long debate on the application of nanostructured devices in tumor targeting can be done to potentially evaluate the efficacy of them. Despite efforts made through passive targeting 8

approaches for drug delivery to the cancer cells, only a limited success has been reached for achieving efficacy and safety of the therapy. The potential reasons could be more than one, but the reason behind failure of passive targeting based chemotherapy is lack of selective targeting efficiency to the malignant cells of the tumor mass [52]. Though a leaky vasculature of the endothelium pertaining to the blood-tumor barrier gives room for passive drug targeting, yet the erstwhile approach has no room in modern day cancer nanotechnology where we efficacy as well as safety both [53, 54]. On the contrary, the active drug targeting has much acceptable benefit, as

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it has proven ability for tumor specific drug targeting using the cancer cell surface receptors or ligands [55, 56]. Several nanocarriers-based strategies have been tried for active targeting of drugs to the cancer cells. MSNPs are one of the newly developed carriers with promising

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applications in cancer drug targeting. Some of the targeting ligands like folic acid (FA), mannose and transferrin can be conjugated on the surface of MSNPs for tumor targeting of the loaded

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therapeutic cargos.

The folate-based targeting was attempted by some researchers where folate moiety chemically

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conjugated to polyethylenimine through amide linkage on the surface of silica MSNPs exhibited promising results with respect to better antitumor tumor activity on the basis of high cellular

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uptake ability and cellular cytotoxicity both in human breast cancer and cervical cell lines as compared to that of the non-targeted nanocarriers [Figure 4(A–E)] [57, 58]. Using MSNPs at times, the tumor targeting is highly challenging owing to their bulky molecular structure, which

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causes extravasation in the blood vessels. Thus, the approach of targeting to tumor vasculature provides another promising opportunity for active drug targeting method [9]. The process of angiogenesis involving the formation of new blood vessels in the tumor vasculature requires a complete cascade of events where vascular endothelial growth factor (VEGF) and VEGF receptor plays key role in tumor metastasis [59]. Although a hefty score of literature reports are

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available on achieving efficient drug targeting to the VEGF receptors using specific ligands. Interestingly, some researchers have studied the application of MSNPs conjugated with VEGF121 to form nanocomplex for active targeting of Sunitinib, which was confirmed with the help of positron emission tomography imaging. The observed results indicated superior tumor accumulation potential of the targeted MSNPs (3-fold higher) as compared to the native drug on human glioblastoma (U87MG) bearing murine models [60]. In another example the researchers have explored the application of Arg-Gly-Asp (RGD) peptide for receptor selective targeting of 9

the MSNP with higher affinity, specificity and selectivity to the integrin avb3 receptors [61]. Similar approach was also used for investigating the application of the integrated use of the RGD peptide in conjugation with the MSNPs by disulfide bonds for attaining efficient targeting of the drugs via redox-responsive mechanism revealed maximal intracellular drug localization and inhibition of tumor growth [62]. Despite proven efficacy of MSNPs in majority of the preclinical studies, their applications in real-time scenario for clinical application in active drug targeting still require concerted efforts. In this regard, the focus on adopting MSNPs-based treatment

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strategies for tumor targeting by using the EPR mechanism paves the way for its potential application for delivering the nanoparticles to the tumor site for attaining meaningful effects.

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3.2 Chemotherapeutic applications

Cancer chemotherapy is a promising field requires targeting of the drug molecules to the cancer

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cells. Although much research has been taken place in this area, yet the outcomes are still not very promising as far as the number of clinically successful therapies is concerned. In a regular

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attempt for designing nanocarrier systems like polymeric and lipidic particulate systems, MSNPs stands quite well as one of the efficient nanomaterials with unique properties for delivering drugs to the specific cancer cells only. These are suitable to carry both the soluble and insoluble

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anticancer drugs for ensuring effective targeting to the cancer cells. Some of the recent examples of MSNPs-based chemotherapeutic applications include doxorubicin (DOX) delivery, where

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researchers have reported high reliability in terms of its outstanding drug loading capacity over other nanocarriers due to their bulky and porous structures [63-66]. Another instance of MSNPs include delivery of paclitaxel (PTX) for effective drug delivery by addressing the challenges related to its extremely poor solubility, limited permeability, low and inconsistent oral bioavailability for management of a variety of cancers [67-69]. MSNPs also offer potential

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solutions by improving loading of PTX in their nanosized mesoporous structures and provide good biodistribution to the cancer cells in the body [70-72]. Some of the researchers have also explored utility of the MSNPs in co-delivery of combination of drugs like gemcitabine (GEM) and PTX for pancreatic tumor treatment, where co-delivery of drugs showed higher efficiency in suppressing the stromal volume and tumor size as compared to the monotherapy in xenograft and orthotopic animal models [73]. Besides, a score of chemotherapeutic drug delivery has been attempted using MSNPs which include Cisplatin [74-76], Irinotecan [77], 5-Fluorouracil [78,

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79], Temozolomide [80] for a number of cancer treatment applications. Table 1 summarizes the cluster of applications of the MSNPs in details for cancer chemotherapeutic applications. 3.3 Gene therapy applications The application of nanocarriers in gene delivery helps in attaining good transfection efficiency for effective immunization against the cancer cells. The gene therapy involves substances like DNA, siRNA, miRNA and antisense oligonucleotides, which can be effectively delivered for altering the expression of the genes responsible for cancer treatmnt [81]. However, gene therapy

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possesses major challenge with respect to the effective penetration of the genes into the intracellular sites. This requires the help of smart delivery solutions for needful transfection into

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the cellular nucleus. It is often highly challenging to deliver the genes due to the surface negative charge on them, which causes obstacle during the nuclear transfection process [82]. Although

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several lipidic and polymeric nanocarrier systems have proven ability for gene targeting, yet the problem lies with getting satisfactory cellular immunization with the targeted genes. MSNPs

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have recently gained attention due to their ability to high gene payload carrying capacity along with good biocompatibility, large surface area, and tunable pore size over other nanocarriers, thus greatly helps in establishing a nucleic acid-guided platform for therapeutic management of

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the diseases [83-86]. Some of the instances include MSNPs-based siRNA delivery guided by VEGF ligand by adopting capping with the help of polyethylenimine moieties, along with

