Mesoporous silica nanoparticles inflame tumors to overcome anti-PD-1 resistance through TLR4-NFκB axis

BackgroundThe clinical benefits of antiprogrammed cell death protein 1 (PD-1) therapy are compromised by resistance in immunologically cold tumors. Convergence of immunotherapy and bioengineering is potential to overcome the resistance. Mesoporous silica nanoparticles (MSNs) are considered the most promising inorganic biological nanomaterials for clinical transformation, however, the fundamental influence of MSNs on immunotherapy is unclear. In this study, we aimed to investigate the role of MSNs in tumor resensitization and explore the feasibility of MSNs combined with anti-PD-1 in cancer therapy.MethodsIntrinsic and acquired resistant tumors, as well as spontaneous and secondary tumor recurrence models, were used to evaluate the influence of MSNs and the synergistical effect with anti-PD-1 therapy. The roles of CD8+ cytotoxic T-lymphocytes (CTLs) and macrophages were assessed in Rag-1-/- mice, ovalbumin/OT-1 TCR transgenic T-cell system, and other blocking mice models. Mechanistic studies were processed by transcriptomics analysis and conducted in primary cells, in vitro coculture systems, and Toll-like receptor 4 (TLR4) knockout mice.ResultsBoth granular and rod-shaped MSNs efficiently overcame tumor resistance with dependence on diameter and aspect ratio. Only once injection of MSNs in prior to anti-PD-1 markedly improved the treatment efficacy, protective immunity, and prognosis. MSNs per se boosted infiltration of CTLs as the early event (days 2–3); and synergistically with anti-PD-1 therapy, MSNs rapidly established a T cell-inflamed microenvironment with abundant high-activated (interferon-γ/tumor necrosis factor-α/Perforin/GranzymeB) and low-exhausted (PD-1/lymphocyte-activation gene 3 (LAG-3)/T-cell immunoglobulin and mucin-domain containing-3 (TIM-3)) CTLs. Chemokines Ccl5/Cxcl9/Cxcl10, which were produced predominantly by macrophages, promoted MSNs-induced CTLs infiltration. MSNs led to high Ccl5/Cxcl9/Cxcl10 production in vitro and in mice through regulating TLR4-NFκB axis. Blocking TLR4-NFκB axis in macrophages or CTLs infiltration abrogated MSNs-induced resensitization to anti-PD-1 therapy.ConclusionsMSNs efficiently and rapidly inflame immunologically cold tumors and resensitize them to anti-PD-1 therapy through TLR4-NFκB-Ccl5/Cxcl9/Cxcl10 axis. MSNs-based theranostic agents can serve as sensitizers for patients with resistant tumors to improve immunotherapy.

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Multifunctional spherical gold nanocluster aggregate@polyacrylic acid@mesoporous silica nanoparticles for combined cancer dual-modal imaging and chemo-therapy

Journal of Materials Chemistry B ◽

10.1039/c4tb02009j ◽

2015 ◽

Vol 3 (12) ◽

pp. 2421-2425 ◽

Cited By ~ 21

Author(s):

Xiaotong Wu ◽

Lu Li ◽

Lingyu Zhang ◽

Tingting Wang ◽

Chungang Wang ◽

...

Keyword(s):

Liver Cancer ◽

Mesoporous Silica ◽

Silica Nanoparticles ◽

Polyacrylic Acid ◽

Mesoporous Silica Nanoparticles ◽

Enhanced Fluorescence ◽

Gold Nanocluster ◽

Theranostic Agents

Multifunctional nanoparticles with aggregation enhanced fluorescence (AEF) properties were fabricated. The resulting NPs were employed as novel theranostic agents for simultaneous dual-modal imaging and chemo-therapy of liver cancer in vivo and in vitro.

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Silica-Based Nanoparticles Targeting Dendritic Cells for Cancer Immunotherapy

10.21203/rs.3.rs-87251/v1 ◽

2020 ◽

Author(s):

Yajing Liu ◽

Lintong Yao ◽

Yun Zhang ◽

Wenhui shen ◽

Chunxia Chen ◽

...

