Int J App Pharm, Vol 16, Issue 5, 2024, 31-37Review Article

DIAGNOSTIC AND THERAPEUTIC ROLE OF MESOPOROUS SILICA NANOPARTICLES IN COMBATING CANCER

NUPUR KATARIYA1, ARVIND SINGH FARSWAN2*, NIDHI NAINWAL1*, GANESH KUMAR2

1Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Premnagar, Dehradun-248007, Uttarakhand, India. 2Himalayan School of Pharmaceutical Sciences, Swami Ram Himalayan University, Jolly Grant, Dehradun-248016, Uttarakhand, India
*Corresponding author: Arvind Singh Farswan; Email: nidhi.nainwal87@gmail.com

Received: 30 May 2024, Revised and Accepted: 19 Jul 2024

ABSTRACT

Cancer is a global health problem of human beings that is growing day by day despite several advancements in the medical field. The main concern of cancer treatment is the timely and proper diagnosis of this disease and the targeting of therapeutic moieties to the cancer site. Nanotechnology has emerged as a boon for the healthcare system in treating various life-threatening diseases. Mesoporous Silica Nanoparticles (MSNs), have drawn interest in the diagnosis and treatment of cancers and various other diseases. MSNs can be easily adjusted to specifically target cancer cells, improve drug targeting and minimize the undesirable effects. In the imaging and diagnosis of cancer, MSNs can be altered with imaging agents or used as contrast agents in imaging techniques like Magnetic Resonance Imaging (MRI) and Computed Tomography (CT). MSNs can be used to deliver different types of therapeutic molecules alone or in combinations to provide a synergistic effect in eradicating cancer. The current review focused on highlighting the role of MSNs in combating cancer. In addition, the biodegradation, clearance and toxicity profile of MSNs is explained to evaluate their suitability for clinical applications.

Keywords: Mesoporous silica nanoparticles, Cancer, Applications, Therapeutics, Diagnostics

© 2024 The Authors. Published by Innovare Academic Sciences Pvt Ltd. This is an open access article under the CC BY license (https://creativecommons.org/licenses/by/4.0/)
DOI: https://dx.doi.org/10.22159/ijap.2024v16i5.51647 Journal homepage: https://innovareacademics.in/journals/index.php/ijap

INTRODUCTION

After Cardiovascular disease, cancer is responsible for most deaths in the world. A cancerous condition includes uncontrolled, abnormal cell proliferation that eventually spreads to other tissues and causes metastases [1]. Over 23.6 million new cancer patients are projected to be found globally by 2030, and the number is expected to rise yearly [2]. Cancer is mainly treated by chemotherapy, gene therapy and radiotherapy [3]. These methods are designed to target malignant cells to effectively destroy them while causing the least damage to noncancerous healthy cells [4]. Unfortunately, the only tumor that can be treated with radiotherapy and surgery is the localized one in a particular region of the body [5]. Chemotherapy is used to treat advanced tumors that have spread to the blood circulation or lymphatic system. Most chemotherapeutic agents have negative effects on healthy cells. They are only effective up to a point because cancer cells tend to become multi-drug resistant (MDR) [6, 7]. The drawbacks of the chemotherapy include nausea, reduction in lymphocyte count, MDR, poor aqueous solubility, low therapeutic index, nonspecific tumour targeting, invasive methods, side effects, and poor patient compliance [8, 9]. To release anticancer medications at the target site, and to get rid of side effects from conventional treatments, metastasis, and tumor recurrence, it is crucial to develop innovative treatment approaches [10].

MSNs can be designed to target cancer cells with several therapeutic agents, including medications, peptides, nucleic acids, and imaging agents [11]. They can be utilized in drug delivery applications to target medications to certain cells or tissues [12]. MSNs increase the water solubility and bioavailability of hydrophilic drugs [13]. MSNs can be employed as catalyst support in catalysis applications. Because of their high surface area and homogenous pore size distribution, MSNs provide excellent catalytic activity and selectivity [14]. The features of MSNs can be further tailored by adding functional groups to their surface or by employing various synthesis techniques to control their size, morphology, and pore structure [15]. Numerous encouraging findings have been reported in preclinical and clinical research on applying MSNs for cancer therapy [16, 17]. This review is drafted with the help of papers from the past 20 years (2004-2024) and mostly after 2020 from specialised databases such as Science Direct, Pubmed, and Cambridge using the keywords Mesoporous silica nanoparticles, cancer, applications, therapeutics, diagnostics. Other selections include articles from Springer, Taylor and Francis, MDPI, and Wiley, information from Internet sources, and online published articles from ACS, Bentham etc.

Role of mesoporous silica nanoparticles in cancer

Nanotechnology emerged as a boon for treating cancer [18–20]. Quantum dots, carbon nanotubes, polymeric micelles, carbon dots [21] dendrimers, stimuli-based nanomaterials [22], polymeric nanoparticles, lipid nanoparticles, metal nanoparticles, magnetic nanoparticles, solid lipid nanoparticles [23] and MSNs [24–27] are some widely studied nanotechnology-based drug-delivery systems for cancer [13, 28–30]. The four key ingredients required for the formulation of MSNs are a catalyst, a silica precursor like silane, solvents, and a surfactant. MSNs can be generated with different characteristics, including diameter, pore size, surface area, and shape, even though the synthesis only required four basic components as mentioned above [31, 32]. MSNs have been researched to treat a variety of diseases, including cancer [33], Diabetes [34], inflammation [35], and bone/tendon tissue engineering [36]. The dual application of MSNs in the diagnosis and treatment of cancer is described in this review paper.

Mesoporous silica nanoparticles (MSNs) in the diagnosis of cancer

Nowadays, cancer is diagnosed using several medical procedures like examination of blood, and or urine, imaging methods like Magnetic Resonance Imaging (MRI), and Positron Emission Tomography (PET), followed by a biopsy. Conventional anatomical imaging methods typically identify tumours when they are a few millimetres using MRI or a few centimetres using PET. However, at this state tumour contains millions of cancer cells [37]. Therefore, the cancer imaging technique should be focused on identifying and/or scanning even a small number of tumour cells as possible in the initial stages, ideally before the angiogenic transition. Specialists who diagnose cancer and identify its stage to treat human cancer can only use various imaging techniques such as X-ray, Computed Tomography (CT) scan, MRI, optical microscopy, PET, Single Photon Emission Computed Tomography (SPECT), and Ultra Sound (US). However, only CT scans, MRI, PET and SPECT techniques can provide Three-Dimensional (3-D) images for cancer detection throughout the human body [38]. All these methods rely on spotting cancer when it begins to show itself physically, at a thickness of about 1 cm3, by which time the tumour mass will already have about 1 billion cancer cells in it [39].