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PEGylation and fusogenic peptide KALA modification demonstrated significant improvement in the transfection efficiency for reducing the lung cancer metastasis [87]. In another study, MSNPs functionalized

with

cyclodextrin-grafted

polyethylenimine

system

revealed

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transfection efficiency ostensibly owing to the presence of positive charge imparted by the MSNPs for effective loading of negatively charged siRNA through potential electrostatic

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interactions, which helps in effective endosomal escape of siRNA [88]. Moreover, recent investigations have showed that MSNPs-base gene therapy can be combined with the chemotherapy for co-administration in order to overcome drug resistance and exploring potential therapeutic benefits for the treatment of many complicated diseases. In a study, the researchers have explored a unique type of MSNPs containing a core-shell hierarchical mesoporous structure of organosilicate system. The developed nanoporous carrier yielded effective inhibition of Pglycoprotein efflux for maximizing the cellular and nuclear localization of the siRNA and doxorubicin by avoiding drug substances. Such siRNA-loaded MSNPs also revealed targeted 11

knocked down of the drug resistance genes and attaining better sensitivity of the drug resistance cancer cells to the DOX [89]. 3.4 Photodynamic therapy Application of MSNPs for photodynamic therapy used for cancer treatment has been lately explored. MSNPs can be very useful for designing the nanocarriers-based photothermal therapy (PTT), photodynamic therapy (PDT) or their combination, as a means of designing a rational treatment system for killing the cancer cells. Use in combination, PDT has the mechanism to

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damage the cancer cells with the aid of photosensitizers to generate the reactive oxygen species (ROS) or singlet oxygen species (1O2) for cytotoxicity on the cancer cells, while PTT helps in

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killing the cancer cells for inducing the hyperthermia by the application of light radiations for photothermal excitations [90]. Although reports on the usage of a range of nanomaterials for

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PDT/PTT are available, yet achieving compliance in this regard is a questionable as of now. Recently, the strategy adopted utilizes multifunctional MSNPs-based systems containing

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GdOF:Ln@SiO2 agents for effective use in PDT for applications in achieving cytotoxicity of the cancer cells [91].

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4. Biocompatibility, biodegradability, toxicity and safety of MSNPs Unlike the lipidic and polymeric nanoparticulate systems, MSNPs posses some of the questionable properties with respect to biocompatibility and biodegradability. For any

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nanomaterial to be useful for biomedical applications, it must qualify regulatory requirements with respect to its biosafety without any toxicity. In this context, adequate data generated on in vivo toxicity evaluation of the nanomaterials in animal and human models is required. The studies particularly evaluating the biological fate of the MSNPs for understanding the pharmacokinetic and biodistribution profiles has to be planned. The criticality with respect to the

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size, shape, porosity, surface area and charge and chemical functionality has direct link with the toxicity and clearance of the MSNPs [92]. Two researchers, Lin and Haynes studied the effect of varying particle size of the MSNPs ranging between 25 to 225 nm through hemolysis assay on the red blood cells (RBCs), which showed higher percent hemolysis observed at smaller particle size of the MSNPs vis-à-vis the particle with larger size ostensibly owing to the higher surface area [93]. In another study, Huang and coworkers documented a study on biological clearance of the rod-shaped MSNPs, where MSNPs with smaller particle size showed rapid clearance time 12

from the body through urine and faeces in comparison to the ones with larger particle size [8]. The toxicity evaluation of the tetramethyl orthosilicate-based MSNPs was lately investigated on MDA-MB-231 breast cancer cells, which construed insignificant effect of the said nanocarrier on proliferation of the cells and thus confirmed its biocompatibility properties [94]. Also, the literature reports on toxicity evaluation of the MSU-2 and MCM-41 MSNPs indicated their biocompatibility on a noncancerous CHO cell line model [95]. Of late, another research study confirmed the presence of silanol groups on the surface of MSNPs can further induce progressive

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damage to the cellular lipids and/or proteins, thus possesses questionable safety and biocompatibility characteristics [94]. Some researchers have also evaluated the toxicological profiles of the bare/native MSNPs on animal models and observed high sensitivity on

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reticuloendothelial systems, thus making them unfavorable for intravenous administration by coupling with the drug molecules [96]. Further, the toxicity reduction has been attempted

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through conjugation of the MSNPs with lipid matrices, which have ultimately shown a considerable reduction in the toxicity on MCF-7 cells vis-à-vis the noncoated MSNPs after 48 h

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incubation period. The hemolysis study also indicated relatively safe nature of the lipid-coated MSNPs over the uncoated ones [97]. Also, conjugation of cyclodextrin and folate-based moieties

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with tetraethylorthosilicate MSNPs yielded good biocompatible property as well as reduced toxicity on the mice model [98]. The conjugation of MSNPs with poly(N-isopropylacrylamide)co-acrylic acid hydrogel has also shown significant improvement in the biocompatibility [99].

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The idea of grafting PEG on the surface of MSNPs has also been shown to reduce cytotoxicity and hemolytic activity as compared to the non-modified MSNPs ostensibly owing to the shielding of negatively charged silanol groups. Moreover, higher hemolytic activity and cytotoxic effect was observed with MSNPs coated with PEG with higher molecular weight on the MCF-7 [100]. The studies performed on amine-functionalized and carboxymethyl cellulose

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coated MSNPs have also construed negligible toxicity in MDA- MB-231 cell line model [101]. Another research study on calcium hydroxyapatite embedded onto the MSNPs yielded good biodegradable property as compared to the native MSNPs [102]. Very recently, the literature studies on the development of organic-inorganic hybrid silica nanosystem (HMONs) coated with PEG indicated significantly enhanced biodegradability and biocompatibility property. The in vivo cytotoxicity evaluation of the developed HMONs also revealed no remarkable pathophysiological changes in the major organs (heart, liver, spleen, lung and kidney), which 13

also confirmed in vivo biocompatibility of the PEG-conjugated HMONs [Figure 5(A–C)] [103]. Likewise, a considerable amount of efforts have been made by Goel et al. in synthesizing the core-satellite hybrid mesoporous silica nanoshells with good biocompatibility and reduced toxicity characteristics [104]. Apart from the biocompatibility and biodegradability, another feature that should be critically assessed prior to clinical/market development is the actual relationship between the in vitro and in vivo studies. Therefore, more efforts should be made towards the translation of nanocarriers

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design and in vitro laboratory results into the needed biodistribution studies, suitable in vivo investigations and clinical product development, closer to patient needs. Furthermore,

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understanding the relationships between the properties of the delivered nano-encapsulated drugs (e.g., structure, solubility, and diffusivity/mobility) and pharmacokinetic behavior for the safe

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and efficient use is highly important for drug delivery applications. In this regard, comprehensive toxicology studies must be conducted with the different nanomaterials and possible safety guidelines formulated. In this perspective, joint interdisciplinary efforts can enable the

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production of new generations of smart therapeutic systems, based on true vectorized nanocarriers. Regrettably, the lack of the consistent and internationally unified/accepted in vitro

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and/or in vivo testing methodologies has limited rapid and global progress in the use of MSNPs towards the advanced nanomedicinal drug therapy.