Keyword(s):

Dendritic Cells ◽

T Cell ◽

Mesoporous Silica ◽

Silica Nanoparticles ◽

Mesoporous Silica Nanoparticles ◽

Tumor Immunotherapy ◽

Cross Presentation ◽

Dc Maturation

Abstract BackgroundVaccination is a promising anticancer strategy, but the limited delivery routes and short retention of antigens and immunomodulatory agents are problems that need to be solved in vaccine design. Because silicon nanoparticles have a tunable pore size and high loading capacity, they have been used in a variety of drug delivery systems, but their roles in tumor vaccine and tumor immunotherapy need to be examined.MethodsCD40 mAb was attached to mesoporous silica nanoparticles (MSNs) through covalent conjunction, and MSN-CD40/OVA/CpG nanoparticles were examined by Fourier transform-infrared spectroscopy, transmission electron microscopy and nanoparticle analyzer. In vitro functions of nanoparticles were detected by cytotoxicity, cellular uptake, DC maturation, cross-presentation and T cell priming. In vivo functions were monitored by tumor elimination, DC maturation, cross-presentation and T cell activity.ResultsWe encapsulated anti-CD40 monoclonal antibodies, ovalbumin (OVA) antigen, and a toll-like receptor-9 agonist (CpG) in mesoporous silica nanoparticles (MSNs). The resulting MSN-CD40/OVA/CpG nanoparticles were efficiently phagocytized by splenocytes and bone marrow-derived dendritic cells (BMDC). The MSN-CD40/OVA/CpG nanoparticles induced the BMDC to express the costimulatory molecules CD80 and CD86, and release tumor necrosis factor-α. We found that MSN-CD40/OVA/CpG nanoparticles correctly enhanced antigen cross-priming, and stimulated T cell proliferation and interferon γ (IFNγ) production in vitro. In vivo, the MSN-CD40/OVA/CpG nanoparticles strongly increased intracellular IFNγ secretion and its release from OVA257–264 peptide-specific splenocytes into the cell supernatant, induced dendritic cell expression of major histocompatibility complex-II, and stimulated lymphocyte CD80 and CD86 expression. The MSN-CD40/OVA/CpG nanoparticles also inhibited tumor growth, enhanced tumor infiltration of CD8+ and CD4+ T cells, and stimulated IFNγ secretion from splenocytes. In conclusion, we believe these MSN-CD40/OVA/CpG nanoparticles are a promising strategy for improving antigen cross-presentation, cytotoxic T lymphocyte immune activity, and anti-tumor immunotherapy.

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In Vitro Evaluation of pH Responsive Doxazosin Loaded Mesoporous Silica Nanoparticles: A Smart Approach in Drug Delivery

Current Drug Delivery ◽

10.2174/1567201812666150722123704 ◽

2016 ◽

Vol 13 (4) ◽

pp. 574-581 ◽

Cited By ~ 3

Author(s):

Arijit Guha ◽

Nikhil Biswas ◽

Kaustav Bhattacharjee ◽

Piu Das ◽

Ketousetuo Kuotsu

Keyword(s):

Drug Delivery ◽

Mesoporous Silica ◽

Silica Nanoparticles ◽

Mesoporous Silica Nanoparticles ◽

Ph Responsive ◽

In Vitro Evaluation

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Mesoporous Silica Nanoparticles and Mesoporous Bioactive Glasses for Wound Management: From Skin Regeneration to Cancer Therapy

Materials ◽

10.3390/ma14123337 ◽

2021 ◽

Vol 14 (12) ◽

pp. 3337

Author(s):

Sara Hooshmand ◽

Sahar Mollazadeh ◽

Negar Akrami ◽

Mehrnoosh Ghanad ◽

Ahmed El-Fiqi ◽

...

Keyword(s):