For more effective treatment of cancer, early lesion diagnosis is crucial. Early lesions typically have modest biological signals. Due to inadequate sensitivity or lack of specificity, small tumours may go undiagnosed. Therefore, it is crucial to focus on the delivery of imaging agents to the lesion site to improve the signal and increase specificity. MSNs can be coupled to imaging agents appropriate for fluorescence, MRI, and PET imaging [40]. Various nanomaterials, including silica nanoparticles [41], Quantum Dots (QDs) [42], and gold nanoparticles [43], have been used for cancer diagnosis and early detection over the past several years [44]. Small molecules like gadolinium chelates and, calcium and other metal ions [45] are commonly employed as contrast agents for MRI and ultrasound. However, these agents cannot produce high-contrast pictures for early cancer diagnosis because of their limited specificity and intrinsic imaging noise [42]. Silica nanoparticles are also utilized as a contrast agent for ultrasound and MRI. MSNs have selective targeting to the tumour sites, and they also provide high drug loading capacity, robustness in designing various functionalizations, and easy biodegradation. Many imaging techniques have been used for the diagnosis, treatment, and monitoring of cancer. Each technique provides a different level of insight into the disease and its location. There is no ideal imaging approach because each method has its pros and cons [37]. MRI gives the best soft tissue contrast, but this method lacks sensitivity. PET also provides the greatest soft tissue contrast, but it has a limited spatial resolution. CT scan is fast, but it has low soft tissue contrast. IR is rapid and very sensitive but has a shallow depth of penetration.

Mesoporous materials are useful for diagnostic applications because of their improved image contrast and chemical stability. Additionally, the ability of MSNs to conjugate functional molecules within the pores creates new opportunities for numerous measurements and detection. Drugs and dyes can be used to track the position and activity of therapeutic medicines due to the low toxicity of silica-based porous materials and their capacity to contain a range of luminous markers [40]. A detailed description of the diagnostic application of MSNs in cancer has been given in table 1.

Table 1: MSNs in cancer diagnosis

Formulation Imaging model Model Application Clinical findings Reference
Gadolinium-MSN (Gd-MSN) MRI - Diagnosis High proton relaxivity, imaging-capable nanoparticles that can enter the cells easily. [46]
Gd-Fluorescein Isothiocyanate Msns (Gd-Dye@MSN) MRI Mouse brain Stem cell tracking These are perfect T1-agent carriers for MRI stem cell tracking due to their benefits of biocompatibility, longevity, high internalizing efficiency, and pore architecture. [47]
Mesoporous silica-coated hollow manganese oxide HMnO@mSiO2) MRI Mouse T1 MRI contrast agent Provided T1-weighted images under strong magnetic fields. [48]
Dox@Gome (Gold/Mesoporous Silica Hybrid Nanoparticle) PET imaging Mouse Diagnosis of lung tumour It is a good tool for the detection of clinically relevant spontaneous lung tumours. [49]
MagneticMag-Dye@MSNs MRI Mice Intracellular Labeling and animal MRI studies MSNs simultaneously serve as bimodal imaging probes and drug carriers. [50]
Copper sulfide-mesoporous silica-polyethylene glycol (CuS@mSiO2-PEG) nanocomposites Near-Infrared (NIR) Irradiation - Combination of chemotherapy and photothermal therapy. It demonstrated satisfactory photothermal effectiveness and pH-responsive drug-release behaviour. [51]
Gold (Au) capped MSNs TEM Imaging - Enzymes and substrate’s intracellular codelivery Tumour growth monitoring the record of treatment responses and determining therapeutic efficacy. [52]
Camptothecin-loaded Fluorescent MSNs TEM Imaging Mice Can promote the accumulation of anticancer medicines in tumours, enhancing their effectiveness. They deliver medications to tumours effectively, preferentially accumulate in tumours, and inhibit the growth of tumours. [53]
Magnetic mesoporous silica nanoparticles-based, polyelectrolyte (poly-ethylenimine, PEI) and fusogenic peptide-functionalized siRNA delivery system (MSN_siRNA@PEI-KALA peptides) TEM, Confocal laser scanning microscopy Mice siRNA delivery for cancer therapy MSNs are highly protective of siRNA and have a low level of cytotoxicity. An in vivo study confirmed the decrease in tumour growth. [53]
Perfluorohexane-encapsulated MSNs with indocyanine green–polydopamine layer and poly(ethylene glycol)–folic acid coating, (MSNs PFH@PDA-ICG-PEG-FA) US/NIRF dual-modal imaging Mice Cancer phototherapy Showed tremendous potential to be used as a flexible multifunctional nanocarrier for cancer imaging and treatment. [54]
Doxorubicin Chitosan-Folate conjugate (DOX-MSN-SS-CH-FA) MSNs TEM Mice A targeted drug delivery system for breast cancer that responds to both pH and redox stimuli MSNs showed excellent tumor-suppressing action against Ehrlich Ascites Carcinoma (EAC) in mice. MSNs cured the tumour locally and prevented it from spreading. [55]
Doxorubicin@Gd doped-MSNs, conjugating with indocyanine green loaded thermosensitive liposomes (DOX@GdMSNs-ICG-TSLs) Near-Infrared Fluorescence (NIRF), Photo acoustic (PA), magnetic resonance (MR) triple-modal imaging. Mice Multimodel imaging-guided chemotherapy and phototherapy for cancer eradication. The good anticancer effectiveness of the MSNs and satisfactory NIRF, PA, and MRI imaging effects. [56]
Anastrozole-Chitosan-Folic acid loaded MSNs (MSN-ATZ-CH-FA) TEM, Fourier transform Infrared (FTIR) Mice pH-responsive MSNs that target breast cancer Breast cancer caused by EAC was more effectively treated with MSN-ATZ-CH-FA. [57]
polyethyleneimine-polyethylene glycol epirubicin HCl MSNs (MSN-PEI-PEG-EPI) TEM, FTIR Mice Cancer treatment. MSN-PEI-PEG-EPI had a larger tumour accumulation than free epirubicin hydrochloride (EPI). [58]
MSNs of Arsenic Trioxide (ATO) grafted with Polyacrylic Acid (PAA) TEM Mice pH-triggered MSNs for poor pharmacokinetics or dose-limited toxicity in the treatment of solid tumours. Significantly improved anticancer efficacy in vitro and in vivo studies [59]
Paclitaxel (PTX)-loaded MSNs SEM Mouse Pore size controllable drug delivery system for chemotherapy MSNs containing PTX-increased all MCF-7 cells' rates of early and late apoptosis compared to free PTX [60]