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4. Conclusions and future perspectives

The utility of MSNPs have gained tremendous importance in the last one decade, thus leading to the generation of many effective therapeutically active treatment solutions. Much exploration has been taken place for evaluating the material properties of MSNPs for their suitability in drug delivery as well as biomedical applications. With the availability of the highly mesoporous

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structure providing ability for loading of cargos into its structure along with chemical functionalization on its. A wide range of therapeutic carriers including anticancer drugs, biologicals, diagnostic agents have been satisfactory delivered to the cancer cells for effective therapeutic action. At length, MSNPs have shown advantages of achieving improvement in the solubility by faster dissolution rate of the drugs along with excellent ability for augmenting the systemic availability and stability under in vivo environment. A score of literature reports have been published till date exclusively for cancer treatment application. Despite promising 14

advantages of MSNPs as the multimodal treatment modalities for cancer management, the realtime achievement lies with meaningful clinical application to provide patients benefit. Thus, adequate clinical evidences on the biocompatibility and safety of the MSNPs as per the regulatory requirements proposed by US Food and Drug Administration are the need of the hour. Finally, our efforts should focus not only on the laboratory synthesis/functionalization but also on the further improvement of the targeting ability of MSN nanocarriers for cancer treatment. Evidently, there is plenty of work ahead for the scientific community in order to successfully

and therapeutic methods, and eventually marketable healthcare products.

The author(s) declared no potential conflicts of interest.

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References: References:

Rosenholm JM, Mamaeva V, Sahlgren C, Lindén M. Nanoparticles in targeted cancer

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Declaration of conflicting interests

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translate this new family of drug delivery systems from laboratory research into practical clinical

therapy: mesoporous silica nanoparticles entering preclinical development stage.

2.

lP

Nanomedicine (Lond) 2012;7(1):111-20.

Llinàs M C, Martínez-Edo G, Cascante A, Porcar I, Borrós S, Sánchez-García D. Preparation of a mesoporous silica-based nano-vehicle for dual DOX/CPT pH-triggered

3.

ur na

delivery. Drug delivery 2018;25(1):1137–1146. Li Z, Barnes JC, Bosoy A, Stoddart JF, Zink JI. Mesoporous silica nanoparticles in biomedical applications. ChemSoc Rev 2012; 41(7): 2590-605. 4.

Aneja P, Rahman M, Beg S, Aneja S, Dhingra V, Chugh S. Cancer targeted magic bullets for effective treatment of cancer. Recent Pat Antiinfect Drug Discov 2014; 9:121-135. Rahman M, Ahmad MZ, Kazmi I, Akhter S, Afzal M, Gupta G, et al. Emergence of

Jo

5.

nanomedicine as cancer targeted magic bullets: Recent development and need to address the toxicity apprehension. Curr Drug DiscovTechnol 2012;9(4):319-329.

6.

Aneja P, Rahman M, Beg S, Aneja S, Dhingra V, Chugh R. Cancer targeted magic bullets for effective treatment of cancer. Recent Pat Antiinfect Drug Discov (2014);9(2):121-135.

15

7.

Li T, Shi S, Goel S, Shen X, Xie X, Chen Z, et al. Recent advancements in mesoporous silica nanoparticles towards therapeutic applications for cancer. ActaBiomater 2019; 15;89:1-13.

8.

Huang X, Li L, Liu T, Hao N, Liu H, Chen D, et al. The shape effect of mesoporous silica nanoparticles on biodistribution, clearance, and biocompatibility in vivo. ACS Nano 2011;5(7):5390-9.

9.

Shi SX, Chen F, Goel SY, Graves SA, Luo HM, Theuer CP, et al. In vivo tumor-targeted

of

dual-modality PET/optical imaging with a yolk/shell-structured silica nanosystem. NanoMicro Lett 2018:10(4);65. 10.

Chen F, Ma K, Benezra M, Zhang L, Cheal SM, Phillips E, et al. Cancer-targeting

ro

ultrasmall silica nanoparticles for clinical translation: physicochemical structure and biological property correlations, Chem. Mater2017;29(20):8766–8779.

M. Benezra,Penate-Medina O, Zanzonico PB, Schaer D, Ow H, Burns A, et al. Multimodal

-p

11.

Clin Invest2011;121(7):2768–2780. 12.

re

silica nanoparticles are effective cancer-targeted probes in a model of human melanoma, J

Mamaeva V, Sahlgren C, Lindén M. Mesoporous silica nanoparticles in medicine--recent

13.

lP

advances. Adv Drug Deliv Rev 2013;65(5):689-702.

deSmet M, Heijman E, Langereis S, Hijnen NM, Grüll H. Magnetic resonance imaging of high intensity focused ultrasound mediated drug delivery from temperature-sensitive

14.

ur na

liposomes: an in vivo proof-of-concept study. J Control Release 2011;150(1):102-10. Vallet-Regí M,Rámila A,del Real RP, Pérez-Pariente J. A new property of MCM-41: Drug delivery system. Chem Mater 2001;13:308–311. 15.

Huo Q,Margolese DI,Stucky GD. Stucky Surfactant Control of Phases in the Synthesis of Mesoporous Silica-Based Materials. Chem Mater 1996; 8: 1147–1160. Beck JS, Vartuli JC,RothWJ, Leonowicz ME, Kresge CT, Schmitt KD, et al. A new family

Jo

16.

of mesoporous molecular sieves prepared with liquid crystal templates. J Am ChemSoc 1992;114: 10834–10843.

17.