Mesoporous Silica ◽

Silica Nanoparticles ◽

Mesoporous Silica Nanoparticles ◽

Skin Regeneration ◽

Bioactive Molecules ◽

Wound Management ◽

Bioactive Glasses ◽

Wide Range

Exploring new therapies for managing skin wounds is under progress and, in this regard, mesoporous silica nanoparticles (MSNs) and mesoporous bioactive glasses (MBGs) offer great opportunities in treating acute, chronic, and malignant wounds. In general, therapeutic effectiveness of both MSNs and MBGs in different formulations (fine powder, fibers, composites etc.) has been proved over all the four stages of normal wound healing including hemostasis, inflammation, proliferation, and remodeling. The main merits of these porous substances can be summarized as their excellent biocompatibility and the ability of loading and delivering a wide range of both hydrophobic and hydrophilic bioactive molecules and chemicals. In addition, doping with inorganic elements (e.g., Cu, Ga, and Ta) into MSNs and MBGs structure is a feasible and practical approach to prepare customized materials for improved skin regeneration. Nowadays, MSNs and MBGs could be utilized in the concept of targeted therapy of skin malignancies (e.g., melanoma) by grafting of specific ligands. Since potential effects of various parameters including the chemical composition, particle size/morphology, textural properties, and surface chemistry should be comprehensively determined via cellular in vitro and in vivo assays, it seems still too early to draw a conclusion on ultimate efficacy of MSNs and MBGs in skin regeneration. In this regard, there are some concerns over the final fate of MSNs and MBGs in the wound site plus optimal dosages for achieving the best outcomes that deserve careful investigation in the future.

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Antimicrobial and antibiofilm activities of meropenem loaded-mesoporous silica nanoparticles against carbapenem-resistant Pseudomonas aeruginosa

Journal of Biomaterials Applications ◽

10.1177/08853282211003848 ◽

2021 ◽

pp. 088532822110038

Author(s):

Mohammad Yousef Memar ◽

Mina Yekani ◽

Hadi Ghanbari ◽

Edris Nabizadeh ◽

Sepideh Zununi Vahed ◽

...

Keyword(s):

Pseudomonas Aeruginosa ◽

Mesoporous Silica ◽

Silica Nanoparticles ◽

Mesoporous Silica Nanoparticles ◽

Carbapenem Resistant ◽

Toxicity In Vitro ◽

Different Levels

The aims of the present study were the determination of antimicrobial and antibiofilm effects of meropenem-loaded mesoporous silica nanoparticles (MSNs) on carbapenem resistant Pseudomonas aeruginosa ( P. aeruginosa) and cytotoxicity properties in vitro. The meropenem-loaded MSNs had shown antibacterial and biofilm inhibitory activities on all isolates at different levels lower than MICs and BICs of meropenem. The viability of HC-04 cells treated with serial concentrations as MICs and BICs of meropenem-loaded MSNs was 92–100%. According to the obtained results, meropenem-loaded MSNs display the significant antibacterial and antibiofilm effects against carbapenem resistant and biofilm forming P. aeruginosa and low cell toxicity in vitro. Then, the prepared system can be an appropriate option for the delivery of carbapenem for further evaluation in vivo assays.

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Polymeric Mesoporous Silica Nanoparticles for Enhanced Delivery of 5-Fluorouracil In Vitro

Pharmaceutics ◽

10.3390/pharmaceutics11060288 ◽

2019 ◽

Vol 11 (6) ◽

pp. 288 ◽

Cited By ~ 19

Author(s):

Thashini Moodley ◽

Moganavelli Singh

Keyword(s):

Side Effects ◽

Mesoporous Silica ◽

Silica Nanoparticles ◽

Therapeutic Potential ◽

Mesoporous Silica Nanoparticles ◽

Drug Loading ◽

Hek293 Cells ◽

Cancer Drug ◽

Delivery Vehicles

There is a need for the improvement of conventional cancer treatment strategies by incorporation of targeted and non-invasive procedures aimed to reduce side-effects, drug resistance, and recurrent metastases. The anti-cancer drug, 5-fluorouracil (5-FU), is linked to a variety of induced-systemic toxicities due to its lack of specificity and potent administration regimens, necessitating the development of delivery vehicles that can enhance its therapeutic potential, while minimizing associated side-effects. Polymeric mesoporous silica nanoparticles (MSNs) have gained popularity as delivery vehicles due to their high loading capacities, biocompatibility, and good pharmacokinetics. MSNs produced in this study were functionalized with the biocompatible polymers, chitosan, and poly(ethylene)glycol to produce monodisperse NPs of 36–65 nm, with a large surface area of 710.36 m2/g, large pore volume, diameter spanning 9.8 nm, and a favorable zeta potential allowing for stability and enhanced uptake of 5-FU. Significant drug loading (0.15–0.18 mg5FU/mgmsn), controlled release profiles (15–65%) over 72 hours, and cell specific cytotoxicity in cancer cells (Caco-2, MCF-7, and HeLa) with reduced cell viability (≥50%) over the non-cancer (HEK293) cells were established. Overall, these 5FU-MSN formulations have been shown to be safe and effective delivery systems in vitro, with potential for in vivo applications.

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