Table 2: Application of MSNs in cancer

Drug Application Route of administration Key findings Reference
Doxorubicin (DOX)MSNs Mesothelioma therapy Intraperitoneal administration Improved therapeutic efficacy and increased intracellular absorption of DOX by DOX-loaded MSNs. [69]
Docetaxel (Dtxl) PEGylated silica nano rattles Liver cancer Intravenous administration Enhanced anticancer medicines' bioavailability, boost their effectiveness and lessen their side effects. [70]
Mannose-Multi functionalized MSNs Two-photon photodynamic therapy of solid tumour Subcutaneous administration. MSNs are effective in two-photon excitation (TPE) Photodynamic therapy in breast and colon cancer cell lines. [71]
Oxaliplatin
MSNs		 Pancreatic cancer Direct tumour injection, I. V. administration Significant reduction or eradication of tumours. [72]
Mesoporous Silica Microrod (MSR)-Polyethyleneimine (PEI) vaccine Cancer Vaccination Subcutaneous administration in intrascapular region. Improved dendritic activation and T cell response of host cells. The vaccine eliminated lung metastases that had already formed, inhibited cancer growth, and worked in conjunction with anti-CTLA4 therapy. [73]
Enzyme (Catalase) encapsulated photosensitizer-loaded hollow silica nanoparticles Photodynamic Therapy (PDT) in cancer Intravenous administration Effective PDT by the generation of reactive oxygen species (ROS) by mitochondria targeting and catalase. [74]
Lipid-coated biodegradable hollow MSNs Chemo-immunotherapy using All-Trans-Retinoic Acid (ATRA), doxorubicin and Inter Leukin-2 (IL-2) Intravenous administration IFN-γ and IL-12 secretion is encouraged, tumour-infiltrating T lymphocytes and natural killer cells become active, and IL-10, TGF-β, and immunosuppressive myeloid-derived suppressor cells become less active. [75]
Mesoporous nano vehicle loaded with photosensitizer and Dabrafenib, Trametinib Microneedle-assisted photodynamic therapy of Deep-seated melanoma Subcutaneous administration Skin cancer cells are killed synergistically by reactive oxygen species and caspase-activated apoptosis. [76]
large-pore silica-coated upconversion nanoparticles Cancer photodynamic immunotherapy Subcutaneous administration Stimulation of effector memory T cells, CD4+, and CD8+ cells. [77]
Pegylated lipid bilayer supported MSNs of Axitinib Celastrol Multitargeted cancer therapy Intravenous administration Enhancement of the antitumor efficacy by suppression of mitochondrial activity and angiogenesis. [78]
Poly (L-histidine) and polyethylene glycol-coated MSNs of sorafenib Antitumor effect Intravenous administration Antiproliferation and tumour growth inhibition without any significant toxicity and negligible hemolysis. [79]
Hollow MSNs containing photosensitizers Photodynamic and starvation therapy against tumour metastasis Intravenous administration Enhancement of PDT and starvation therapy to prevent the spread of tumors. [80]
Bioinspired diselenide bridged MSNs loaded with cytotoxic ribonuclease A (RNase A) Dual responsive protein delivery on cancer Intravenous administration Homologous targeting and immune invasion
characteristics.		 [81]
CX-5461loaded MSNs Cancer therapy Intravenous administration Inhibition of cancer cells without causing toxic effects on main organs. [82]
Mesoporous silica/organosilica nanosystem encapsulating doxorubicin and si-RNA Multidrug Resistant (MDR) cancer Intratumoral administration The first big siRNA molecules released from the organosilica shell improved the anticancer effect of later released small DOX molecules from the silica core by reversing the MDR of cancer cells and downregulating P-gp expression in the cell membrane. [83]
Glutathione-depletion dendritic mesoporous organosilica nanoparticles containing ovalbumin and toll-like receptor-9 Cancer immunotherapy Subcutaneous administration Decreasing the development of tumours and promoting the production of Cytotoxic T Lymphocytes (CTLs). [84]
Mesoporous silica-coated gold nanorods Photodynamic and photothermal tumour therapy (PTT) Subcutaneous administration Antitumor activity with fewer side effects and extension of tumour-bearing mice survival time. [85]
Hollow and nonhollow mesoporous silica nanospheres Cancer vaccine adjuvant - Hollow nanospheres enhanced anti-cancer immunity, CD4+ and CD8+T cell populations in mouse splenocytes. [86]
Asymmetric Head-Tail (HT) MSNs Vaccine development and Immunotherapy - Asymmetrical HTMSN showed a greater level of intake and in vitro maturation of dendritic cells and macrophages. [87]
Multi-shelled dendritic mesoporous organosilica hollow spheres Cancer immunotherapy - Immuno-adjuvant effect of MSNs [88]
Hollow MSNscontaining HGP10025-33, and TPR2180-188, Antitumor immune response Subcutaneous administration Tumour suppression without compromising safety. [89]
Mesoporous Silica Micro Rods-Supported Lipid Bilayers (MSRs-SLBs) T-cell receptor stimulation Intravenous administration Improved ex vivo growth of human and murine T cells using polyclonal and antigen-specific methods compared to commercial beads. [90]

Mesoporous silica nanoparticles (MSNs) in cancer therapy

MSNs can be categorized into many families based on their pore size, particle diameter, surface area, and manufacturing technique. These families have been explored extensively for drug delivery, including the Santa Barbara Amorphous (SBA), Movable Crystalline Material (MCM), and Michigan State University Materials (MSU) families [61].

MSNs can resolve the insolubility issue of various poorly soluble drugs. Although having outstanding anticancer activity in vitro, Paclitaxel (PTX) and Camptothecin (CPT) have little anticancer effects in vivo due to their poor aqueous solubility. The pore size and the shape of MSNs are adjustable therefore, they significantly boost the solubility of the medications when used as a carrier. Additionally, the MSN carrier raises the drugs' cytotoxic effects by 86% for CPT against human pancreatic cancer Capan-1 cells and HepG2 human liver cancer cells by 4.3-fold for PTX[62,63]. To treat mice harbouring the C26 tumor, Babaei et al. [64] formulated PEGylated MSNs (PEG@MSNR-CPT). The MSNs were loaded with CPT and assessed their effectiveness in comparison to CPT. MSNs can be multi-functionalized to regulate the release of medications. [65] To create redox and pH-responsive nanoparticles that may actively target breast cancer cells, Bhavsar et al. [66] formulated Doxorubicin (DOX)-loaded MSNs nanoparticles. The formulation was functionalized with cystamine dihydrochloride and then capped with chitosan-folate. After being exposed to acidic redox conditions (cancer environment; pH 5.5; 10 mmol reduced glutathione (GSH)), the drug was liberated from the particles. Intravenous administration of the formulation was determined to be safe [67].