Trewyn BG, Slowing II,Giri S, Chen HT, Lin VSY. Synthesis and Functionalization of a Mesoporous Silica Nanoparticle Based on the Sol–Gel Process and Applications in Controlled Release. AccChem Res 2007; 40:846–853.

16

18.

Narayan R, Nayak UY, Raichur AM, Garg S. Mesoporous Silica Nanoparticles: A Comprehensive

Review

on

Synthesis

and

Recent

Advances.

Pharmaceutics.

2018;10(3):118. 19.

Zhao D,Huo Q, Feng J, Chmelka BF,Stucky GD. Nonionic Triblock and Star Diblock Copolymer and Oligomeric Surfactant Syntheses of Highly Ordered, Hydrothermally Stable, Mesoporous Silica Structures. J Am ChemSoc 1998; 120: 6024–6036.

20.

Tozuka Y, Wongmekiat A, Kimura K,Moribe K, Yamamura S, Yamamoto K. Effect of

of

Pore Size of FSM-16 on the Entrapment of Flurbiprofen in Mesoporous Structures. Chem Pharm Bull 2005; 53: 974–977. 21.

Argyo C, Weiss V, Brauchle C, Bein T. Multifunctional Mesoporous Silica Nanoparticles

22.

ro

as a Universal Platform for Drug Delivery. Chem Mater 2014; 26(1): 435-451.

Wu SH, Mou CY, Lin HP. Synthesis of mesoporous silica nanoparticles. ChemSoc Rev

23.

-p

2013;42(9):3862-75.

Yu-Shen Lin, Katie R, Hurley Christy L, Haynes. Critical Considerations in the Biomedical

24.

re

Use of Mesoporous Silica Nanoparticles. J PhysChemLett2012; 3(3): 364-374. Vivero-Escoto JL, Slowing II, Trewyn BG, Lin VS. Mesoporous silica nanoparticles for

25.

lP

intracellular controlled drug delivery. Small 2010;6(18):1952-67. Tang F1, Li L, Chen D. Mesoporous silica nanoparticles: synthesis, biocompatibility and drug delivery. Adv Mater 2012;24(12):1504-34. Hoffmann F, Cornelius M, Morell J, Fröba M. Silica-based mesoporous organic-inorganic

ur na

26.

hybrid materials. AngewChemInt Ed Engl 2006;45(20):3216-51. 27.

Zhao D, Feng J, Huo Q, Melosh N, Fredrickson GH, Chmelka BF, et al.Triblock copolymer syntheses of mesoporous silica with periodic 50 to 300 angstrom pores. Science1998;279(5350):548-52.

Vartuli JC, Schmitt KD,Kresge CT, Roth WJ,Leonowicz ME,McCullen SB, et al. Effect of

Jo

28.

Surfactant/Silica Molar Ratios on the Formation of Mesoporous Molecular Sieves: Inorganic Mimicry of Surfactant Liquid-Crystal Phases and Mechanistic Implications. Chem Mater 1994; 6 (12): 2317.

29.

Tanev PT,Pinnavaia TJ. A neutral templating route to mesoporous molecular sieves. Science 1995; 267(5199): 865.

17

30.

Chithrani BD,Ghazani AA, Chan WCW. Determining the size and shape dependence of gold nanoparticle uptake into mammalian cells. Nano Lett 2006; 6(4): 662-8.

31.

Fowler CE, Khushalani D, Lebeau B, Mann S. Nanoscale Materials with Mesostructured Interiors. Adv Mater 2001; 13: 649.

32.

Ma K, Werner-Zwanziger U,Zwanziger J,Wiesner U. Controlling Growth of Ultrasmall Sub-10 nm Fluorescent MesoporousSilica Nanoparticles. Chem Mater 2013; 25(5): 677.

33.

Kim MH, Na HK, Kim YK,Ryoo SR, Cho HS, Lee KE, et al. Facile synthesis of

of

monodispersedmesoporous silica nanoparticles with ultralarge pores and their application in gene delivery. ACS Nano 2011; 5(5): 3568. 34.

Zhang K,Xu LL, Jiang JG, Calin N, Lam KF, Zhang SJ, et al. Facile large-scale synthesis

ro

of monodispersemesoporous silica nanospheres with tunable pore structure. J Am ChemSoc 2013; 135(7): 2427.

Stein A,Melde BJ, Schroden RC. Hybrid Inorganic–Organic Mesoporous Silicates—

-p

35.

Nanoscopic Reactors Coming of Age. Adv Mater 2000; 12: 1403. Ford DM,Simanek EE, Shantz DF. Engineering nanospaces: ordered mesoporoussilicas as

re

36.

model substrates for building complex hybrid materials. Nanotechnology 2005;16(7):

37.

lP

S458.

Park C, Oh K, Lee SC, Kim C. Controlled release of guest molecules from mesoporous silica particles based on a pH-responsive polypseudorotaxane motif. AngewChemInt Ed

38.

ur na

Engl 2007;46(9):1455-7.

Lin YS, Tsai CP, Huang HY,Kuo CT, Hung Y, Huang DM, et al. Well-Ordered Mesoporous Silica Nanoparticles as Cell Markers. Chem Mater 2005; 17: 4570.

39.

Manzano M,Vallet-Regí M. New developments in ordered mesoporous materials for drug delivery. J Mater Chem 2010;20: 5593-5604. Cauda V,Schlossbauer A,Kecht J,Zürner A,Bein T. Multiple core-shell functionalized

Jo

40.

colloidal mesoporous silica nanoparticles. J Am ChemSoc 2009; 131: 11361.

41.

Kecht J, Schlossbauer A,Bein T. Selective Functionalization of the Outer and Inner Surfaces in Mesoporous Silica Nanoparticles Chem Mater 2008; 20: 7207.

42.

Li Z, Barnes JC, Bosoy A, Stoddart JF, Zink JI. Mesoporous silica nanoparticles in biomedical applications. ChemSoc Rev 2012; 41(7):2590–605.

18

43.

Schlossbauer A,Kecht J, Bein T. Biotin-avidin as a protease-responsive cap system for controlled guest release from colloidal mesoporous silica. AngewChemInt Ed 2009; 48(17):3092.

44.

Cauda V,Argyo C,Schlossbauer A,Bein T. Impact of different PEGylation patterns on the long-term bio-stability of colloidal mesoporous silica nanoparticles. J Mater Chem 2010; 20(21): 4305.

45.

Sauer AM,Schlossbauer A,Ruthardt N,Cauda V,Bein T,Brauchle C. Role of endosomal

of

escape for disulfide-based drug delivery from colloidal mesoporous silica evaluated by live-cell imaging. Nano Lett2010; 10(9): 3684. 46.

Giri S, Trewyn BG, Stellmaker MP, Lin VS. Stimuli-responsive controlled-release delivery

ro

system based on mesoporous silica nanorods capped with magnetic nanoparticles. AngewChemInt Ed Engl 2005;44(32):5038-44.

Chen LF, Wen YQ, Su B, Di JC, Song YL,Jiang L. Programmable DNA switch for

-p

47.

bioresponsive controlled release. J Mater Chem 2011; 21(36): 13811. Bernardos A, Mondragon L, Aznar E, Marcos MD, Martinez-Manez R, Sancenon F, et al.

re

48.

Enzyme-responsive intracellular controlled release using nanometric silica mesoporous

49.

lP

supports capped with "saccharides". ACS Nano 2010; 4(11): 6353. Cauda V, Engelke H, Sauer A,Arcizet D,Bräuchle C,Rädler J, et al. Colchicine-loaded lipid bilayer-coated 50 nm

mesoporous

nanoparticles efficiently induce microtubule

50.

ur na

depolymerization upon cell uptake. Nano Lett 2010; 10 (7):2484. Mackowiak SA, Schmidt A, Weiss V,Argyo C, von Schirnding C,Bein T, et al. Targeted drug delivery in cancer cells with red-light photoactivatedmesoporoussilica nanoparticles. Nano Lett2013; 13(6): 2576. 51.

Lu J, Choi E,Tamanoi F, Zink JI. Light-activated nanoimpeller-controlled drug release in

Jo

cancer cells. Small 2008; 4(4): 421.

52.

Ni D, Jiang D, Ehlerding EB, Huang P, Cai W. Radiolabeling silica-based nanoparticles via coordination chemistry: basic principles, strategies, and applications.AccChem Res 2018; 51(3): 778–788.

53.

Wang CE, Stayton PS, Pun SH, Convertine AJ. Polymer nanostructures synthesized by controlled living polymerization for tumor-targeted drug delivery. J Control Release 2015;219:345–354. 19

54.

Maeda H, Nakamura H, Fang J. The EPR effect for macromolecular drug delivery to solid tumors: improvement of tumor uptake, lowering of systemic toxicity, and distinct tumor imaging in vivo.Adv Drug DelivRev 2013;65(1):71-9.

55.

Zou Z, He X, He D, Wang K, Qing Z, Yang X, et al. Programmed packaging of mesoporous silica nanocarriers for matrix metalloprotease 2-triggered tumor targeting and release. Biomaterials 2015; 58: 35–45.

56.

Rao W, Wang H, Han J, Zhao S, Dumbleton J, Agarwal P, et al. Chitosan-decorated

of

doxorubicin-encapsulated nanoparticle targets and eliminates tumor reinitiating cancer stem-like cells. ACS Nano 2015;9(6): 5725–5740. 57.

Li T, Shen X, Geng Y, Chen Z, Li L, Li S, et al. Folate-functionalized magnetic-

ro

mesoporous silica nanoparticles for drug/gene codelivery to potentiate the antitumor efficacy. ACS Appl Mater Interfaces 2016;8(22):13748–13758.

Yang H, Li Y, Li T, Xu M, Chen Y, Wu C, et al. Multifunctional core/shell nanoparticles

-p

58.

cross-linked polyetherimide-folic acid as efficient Notch-1 siRNA carrier for targeted

59.

re

killing of breast cancer.Sci Rep 2014;4:7072.

Mekaru H, Lu J, Tamanoi F. Development of mesoporous silica-based nanoparticles with

60.

lP

controlled release capability for cancer therapy.Adv Drug Deliv Rev 2015;95:40-9. Goel S, Chen F, Hong H, Valdovinos HF, Hernandez R, Shi S, et al. VEGF₁₂₁-conjugated mesoporous silica nanoparticle: a tumor targeted drug delivery system. ACS Appl Mater

61.

ur na

Interfaces 2014;6(23):21677–21685.

Huo D, Liu S, Zhang C, He J, Zhou Z, Zhang H, Hu Y1. Hypoxia-targeting, tumor microenvironment responsive nanocluster bomb for radical-enhanced radiotherapy. ACS Nano 2017; 11(10):10159–10174.

62.

Li ZY, Hu JJ, Xu Q, ChenS, Jia HZ, Sun YX, et al. A redoxresponsive drug delivery

Jo

system based on RGD containing peptide-capped mesoporous silica nanoparticles. J Mater Chem B 2015;3(1): 39–44.

63.

Martínez-Carmona M, Lozano D, Colilla M, Vallet-Regí M.Lectin-conjugated pHresponsive mesoporous silica nanoparticles for targeted bone cancer treatment. ActaBiomater 2018; 65: 393–404.

64.

Cheng W, Liang C, Xu L, Liu G, Gao N, Tao W, et al. TPGS-functionalized polydopaminemodifiedmesoporous silica as drug nanocarriers for enhanced lung cancer 20

chemotherapy

against

multidrug

resistance.

Small

2017;

13(29):doi:

10.1002/smll.201700623. 65.

Cheng W, Nie J, Xu L, Liang C, Peng Y, Liu G, et al. pH-sensitive delivery vehicle based on folic acid-conjugated polydopamine-modified mesoporous silica nanoparticles for targeted cancer therapy. ACS Appl Mater Interfaces. 2017; 9(22):18462-18473.

66.

Chen Y, Ai K, Liu J, Sun G, Yin Q, Lu L. Multifunctional envelope-type mesoporous silica nanoparticles for pH-responsive drug delivery and magnetic resonance imaging.

67.

of

Biomaterials 2015; 60:111–120. Shan L, Zhuo X, Zhang F, Dai Y, Zhu G, Yung BC. A paclitaxel prodrug with bifunctionalfolate and albumin binding moieties for both passive and active targeted cancer

68.

ro

therapy.Theranostics 2018;8(7):2018-2030.

Jia L, Li Z, Shen J, Zheng D4, Tian X, Guo H, et al. Multifunctional mesoporous silica

resistance. Int J Pharm 2015;489(1-2):318-30.