MSNs have a high degree of stability, which helps to safeguard and stabilize loaded drugs. To create single-and multimodal anticancer treatments, numerous co-therapeutic treatments, including photosensitizers, photothermal reagents, and chemotherapeutic drugs, can also functionalize MSNs [4, 68]. Table 2 provides an overview of MSNs' therapeutic use in cancer.

Toxicity of MSNs

All inorganic materials like gold, silver, iron oxide, silica, and zinc oxide nanoparticles on chronic exposure can cause inflammation, fibrosis, impaired renal clearance, and oxidative stress [91]. The toxicity of these NPs depends on dose, frequency, route of administration, composition, and physicochemical properties [92]. The toxicity of nanoparticles is an important parameter to govern their safety for clinical applications. Acute and subacute toxicity studies are usually conducted to evaluate different parameters like haematological, neurological, and cardiac effects safety. Clinical manifestations of NPs on cardiovascular, respiratory, gastrointestinal effects, dermatological effects, necroscopy, and histopathological investigations and mortality have been used to assess their safety [93]. MSNs are mostly studied for their acute toxicities [94]. MSNs may interact with blood components after administration; hence it is critical to study their hemotoxicity for possible intravenous uses [95]. Indeed, amorphous silica compounds have been demonstrated to induce hemolysis in mammalian Red Blood Cells (RBCs), posing serious biosafety concern.

Biodegradability and clearance of MSNs

Degradation of inorganic materials is difficult. Therefore, it can be assumed that MSNs are not degraded easily and accumulate in the Reticuloendothelial System (RES) organs like the liver and spleen. This can lead to accumulation for a few weeks to some months. The slow degradation of MSNs in the body may cause severe tissue toxicity [30, 96, 97]. The degradation rate of MSNs is affected by their physical properties e. g., size, shape, surface area, aggregation state, surface coatings or surface modification. The degradation of MSNs is affected by the pH and temperature of the site, protein content and their concentration. The degradation of MSNs in the physiological fluids should be studied while evaluating their cytotoxicity [98, 99].

The clearance of MSNs is an important parameter regarding their clinical safety. It has been found that MSNs can be metabolized and excreted through urine by the kidney and thus don’t accumulate in the body. Various studies have reported that the MSN scaffold is degraded into orthosilicic acid a tolerable water-soluble compound and excreted by the kidney [100, 101].

CONCLUSION

MSNs have great potential for nanocarrier-based cancer therapy. In this review, we discussed mesoporous materials and their use as MSNs. The potential of MSNs to detect and treat cancer is reviewed in this paper. To deliver therapeutic drugs with high specificity and to selectively aggregate at the tumour site, MSNs can be functionalized with targeting moieties, such as antibodies or peptides. However, there is a need for more advancement that may offer an interesting possibility for the enhancement of the characteristics of MSNs. The eradication of incurable diseases like cancer is only possible after understanding this disease and targeting the molecules to combat the cancer cells without affecting healthy cells. It is expected that MSNs will remain an important area of cancer research in future.

AUTHORS CONTRIBUTIONS

Ms Nupur Katariya and Dr Nidhi Nainwal drafted the manuscript. Dr Ganesh Kumar revised and edited the manuscript. Dr Arvind S. Farswan formatted the manuscript as per journal guidelines.

FUNDING

Nil

ACKNOWLEDGEMENT

All authors are thankful to their respective Universities for providing support in the publication of this manuscript.

CONFLICT OF INTERESTS

None

REFERENCES

  1. ReferencesAghebati Maleki A, Dolati S, Ahmadi M, Baghbanzhadeh A, Asadi M, Fotouhi A. Nanoparticles and cancer therapy: perspectives for application of nanoparticles in the treatment of cancers. J Cell Physiol. 2020;235(3):1962-72. doi: 10.1002/jcp.29126, PMID 31441032.

  2. Siegel RL, Miller KD, Goding Sauer A, Fedewa SA, Butterly LF, Anderson JC. Colorectal cancer statistics 2020. CA Cancer J Clin. 2020;70(3):145-64. doi: 10.3322/caac.21601, PMID 32133645.

  3. Kiran AVVVR, Kumari GK, Krishnamurthy PT. Carbon nanotubes in drug delivery: focus on anticancer therapies. J Drug Deliv Sci Technol. 2020;59:101892. doi: 10.1016/j.jddst.2020.101892.

  4. Rastegari E, Hsiao YJ, Lai WY, Lai YH, Yang TC, Chen SJ. An update on mesoporous silica nanoparticle applications in nanomedicine. Pharmaceutics. 2021;13(7)1067. doi: 10.3390/pharmaceutics13071067, PMID 34371758.

  5. Ale Y, Nainwal N. Progress and challenges in the diagnosis and treatment of brain cancer using nanotechnology. Mol Pharm. 2023;20(10):4893-921. doi: 10.1021/acs.molpharmaceut.3c00554, PMID 37647568.

  6. Kankala RK, Liu CG, Yang DY, Wang SB, Chen AZ. Ultrasmall platinum nanoparticles enable deep tumor penetration and synergistic therapeutic abilities through free radical species assisted catalysis to combat cancer multidrug resistance. Chem Eng J. 2020;383:123138. doi: 10.1016/j.cej.2019.123138.

  7. Bukowski K, Kciuk M, Kontek R. Mechanisms of multidrug resistance in cancer chemotherapy. Int J Mol Sci. 2020;21(9):3233. doi: 10.3390/ijms21093233, PMID 32370233.

  8. He Q, Shi J. MSN anticancer nanomedicines: chemotherapy enhancement overcoming of drug resistance and metastasis inhibition. Adv Mater. 2014;26(3):391-411. doi: 10.1002/ADMA.201303123, PMID 24142549.

  9. Sharifi F, Nazir I, Asim MH, Jahangiri M, Ebrahimnejad P, Matuszczak B. Zeta potential changing self emulsifying drug delivery systems utilizing a novel Janus-headed surfactant: a promising strategy for enhanced mucus permeation. J Mol Liq. 2019;291:111285. doi: 10.1016/j.molliq.2019.111285.

  10. Rahikkala A, Pereira SA, Figueiredo P, Passos ML, Araujo AR, Saraiva ML. Mesoporous silica nanoparticles for targeted and stimuli responsive delivery of chemotherapeutics: a review. Adv Biosys. 2018;2(7):1800020. doi: 10.1002/adbi.201800020.

  11. Shchipunov YA, Burtseva YV, Karpenko TY, Shevchenko NM, Zvyagintseva TN. Highly efficient immobilization of endo-1,3-β-d-glucanases (laminarinases) from marine mollusks in novel hybrid polysaccharide silica nanocomposites with regulated composition. Journal of Molecular Catalysis B: Enzymatic. 2006;40(1-2):16-23. doi: 10.1016/j.molcatb.2006.02.002.