Li F, Lu J, Liu J, Liang C, Wang M, Wang L, et al. A water-soluble

re

69.

-p

nanoparticles mediated co-delivery of paclitaxel and tetrandrine for overcoming multidrug

nucleolinaptamerpaclitaxel conjugate for tumor-specific targeting in ovarian cancer, Nat

70.

lP

Commun 2017;8(1):1390.

Jia L1, Shen J, Li Z, Zhang D, Zhang Q, Duan C, et al. Successfully tailoring the pore size of mesoporous silica nanoparticles: exploitation of delivery systems for poorly water-

71.

ur na

soluble drugs Int J Pharm 2012;439 (1–2): 81–91. Fu Q, Hargrove D, Lu X. Improving paclitaxel pharmacokinetics by using tumor-specific mesoporous

silica

nanoparticles

with

intraperitoneal

delivery.

Nanomedicine

2016;12(7):1951-1959. 72.

Liu C, Zheng J, Deng L, Ma C, Li J, Li Y, et al. Targeted intracellular controlled drug

Jo

delivery and tumor therapy through in situ forming Ag nanogates on mesoporous silica nanocontainers. ACS Appl Mater Interfaces 2015;7(22):11930-8.

73.

Meng H, Wang M, Liu H, Liu X, Situ A, Wu B, et al. Use of a lipid-coated mesoporous silica nanoparticle platform for synergistic gemcitabine and paclitaxel delivery to human pancreatic cancer in mice. ACS Nano 2015;9(4):3540-57.

21

74.

Alvarez-Berríos MP, Vivero-Escoto JL. In vitro evaluation of folic acidconjugated redoxresponsive mesoporous silica nanoparticles for the delivery of cisplatin. Int J Nanomedicine 2016;11:6251-6265.

75.

Zhang W1,2, Shen J3, Su H1, Mu G1, Sun JH1, Tan CP, et al. Co-delivery of cisplatin prodrug and chlorin e6 by mesoporous silica nanoparticles for chemo-photodynamic combination therapy to combat drug resistance. ACS Appl Mater Interfaces 2016;8(21):13332-40. van Rijt SH, Bölükbas DA, Argyo C, Datz S, Lindner M, Eickelberg O, et al. Protease-

of

76.

mediated release of chemotherapeutics from mesoporous silica nanoparticles to ex vivo human and mouse lung tumors. ACS Nano 2015;9(3):2377-89.

Li T, Shen X, Xie X, Chen Z, Li S, Qin X, et al. Irinotecan/IR-820 coloadednanocomposite

ro

77.

as a cooperative nanoplatform for combinational therapy of tumor. Nanomedicine (Lond)

78.

-p

2018;13(6):595-603.

Pan G, Jia TT, Huang QX, Qiu YY, Xu J, Yin PH, et al. Mesoporous silica nanoparticles

re

(MSNPs)-based organic/inorganic hybrid nanocarriers loading 5-Fluorouracil for the treatment of colon cancer with improved anticancer efficacy. Colloids Surf B Biointerfaces

79.

lP

2017;159:375-385.

Kumar B, Kulanthaivel S, Mondal A, Mishra S, Banerjee B, Bhaumik A, et al. Mesoporous silica nanoparticle based enzyme responsive system for colon specific drug delivery

80.

ur na

through guar gum capping. Colloids Surf B Biointerfaces 2017;150:352-361. Bertucci A, Prasetyanto EA, Septiadi D, Manicardi A, Brognara E, Gambari R, et al. Combined delivery of temozolomide and anti-miR221 PNA using mesoporous silica nanoparticles induces apoptosis in resistant glioma cells. Small 2015;11(42):5687–5695. 81.

Juliano RL. The delivery of therapeutic oligonucleotides. Nucleic Acids Res

Jo

2016;44(14):6518–6548.

82.

Cha W, Fan R, Miao Y, Zhou Y, Qin C, Shan X, et al. Mesoporous silica nanoparticles as carriers for intracellular delivery of nucleic acids and subsequent therapeutic applications. Molecules 2017;22(5): pii: E782.

83.

Wang Z, Chang Z, Lu M, Shao D, Yue J, Yang D, et al. Shape-controlled magnetic mesoporous silica nanoparticles for magnetically-mediated suicide gene therapy of hepatocellular carcinoma. Biomaterials 2018;154:147–157. 22

84.

Li X, Chen Y, Wang M, Ma Y, Xia W, Gu H. A mesoporous silica nanoparticle – PEI – Fusogenic peptide system for siRNA delivery in cancer therapy. Biomaterials 2013;34(4):1391–1401.

85.

Chen LJ, She XD, Wang T, Shigdar S, Duan W, Kong LX. Mesoporous silica nanorods toward efficient loading and intracellular delivery of siRNA. J Nanopart Res 2018;20:37.

86.

Zhao S, Xu MM, Cao CW, Yu QQ, Zhou YH, Liu J, A redox-responsive strategy using mesoporous silica nanoparticles for co-delivery of siRNA and doxorubicin. J Mater Chem

87.

of

B 2017;5(33):6908–6919. Chen Y, Gu H, Zhang DS, Li, Liu T, Xia W. Highly effective inhibition of lung cancer

based nanocarrier. Biomaterials 2014;35(38):10058-69. 88.

ro

growth and metastasis by systemic delivery of siRNA via multimodal mesoporous silica-

Shen J, Kim HC, Su H, Wang F, Wolfram J, Kirui D, et al. Cyclodextrin and

-p

polyethylenimine functionalized mesoporous silica nanoparticles for delivery of siRNA cancer therapeutics. Theranostics 2014;4(5):487-97.

Sun L, Wang D, Chen Y, Wang L, Huang P, Li Y, et al. Coreshell hierarchical

re

89.

mesostructured silica nanoparticles for gene/chemosynergetic stepwise therapy of

90.

lP

multidrug-resistant cancer. Biomaterials 2017;133:219-228. Liu X, Su H, Shi W, Liu Y, Sun Y, Ge D. Functionalized poly(pyrrole-3-carboxylic acid) nanoneedles for dual-imaging guided PDT/PTT combination therapy. Biomaterials

91.

ur na

2018;167:177-190.

Lv R, Yang P, He F, Gai S, Li C, Dai Y, et al. A yolk-like multifunctional platform for multimodal imaging and synergistic therapy triggered by a single near-infrared light. ACS Nano 2015;9(2):1630-47.

92.

Asefa T, Tao Z. Biocompatibility of mesoporous silica nanoparticles. Chem Res Toxicol

Jo

2012; 25(11): 2265–2284.

93.

Lin YS, Haynes CL. Impacts of mesoporous silica nanoparticle size, pore ordering, and pore integrity on hemolytic activity. J Am Chem Soc 2010;132: 4834–4842.

94.

Poonia N, Lather V, Pandita D. Mesoporous silica nanoparticles: a smart nanosystem for management of breast cancer. Drug Discov Today 2018;23(2):315-332.

23

95.

Bollu VS, Barui AK, Mondal SK, Prashar S, Fajardo M, Briones D, et al. Curcumin-loaded silica-based mesoporous materials: synthesis, characterization and cytotoxic properties against cancer cells. Mater Sci Eng C Mater Biol Appl 2016;63:393–410.

96.

Wang LS, Wu LC, Lu SY, Chang LL, Teng IT, Yang CM, et al. Biofunctionalized phospholipid-capped mesoporous silica nanoshuttles for targeted drug delivery: improved water

suspensibility

and

decreased

nonspecific

protein

binding.

ACS

Nano

2010;4(8):4371–4379. Han N, Wang Y, Bai J, Liu J, Wang Y, Gao Y, et al. Facile synthesis of the lipid bilayer

of

97.

coated mesoporous silica nanocomposites and their application in drug delivery. Microporous Mesoporous Mater 2016;219:209–218.

Zhang Q, Wang X, PZ LI, Nguyen KT, Wang XJ, Luo Z, et al. Biocompatible, uniform,

ro

98.

Adv Funct Mater 2014;24(17):2450–2461. 99.

-p

and redispersiblemesoporous silica nanoparticles for cancer-targeted drug delivery in vivo.

Hu X, Hao X, Wu Y, Zhang J, Zhang X, Wang PC, et al. Multifunctional hybrid silica

re

nanoparticles for controlled doxorubicin loading and release with thermal and pH dual response. J Mater Chem B 2013;1(8):1109-1118.

lP

100. Wang Y, Han N, Zhao Q, Bai L, Li J, Jiang T, et al. Redox-responsive mesoporous silica as carriers for controlled drug delivery: a comparative study based on silica and PEG gatekeepers. Eur J Pharm Sci 2015;72:12-20.

ur na

101. Tiwari N, Nawale L, Sarkar D, Badiger MV. Carboxymethyl Cellulose-Grafted Mesoporous Silica Hybrid Nanogels for Enhanced Cellular Uptake and Release of Curcumin. Gels 2017;3(1):8.

102. Hao X, Hu X, Zhang C, Chen S, Li Z, Yang X, et al. Hybrid mesoporous silica-based drug carrier nanostructures with improved degradability by hydroxyapatite. ACS Nano

Jo

2015;9(10):9614-25.

103. Huang P, Chen Y, Lin H, Yu L, Zhang L, Wang L, Molecularly organic/inorganic hybrid hollow mesoporousorganosilicananocapsules with tumor-specific biodegradability and enhanced chemotherapeutic functionality. Biomaterials 2017;125:23-37. 104. Goel S, Ferreira CA, Chen F, Ellison PA, Siamof CM, Barnhart TE, et al. Activatable hybrid

nanotheranostics

for

tetramodal

24

imaging

and

synergistic

photothermal/photodynamic

therapy.

Adv

Mater

2018;30(6).

doi:

10.1002/adma.201704367. 105. Yu Z, Zhou P, Pan W, Li N, Tang B. A biomimetic nanoreactor for synergistic chemiexcited photodynamic therapy and starvation therapy against tumor metastasis. Nat Commun 2018;9(1):5044. 106. Tham HP, Xu K, Lim WQ, Chen H, Zheng M, Thng TGS, et al. Microneedle-assisted topical delivery of photodynamically active mesoporous formulation for combination

of

therapy of deep-seated melanoma. ACS Nano 2018;12(12):11936-11948. 107. Wu M, Zhang H, Tie C, Yan C, Deng Z, Wan Q, et al. MR imaging tracking of inflammation-activatable engineered neutrophils for targeted therapy of surgically treated

ro

glioma. Nat Commun 2018; 9: 4777.

108. Wei Q, Chen Y, Ma X, Ji J, Qiao Y, Zhou B, et al. High-efficient clearable nanoparticles

-p

for multi-modal imaging and image-guided cancer therapy. Adv Funct Mater 2018;28(2): 1704634

re

109. Ding B, Shao S, Yu C, Teng B, Wang M, Cheng Z, et al. Large-pore mesoporous-silicacoated upconversion nanoparticles as multifunctional immunoadjuvants with ultrahigh

lP

photosensitizer and antigen loading efficiency for improved cancer photodynamic immunotherapy. Adv Mater 2018;30(52):e1802479. 110. Shao D, Li M, Wang Z, Zheng X, Lao YH, Chang Z, et al. Bioinspired diselenide-bridged

ur na

mesoporous silica nanoparticles for dual-responsive protein delivery. Adv Mater 2018; e1801198: doi: 10.1002/adma.201801198. 111. Kang MS, Singh RK, Kim TH, Kim JH, Patel KD, Kim HW. Optical imaging and anticancer chemotherapy through carbon dot created hollow mesoporous silica nanoparticles. Acta Biomater 2017;55:466-480.

Jo

112. Choi JY, Ramasamy T, Kim SY, Kim J, Ku SK, Youn YS, et al. PEGylated lipid bilayersupported mesoporous silica nanoparticle composite for synergistic co-delivery of axitinib and celastrol in multi-targeted cancer therapy. Acta Biomater 2016;39:94-105.

113. Duo Y, Yang M, Du Z, Feng C, Xing C, Wu Y, et al. CX-5461-loaded nucleolus-targeting nanoplatform for cancer therapy through induction of pro-death autophagy. Acta Biomater 2018;79:317-330.