  12. Ghaferi M, Koohi Moftakhari Esfahani M, Raza A, Al Harthi S, Ebrahimi Shahmabadi H, Alavi SE. Mesoporous silica nanoparticles: synthesis methods and their therapeutic use recent advances. J Drug Target. 2021;29(2):131-54. doi: 10.1080/1061186X.2020.1812614, PMID 32815741.

  13. Liu M, Zhao Y, Shi Z, Zink JI, Yu Q. Virus like magnetic mesoporous silica particles as a universal vaccination platform against pathogenic infections. ACS Nano. 2023;17(7):6899-911. doi: 10.1021/acsnano.3c00644, PMID 36961475.

  14. Bharti C, Nagaich U, Pal AK, Gulati N. Mesoporous silica nanoparticles in target drug delivery system: a review. Int J Pharm Investig. 2015;5(3):124-33. doi: 10.4103/2230-973X.160844, PMID 26258053.

  15. Asefa T, Tao Z. Biocompatibility of mesoporous silica nanoparticles. Chem Res Toxicol. 2012;25(11):2265-84. doi: 10.1021/tx300166u, PMID 22823891.

  16. Narayan R, Nayak UY, Raichur AM, Garg S. Mesoporous silica nanoparticles: a comprehensive review on synthesis and recent advances. Pharmaceutics. 2018;10(3):118. doi: 10.3390/pharmaceutics10030118, PMID 30082647.

  17. Liu X, Jiang Y, Cai P, Gao R. Editorial: advanced silica nanomaterials for drug delivery. Front Chem. 2021;9:677647. doi: 10.3389/fchem.2021.677647, PMID 33959591.

  18. Suwalski A, Dabboue H, Delalande A, Bensamoun SF, Canon F, Midoux P. Accelerated achilles tendon healing by PDGF gene delivery with mesoporous silica nanoparticles. Biomaterials. 2010;31(19):5237-45. doi: 10.1016/j.biomaterials.2010.02.077, PMID 20334910.

  19. Lozano D, Trejo CG, Gomez Barrena E, Manzano M, Doadrio JC, Salinas AJ. Osteostatin loaded onto mesoporous ceramics improves the early phase of bone regeneration in a rabbit osteopenia model. Acta Biomater. 2012;8(6):2317-23. doi: 10.1016/j.actbio.2012.03.014, PMID 22414621.

  20. Vallet Regi M. Ordered mesoporous materials in the context of drug delivery systems and bone tissue engineering. Chemistry. 2006;12(23):5934-43. doi: 10.1002/chem.200600226, PMID 16832799.

  21. Sinha P, Rathnam G, SM DK, N JK. Overview on carbondots. Int J Curr Pharm Sci. 2023;15(4):9-14. doi: 10.22159/ijcpr.2023v15i4.3013.

  22. Joshi P, Nainwal N, Morris S, Jakhmola V. A review on recent advances on stimuli based smart nanomaterials for drug delivery and biomedical application. Int J App Pharm. 2023;15(5):48-59. doi: 10.22159/ijap.2023v15i5.48186.

  23. Phalak SD, Bodke V, Yadav R, Pandav S, Ranaware M. A systematic review on nano drug delivery system: solid lipid nanoparticles (sln). Int J Curr Pharm Sci. 2024;16(1):10-20. doi: 10.22159/ijcpr.2024v16i1.4020.

  24. Gu L, Lin J, Wang Q, Meng F, Niu G, Lin H. Mesoporous zinc oxide based drug delivery system offers an antifungal and immunoregulatory strategy for treating keratitis. J Control Release. 2024;368:483-97. doi: 10.1016/j.jconrel.2024.03.006, PMID 38458571.

  25. Su X, Li B, Chen S, Wang X, Song H, Shen B. Pore engineering of micro mesoporous nanomaterials for encapsulation controlled release and variegated applications of essential oils. J Control Release. 2024;367:107-34. doi: 10.1016/j.jconrel.2024.01.005, PMID 38199524.

  26. Article, Gharat S, Ghadge A, Phalak SD, Bodke V, Gavand A, Ganvir D. A review on template synthesis of nanoparticle. Int J Pharm Pharm Sci. 2024;16(5):22-9. doi: 10.22159/ijpps.2024v16i5.50661.

  27. Bhosale RR, Janugade BU, Chavan DD, Thorat VM. Current perspectives on applications of nanoparticles for cancer management. Int J Pharm Pharm Sci. 2023:15(11):1-10. doi: 10.22159/ijpps.2023v15i11.49319.

  28. Janjua TI, Cao Y, Ahmed Cox A, Raza A, Moniruzzaman M, Akhter DT. Efficient delivery of temozolomide using ultrasmall large pore silica nanoparticles for glioblastoma. J Control Release. 2023;357:161-74. doi: 10.1016/j.jconrel.2023.03.040, PMID 36965857.

  29. Vallet Regi M, Colilla M, Izquierdo Barba I, Manzano M. Mesoporous silica nanoparticles for drug delivery: current insights. Molecules. 2017;23(1):47. doi: 10.3390/MOLECULES23010047, PMID 29295564.

  30. Li L, Liu H. Biodegradable inorganic nanoparticles: an opportunity for improved cancer therapy. Nanomedicine (Lond). 2017;12(9):959-61. doi: 10.2217/nnm-2017-0057, PMID 28440705.

  31. Croissant JG, Fatieiev Y, Almalik A, Khashab NM. Mesoporous silica and organosilica nanoparticles: physical chemistry biosafety delivery strategies and biomedical applications. Adv Healthc Mater. 2018;7(4). doi: 10.1002/adhm.201700831, PMID 29193848.

  32. Wu SH, Hung Y, Mou CY. Mesoporous silica nanoparticles as nanocarriers. Chem Commun (Camb). 2011;47(36):9972-85. doi: 10.1039/c1cc11760b, PMID 21716992.

  33. Lu J, Liong M, Li Z, Zink JI, Tamanoi F. Biocompatibility biodistribution and drug delivery efficiency of mesoporous silica nanoparticles for cancer therapy in animals. Small. 2010;6(16):1794-805. doi: 10.1002/smll.201000538, PMID 20623530.

  34. Zhao Y, Trewyn BG, Slowing II, Lin VS. Mesoporous silica nanoparticle based double drug delivery system for glucose responsive controlled release of insulin and cyclic AMP. J Am Chem Soc. 2009;131(24):8398-400. doi: 10.1021/ja901831u, PMID 19476380.

  35. Moulari B, Pertuit D, Pellequer Y, Lamprecht A. The targeting of surface modified silica nanoparticles to inflamed tissue in experimental colitis. Biomaterials. 2008;29(34):4554-60. doi: 10.1016/j.biomaterials.2008.08.009, PMID 18790531.

  36. Padiyar N, Nainwal N, Ale Y, Galwan D. Formulation characterization and stability aspects of mesoporous silica nanoparticles. Int J Drug Deliv Technol. 2024;14(2):1217-24. doi: 10.25258/ijddt.14.2.88.

  37. Blasiak B, Van Veggel FC, Tomanek B. Applications of nanoparticles for MRI cancer diagnosis and therapy. J Nanomater. 2013;2013(1). doi: 10.1155/2013/148578.

  38. Frangioni JV. New technologies for human cancer imaging. J Clin Oncol. 2008;26(24):4012-21. doi: 10.1200/JCO.2007.14.3065, PMID 18711192.

  39. Thakor AS, Gambhir SS. Nanooncology: the future of cancer diagnosis and therapy. CA Cancer J Clin. 2013;63(6):395-418. doi: 10.3322/caac.21199, PMID 24114523.

  40. Rosenholm JM, Sahlgren C, Linden M. Multifunctional mesoporous silica nanoparticles for combined therapeutic diagnostic and targeted action in cancer treatment. Curr Drug Targets. 2011;12(8):1166-86. doi: 10.2174/138945011795906624, PMID 21443474.

  41. Wu X, Wu M, Zhao JX. Recent development of silica nanoparticles as delivery vectors for cancer imaging and therapy. Nanomedicine. 2014;10(2):297-312. doi: 10.1016/j.nano.2013.08.008.

  42. Pericleous P, Gazouli M, Lyberopoulou A, Rizos S, Nikiteas N, Efstathopoulos EP. Detection of colorectal circulating cancer cells with the use of a quantum dot labelled magnetic immunoassay method. Hellenic J Surg. 2013;85(2):127-34. doi: 10.1007/s13126-013-0025-5.

  43. Zheng T, Pierre Pierre N, Yan X, Huo Q, Almodovar AJ, Valerio F. Gold nanoparticle enabled blood test for early stage cancer detection and risk assessment. ACS Appl Mater Interfaces. 2015;7(12):6819-27. doi: 10.1021/acsami.5b00371, PMID 25757512.

  44. Feng Y, Panwar N, Tng DJ, Tjin SC, Wang K, Yong KT. The application of mesoporous silica nanoparticle family in cancer theranostics. Coord Chem Rev. 2016;319:86-109. doi: 10.1016/j.ccr.2016.04.019.

  45. Jasanoff A. MRI contrast agents for functional molecular imaging of brain activity. Curr Opin Neurobiol. 2007;17(5):593-600. doi: 10.1016/j.conb.2007.11.002, PMID 18093824.

  46. Ahveninen J, Lin FH, Kivisaari R, Autti T, Hamalainen M, Stufflebeam S. MRI-constrained spectral imaging of benzodiazepine modulation of spontaneous neuromagnetic activity in human cortex. Neuroimage. 2007;35(2):577-82. doi: 10.1016/j.neuroimage.2006.12.033, PMID 17300962.

  47. Hsiao JK, Tsai CP, Chung TH, Hung Y, Yao M, Liu HM. Mesoporous silica nanoparticles as a delivery system of gadolinium for effective human stem cell tracking. Small. 2008;4(9):1445-52. doi: 10.1002/SMLL.200701316, PMID 18680095.

  48. Kim T, Momin E, Choi J, Yuan K, Zaidi H, Kim J. Mesoporous silica coated hollow manganese oxide nanoparticles as positive T1 contrast agents for labeling and MRI tracking of adipose derived mesenchymal stem cells. J Am Chem Soc. 2011;133(9):2955-61. doi: 10.1021/JA1084095, PMID 21314118.

  49. Cheng B, He H, Huang T, Berr SS, He J, Fan D. Gold nanosphere gated mesoporous silica nanoparticle responsive to near infrared light and redox potential as a theranostic platform for cancer therapy. J Biomed Nanotechnol. 2016;12(3):435-49. doi: 10.1166/JBN.2016.2195, PMID 26949379.

  50. Liu HM, Wu SH, Lu CW, Yao M, Hsiao JK, Hung Y. Mesoporous silica nanoparticles improve magnetic labeling efficiency in human stem cells. Small. 2008;4(5):619-26. doi: 10.1002/SMLL.200700493, PMID 18491363.

  51. Liu X, Ren Q, Fu F, Zou R, Wang Q, Xin G. CuS@mSiO2-PEG core shell nanoparticles as a NIR light responsive drug delivery nanoplatform for efficient chemo photothermal therapy. Dalton Trans. 2015;44(22):10343-51. doi: 10.1039/C5DT00198F, PMID 25970690.

  52. Ma M, Chen H, Chen Y, Wang X, Chen F, Cui X. Au capped magnetic core mesoporous silica shell nanoparticles for combined photothermo chemo therapy and multimodal imaging. Biomaterials. 2012;33(3):989-98. doi: 10.1016/j.biomaterials.2011.10.017, PMID 22027594.

  53. Lu J, Liong M, Zink JI, Tamanoi F. Mesoporous silica nanoparticles as a delivery system for hydrophobic anticancer drugs. Small. 2007;3(8):1341-6. doi: 10.1002/SMLL.200700005, PMID 17566138.

  54. Zivojevic K, Mladenovic M, Djisalov M, Mundzic M, Ruiz Hernandez E, Gadjanski I. Advanced mesoporous silica nanocarriers in cancer theranostics and gene editing applications. J Control Release. 2021;337:193-211. doi: 10.1016/j.jconrel.2021.07.029, PMID 34293320.

  55. Bhavsar DB, Patel V, Sawant KK. Design and characterization of dual responsive mesoporous silica nanoparticles for breast cancer targeted therapy. Eur J Pharm Sci. 2020;152:105428. doi: 10.1016/j.ejps.2020.105428, PMID 32553643.

  56. Karthikeyan L, Sobhana S, Yasothamani V, Gowsalya K, Vivek R. Multifunctional theranostic nanomedicines for cancer treatment: recent progress and challenges. Biomedical Engineering Advances. 2023;5:100082. doi: 10.1016/j.bea.2023.100082.

  57. Bhavsar D, Gajjar J, Sawant K. Formulation and development of smart pH responsive mesoporous silica nanoparticles for breast cancer targeted delivery of anastrozole: in vitro and in vivo characterizations. Micropor Mesopor Mater. 2019;279:107-16. doi: 10.1016/j.micromeso.2018.12.026.

  58. Hanafi Bojd MY, Jaafari MR, Ramezanian N, Xue M, Amin M, Shahtahmassebi N. Surface functionalized mesoporous silica nanoparticles as an effective carrier for epirubicin delivery to cancer cells. Eur J Pharm Biopharm. 2015;89:248-58. doi: 10.1016/j.ejpb.2014.12.009, PMID 25511563.