25

114. Sun L, Wang D, Chen Y, Wang L, Huang P4, Li Y, et al. Coreshell hierarchical mesostructured silica nanoparticles for gene/chemosynergetic stepwise therapy of multidrug-resistant cancer. Biomaterials 2017;133:219-228. 115. Lu Y, Yang Y, Gu Z, Zhang J, Song H, Xiang G, et al. Glutathione depletion mesoporous organosilica nanoparticles as a self-adjuvant and codelivery platform for enhanced cancer immunotherapy. Biomaterials 2018;175:82-92. 116. Liu J, Liang H, Li M, Luo Z, Zhang J, Guo X, et al. Tumor acidity activating

photothermaltumor therapy. Biomaterials 2018;157:107-124.

of

multifunctional nanoplatform for NIR-mediated multiple enhanced photodynamic and

117. Li X, Xing L, Hu Y, Xiong Z, Wang R, Xu X, et al. An RGDmodified hollow silica@Au

ro

core/shell nanoplatform for tumor combination therapy. ActaBiomater 2017;62: 273–283. 118. Sun Q, You Q, Wang J, Liu L, Wang Y, Song Y, et al. Theranosticnanoplatform: triple-

-p

modal imaging-guided synergistic cancer therapy based on liposome-conjugated mesoporous silica nanoparticles. ACS Appl Mater Interfaces 2018;10(2):1963-1975.

re

119. Mu S, Liu Y, Wang T, Zhang J, Jiang D, Yu X, et al. Unsaturated nitrogen-rich polymer poly(L-histidine) gated reversibly switchable mesoporous silica nanoparticles using ‘‘graft

Jo

ur na

lP

to” strategy for drug controlled release. Acta Biomater 2017;63:150-162.

26

Figure Captions

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Figure 1: Overview of the classification, functional abilities, applications and biological fate of the MSNPs in drug delivery research

ur na

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Figure 2: Schematic classification of the MSNPs along with their structural view and dimensions

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Figure 3: Modification of the MSNPs via gating, surface coating and internal pore modification mechanisms

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Figure 4: Functionalization strategy used in the preparation of HMONs-PEG based MSNPs and their characterization (modified with permission from Li et al. 2019 [7])

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Figure 5: siRNA delivery using MSNPs for treatment against cancer treatment along with their characterization (modified with permission from Li et al. 2019 [7])

28

of

Table 1: Summary of recent applications of silica based nanoparticles as a cancer therapy Treatment Route of model administration Glucose oxidase i.v. B16-F10 i.v. (GOx),Ce6,CPPO, (metastatic) PFC Dabrafenib, Sub-q A375 Microneedle Trametinib, cells patches assisted Phthalocyanine

DOX

re

-p

ro

Payloads

lP

Surface chemistry –NH2 Cancer cell membrane coating Mesoporousorgano PEG, -silica Phthalocyanine nanoparticles conjugated with four silicate units (Pc-Si) Magnetic MSNPs Neutrophils carrying

ur na

Silica particles framework HMSNPs

Intracranially i.v. injection U87Luc or C6-Luc

Sub-6 nm DOX CuSnanodots coating

Large-pore mesoporous-silicacoated upconversion nanoparticles (UCMSs) Diselenide-bridge MSNPs

Chicken Merocyanine 540 Sub-q ovalbumin (MC540) cells loading Tumor cell fragment (TF) loading

Jo

MSNPs

Mesoporous

Cancer membrane coating –NH2

cell Cytotoxic ribonuclease (RNasNe A) DOX

Sub-q MDA- i.v. MB-231 cells HepG2 cells CT26 subcutaneously immunized injection

Sub-q A cells

Hela i.v

Sub-q

Intratumor 29

Applications

References

Improvement of PDT and starvation therapy against tumor metastasis Enhanced the antitumor effect through combinational PDT and target therapy

[105]

Release neutrophil extracellular traps in the inflammatory region. Precise diagnosis and high antigliomaefficacy PET imaging Photoacoustic imaging Synergetic chemophotothermal therapy Promotion of CD4+, CD8+, and effectormemory T cells.Inhibition of tumor growth

[107]

Homologous targeting and immune-invasion characteristics In vivo imaging

[110]

[106]

[108]

[109]

[111]

injection

lipid Axitinib Celastrol

Sub-q SCC7 cells

i.v.

MSNPs

PEG/Polydopami CX-5461 ne (PDA), AS-1411 aptamer enveloping

Sub-q HeLa cells

Hierarchical mesoporous silica/ organosilica nanoparticles Dendritic mesoporousorgano silica nanoparticles

Polyethyleneimin e (PEI) coating

ro i.v.

Orthotopically implanted MCF-7/ADR tumor model Sub-q B16-OVA cells

Intratumor injection

Mesoporous silica Decorated with b- ICG coated gold cyclodextrin nanorod Peptide RLA ([RLARLAR]2) Polymer CS(DMA)-PEG HMSNPs Au nanostar, DOX RGD coating

Sub-q MCF-7 cells

i.v.

Sub-q U87MG cells

Intratumor injection

Gd-doped MSNPs

Sub-q

i.v.

lP

DOX P-gpsiRNA

-p

PEGylated bilayer coating

Jo

ur na

Large dendritic Ovalbumin mesopores CpG containing PEI coating oligodeoxynucleoti des

ICG-loaded

DOX

30

Inhibition growth

of

tumor

of

MCF-7 cells

re

hollow organosilica nanoparticles MSNPs

subcutaneous injection

Inhibition of angiogenesis and mitochondrial function Enhancement of the antitumor efficacy Inhibition of AKT/mTOR/AMPK pathway Inducing a pro-death autophagy Reversing the MDR of cancer cells Promotion of chemotherapy Facilitating cytotoxic T lymphocyte (CTL) proliferation. Reducing tumour growth Combination therapy of PDT and PTT Extension of tumor bearing mice survival time

[112]

Combination of chemotherapy and PTT target a a vb3 integrin NIRF, PA, and MR

[117]

[113]

[114]

[115]

[116]

[118]

4T1 cells

triple-modal imaging Combination of chemotherapy, PDT and PTT pH-controlled drug release Enhancement of cancer treatment

ro

of

thermosensitive liposomes (ICGTSLs) coating

Poly(L-histidine) sorafenib Sub-q i.v. [119] (PLH) H22 cells and poly(ethylene glycol) (PEG) coating Abbreviations: HMSNPs – Hybrid mesoporous silica nanoparticles; MSNPs - mesoporous silica nanoparticles; PEG - Polyethylene glycol; DOX – Doxorubicin; RGD - Arg-Gly-Asp;

Jo

ur na

lP

re

-p

MSNPs

31