  59. Xiao X, Liu Y, Guo M, Fei W, Zheng H, Zhang R. pH-triggered sustained release of arsenic trioxide by polyacrylic acid capped mesoporous silica nanoparticles for solid tumor treatment in vitro and in vivo. J Biomater Appl. 2016;31(1):23-35. doi: 10.1177/0885328216637211, PMID 27059495.

  60. Jia L, Shen J, Li Z, Zhang D, Zhang Q, Liu G. In vitro and in vivo evaluation of paclitaxel loaded mesoporous silica nanoparticles with three pore sizes. Int J Pharm. 2013;445(1-2):12-9. doi: 10.1016/j.ijpharm.2013.01.058, PMID 23384728.

  61. Trzeciak K, Chotera ouda A, Bak sypien II, Potrzebowski MJ. Mesoporous silica particles as drug delivery systems the state of the art in loading methods and the recent progress in analytical techniques for monitoring these processes. Pharmaceutics. 2021;13(7):950. doi: 10.3390/pharmaceutics13070950, PMID 34202794.

  62. Lu J, Liong M, Zink JI, Tamanoi F. Mesoporous silica nanoparticles as a delivery system for hydrophobic anticancer drugs. Small. 2007;3(8):1341-6. doi: 10.1002/smll.200700005, PMID 17566138.

  63. He Y, Liang S, Long M, Xu H. Mesoporous silica nanoparticles as potential carriers for enhanced drug solubility of paclitaxel. Mater Sci Eng C Mater Biol Appl. 2017;78:12-7. doi: 10.1016/j.msec.2017.04.049, PMID 28575958.

  64. Babaei M, Abnous K, Taghdisi SM, Taghavi S, Sh Saljooghi ASh, Ramezani M. Targeted rod shaped mesoporous silica nanoparticles for the co-delivery of camptothecin and survivin shRNA in to colon adenocarcinoma in vitro and in vivo. Eur J Pharm Biopharm. 2020;156:84-96. doi: 10.1016/j.ejpb.2020.08.026, PMID 32882423.

  65. Koohi Moftakhari Esfahani M, Alavi SE, Cabot PJ, Islam N, Izake EL. Application of mesoporous silica nanoparticles in cancer therapy and delivery of repurposed anthelmintics for cancer therapy. Pharmaceutics. 2022;14(8):1579. doi: 10.3390/pharmaceutics14081579, PMID 36015204.

  66. Bhavsar D, Gajjar J, Sawant K. Formulation and development of smart pH responsive mesoporous silica nanoparticles for breast cancer targeted delivery of anastrozole: in vitro and in vivo characterizations. Micropor Mesopor Mater. 2019;279:107-16. doi: 10.1016/j.micromeso.2018.12.026.

  67. Bhavsar DB, Patel V, Sawant KK. Design and characterization of dual responsive mesoporous silica nanoparticles for breast cancer targeted therapy. Eur J Pharm Sci. 2020;152:105428. doi: 10.1016/j.ejps.2020.105428, PMID 32553643.

  68. Han R, Tang K, Hou Y, Yu J, Wang C, Wang Y. Ultralow intensity near infrared light synchronously activated collaborative chemo/photothermal/photodynamic therapy. Biomater Sci. 2020;8(2):607-18. doi: 10.1039/c9bm01607d, PMID 31793930.

  69. Hillegass JM, Blumen SR, Cheng K, MacPherson MB, Alexeeva V, Lathrop SA. Increased efficacy of doxorubicin delivered in multifunctional microparticles for mesothelioma therapy. Int J Cancer. 2011;129(1):233-44. doi: 10.1002/IJC.25666, PMID 20830711.

  70. Li L, Tang F, Liu H, Liu T, Hao N, Chen D. In vivo delivery of silica nanorattle encapsulated docetaxel for liver cancer therapy with low toxicity and high efficacy. ACS Nano. 2010;4(11):6874-82. doi: 10.1021/NN100918A, PMID 20973487.

  71. Gary Bobo M, Mir Y, Rouxel C, Brevet D, Basile I, Maynadier M. Mannose-functionalized mesoporous silica nanoparticles for efficient two photon photodynamic therapy of solid tumors. Angew Chem Int Ed Engl. 2011;50(48):11425-9. doi: 10.1002/ANIE.201104765, PMID 21976357.

  72. Griffith KA, Zhu S, Johantgen M, Kessler MD, Renn C, Beutler AS. Oxaliplatin-induced peripheral neuropathy and identification of unique severity groups in colorectal cancer. J Pain Symptom Manage. 2017;54(5):701-706.e1. doi: 10.1016/j.jpainsymman.2017.07.033, PMID 28743660.

  73. Li AW, Sobral MC, Badrinath S, Choi Y, Graveline A, Stafford AG. A facile approach to enhance antigen response for personalized cancer vaccination. Nat Mater. 2018;17(6):528-34. doi: 10.1038/S41563-018-0028-2, PMID 29507416.

  74. Yan K, Zhang Y, Mu C, Xu Q, Jing X, Wang D. Versatile nanoplatforms with enhanced photodynamic therapy: designs and applications. Theranostics. 2020;10(16):7287-318. doi: 10.7150/THNO.46288, PMID 32641993.

  75. Kong M, Tang J, Qiao Q, Wu T, Qi Y, Tan S. Biodegradable hollow mesoporous silica nanoparticles for regulating tumor microenvironment and enhancing antitumor efficiency. Theranostics. 2017;7(13):3276-92. doi: 10.7150/THNO.19987, PMID 28900509.

  76. Song M, Liu C, Chen S, Zhang W. Nanocarrier based drug delivery for melanoma therapeutics. Int J Mol Sci. 2021;22(4):1-19. doi: 10.3390/IJMS22041873, PMID 33668591.

  77. Ding B, Shao S, Yu C, Teng B, Wang M, Cheng Z. Large pore mesoporous silica-coated upconversion nanoparticles as multifunctional immunoadjuvants with ultrahigh photosensitizer and antigen loading efficiency for improved cancer photodynamic immunotherapy. Adv Mater. 2018;30(52):e1802479. doi: 10.1002/ADMA.201802479, PMID 30387197.

  78. Choi JY, Ramasamy T, Kim SY, Kim J, Ku SK, Youn YS. Pegylated lipid bilayer-supported mesoporous silica nanoparticle composite for synergistic co-delivery of axitinib and celastrol in multi targeted cancer therapy. Acta Biomater. 2016;39:94-105. doi: 10.1016/j.actbio.2016.05.012, PMID 27163403.

  79. Bansal KK, Mishra DK, Rosling A, Rosenholm JM. Therapeutic potential of polymer coated mesoporous silica nanoparticles. Appl Sci. 2020;10(1):289. doi: 10.3390/APP10010289.

  80. Hong SH, Choi Y. Mesoporous silica based nanoplatforms for the delivery of photodynamic therapy agents. J Pharm Investig. 2018;48(1):3-17. doi: 10.1007/S40005-017-0356-2, PMID 30546918.

  81. Shao D, Li M, Wang Z, Zheng X, Lao YH, Chang Z. Bioinspired diselenide-bridged mesoporous silica nanoparticles for dual responsive protein delivery. Adv Mater. 2018;30:e1801198. doi: 10.1002/ADMA.201801198, PMID 29808576.

  82. Duo Y, Yang M, Du Z, Feng C, Xing C, Wu Y. CX-5461-loaded nucleolus targeting nanoplatform for cancer therapy through induction of pro death autophagy. Acta Biomater. 2018;79:317-30. doi: 10.1016/j.actbio.2018.08.035, PMID 30172068.

  83. Sun L, Wang D, Chen Y, Wang L, Huang P, Li Y. Core shell hierarchical mesostructured silica nanoparticles for gene/chemo synergetic stepwise therapy of multidrug resistant cancer. Biomaterials. 2017;133:219-28. doi: 10.1016/j.biomaterials.2017.04.028, PMID 28441616.

  84. Omar H, Jakimoska S, Guillot J, Alsharaeh E, Charnay C, Cunin F. Dendritic mesoporous organosilica nanoparticles with photosensitizers for cell imaging siRNA delivery and protein loading molecules. 2023;28(14):5335. doi: 10.3390/molecules28145335.

  85. Fernandez Lodeiro A, Djafari J, Fernandez Lodeiro J, Duarte MP, Muchagato Mauricio EM, Capelo Martinez JL. Synthesis of mesoporous silica coated gold nanorods loaded with methylene blue and its potentials in antibacterial applications. Nanomaterials (Basel). 2021;11(5):1338. doi: 10.3390/nano11051338, PMID 34069626.

  86. Wang X, Li X, Ito A, Yoshiyuki K, Sogo Y, Watanabe Y. Hollow structure improved anticancer immunity of mesoporous silica nanospheres in vivo. Small. 2016;12(26):3510-5. doi: 10.1002/smll.201600677, PMID 27191183.

  87. Escriche Navarro B, Escudero A, Lucena Sanchez E, Sancenon F, Garcia Fernandez A, Martinez Manez R. Mesoporous silica materials as an emerging tool for cancer immunotherapy. Advanced Science. 2022;9(26):e202200756. doi: 10.1002/advs.202200756.

  88. Yang Y, Lu Y, Abbaraju PL, Zhang J, Zhang M, Xiang G. Multi shelled dendritic mesoporous organosilica hollow spheres: roles of composition and architecture in cancer immunotherapy. Angew Chem Int Ed Engl. 2017;56(29):8446-50. doi: 10.1002/ANIE.201701550, PMID 28467690.

  89. Lee JY, Kim MK, Nguyen TL, Kim J. Hollow mesoporous silica nanoparticles with extra large mesopores for enhanced cancer vaccine. ACS Appl Mater Interfaces. 2020;12(31):34658-66. doi: 10.1021/acsami.0C09484, PMID 32662625.

  90. Dengler EC, Liu J, Kerwin A, Torres S, Olcott CM, Bowman BN. Mesoporous silica supported lipid bilayers (protocells) for DNA cargo delivery to the spinal cord. J Control Release. 2013;168(2):209-24. doi: 10.1016/j.jconrel.2013.03.009. PMID 23517784.

  91. Lerida Viso A, Estepa Fernandez A, Garcia Fernandez A, Marti Centelles V, Martinez Manez R. Biosafety of mesoporous silica nanoparticles towards clinical translation. Adv Drug Deliv Rev. 2023;201:115049. doi: 10.1016/j.addr.2023.115049, PMID 37573951.

  92. Greish K, Thiagarajan G, Ghandehari H. In vivo methods of nanotoxicology; 2012. p. 235-53. doi: 10.1007/978-1-62703-002-1_17.

  93. Mohammadpour R, Dobrovolskaia MA, Cheney DL, Greish KF, Ghandehari H. Subchronic and chronic toxicity evaluation of inorganic nanoparticles for delivery applications. Adv Drug Deliv Rev. 2019;144:112-32. doi: 10.1016/j.addr.2019.07.006, PMID 31295521.

  94. Nehoff H, Parayath NN, S Taurin, K Greish. In vivo evaluation of acute and chronic nanotoxicity. Chapter 3. Handbook of Nanotoxicology Nanomedicine and Stem Cell use in Toxicology; 2014. p. 65-86. doi: 10.1002/9781118856017.

  95. De La Harpe KM, Kondiah PP, Choonara YE, Marimuthu T, Du Toit LC, Pillay V. The hemocompatibility of nanoparticles: a review of cell nanoparticle interactions and hemostasis. Cells. 2019;8(10):1209. doi: 10.3390/CELLS8101209, PMID 31591302.

  96. Croissant JG, Fatieiev Y, Almalik A, Khashab NM. Mesoporous silica and organosilica nanoparticles: physical chemistry biosafety delivery strategies and biomedical applications. Adv Healthc Mater. 2018;7(4):831. doi: 10.1002/adhm.201700831, PMID 29193848.

  97. Hosseinpour S, Walsh LJ, Xu C. Biomedical application of mesoporous silica nanoparticles as delivery systems: a biological safety perspective. J Mater Chem B. 2020;8(43):9863-76. doi: 10.1039/d0tb01868f, PMID 33047764.

  98. Izquierdo Barba I, Colilla M, Manzano M, Vallet Regi M. In vitro stability of SBA-15 under physiological conditions. Micropor Mesopor Mater. 2010;132(3):442-52. doi: 10.1016/j.micromeso.2010.03.025.

  99. Braun K, Pochert A, Beck M, Fiedler R, Gruber J, Linden M. Dissolution kinetics of mesoporous silica nanoparticles in different simulated body fluids. J Solgel. Sci Technol. 2016;79:319-27. doi: 10.1007/s10971-016-4053-9/metrics.

  100. Ehlerding EB, Chen F, Cai W. Biodegradable and renal clearable inorganic nanoparticles. Adv Sci (Weinh). 2016;3(2):1500223. doi: 10.1002/advs.201500223, PMID 27429897.

  101. Yu M, Zheng J. Clearance pathways and tumor targeting of imaging nanoparticles. ACS Nano. 2015;9(7):6655-74. doi: 10.1021/acsnano.5b01320, PMID 26149184.