Large-pore Mesoporous Silica Nanoparticles Research Articles

One-pot, degradable, silica nanocarriers with encapsulated oligonucleotides for mitochondrial specific targeting

Mutations in nuclear and mitochondrial genes are responsible for severe chronic disorders such as mitochondrial myopathies. Gene therapy using antisense oligonucleotides is a promising strategy to treat mitochondrial DNA (mtDNA) diseases by blocking the replication of the mutated mtDNA. However, transport vehicles are needed for intracellular, mitochondria-specific transport of oligonucleotides. Nanoparticle (NP) based vectors such as large pore mesoporous silica nanoparticles (LP) often rely on surface complexation of oligonucleotides exposing them to nucleases and limiting mitochondria targeting and controlled release ability. In this work, stable, fluorescent, hollow silica nanoparticles (HSN) that encapsulate and protect oligonucleotides in the hollow core were synthesized by a facile one-pot procedure. Both rhodamine B isothiocyanate and bis[3-(triethoxysilyl)propyl]tetrasulfide were incorporated in the HSN matrix by co-condensation to enable cell tracing, intracellular-specific degradation and controlled oligonucleotide release. We also synthesized LP as a benchmark to compare the oligonucleotide loading and release efficacy of our HSN. Mitochondria targeting was enabled by NP functionalization with cationic, lipophilic Triphenylphosphine (TPP) and, for the first time a fusogenic liposome based carrier, previously reported under the name MITO-Porter. HSN exhibited high oligonucleotide incorporation ratios and release dependent on intracellular degradation. Further, MITO-Porter capping of our NP enabled delayed, glutathione (GSH) responsive oligonucleotide release and mitochondria targeting at the same efficiency as TPP functionalized NP. Overall, our NP are promising vectors for anti-gene therapy of mtDNA disease as well as many other monogenic disorders worldwide.Graphical

Co-Delivery of Metabolic Modulators Leads to Simultaneous Lactate Metabolism Inhibition And Intracellular Acidification for Synergistic Cancer Therapy.

Simultaneous lactate metabolism inhibition and intracellular acidification (LIIA) is a promising approach for inducing tumor regression by depleting ATP. However, given the limited efficacy of individual metabolic modulators, a combination of various modulators is required for highly efficient LIIA. Herein, a co-delivery system that combines lactate transporter inhibitor, glucose oxidase, and O2 -evolving nanoparticles is proposed. As a vehicle, a facile room-temperature synthetic method for large-pore mesoporous silica nanoparticles (L-MSNs) is developed. O2 -evolving nanoparticles are then conjugated onto L-MSNs, followed by immobilizing the lactate transporter inhibitor and glucose oxidase inside the pores of L-MSNs. To load the lactate transporter inhibitor, which is too small to be directly loaded into the large pores, it is encapsulated in albumin by controlling the albumin conformation before being loaded into L-MSNs. Notably, inhibiting lactate efflux shifts the glucose consumption mechanism from lactate metabolism to glucose oxidase reaction, which eliminates glucose and produces acid. This leads to synergistic LIIA and subsequent ATP depletion in cancer cells. Consequently, L-MSN-based co-delivery of modulators for LIIA shows high anticancer efficacy in several mouse tumor models without toxicity in normal tissues. This study provides new insights into co-delivery of small-molecule drugs, proteins, and nanoparticles for synergistic metabolic modulation in tumors. This article is protected by copyright. All rights reserved.

Hydrogel Contact Lenses Embedded with Amine-Functionalized Large-Pore Mesoporous Silica Nanoparticles with Extended Hyaluronic Acid Release.

Contact lenses (CLs) have emerged as an effective method for delivering ophthalmic drugs. In this research, we designed hydrogel CLs capable of extended release, utilizing large-pore mesoporous silica nanoparticles (LPMSNs) to deliver hyaluronic acid (HA) for treating dry eye syndrome. LPMSNs were functionalized with amine groups (LPMSN-amine) to enhance HA loading and release capacity. In vitro release studies demonstrated that LPMSN-amine CLs exhibited superior slower HA release than LPMSN-siloxane and standard CLs. Within 120 h, the cumulative amount of HA released from LPMSN-amine CLs reached approximately 275.58 µg, marking a 12.6-fold improvement compared to standard CLs, when loaded from 0.1 wt% HA solutions. Furthermore, LPMSN-amine CLs effectively maintained moisture, mitigating ocular surface dehydration, making them a promising solution for dry eye management. This study successfully developed LPMSN-amine CLs for extended HA release, identifying the optimal functional groups and loading conditions to achieve sustained release.

Enhanced and Extended Ophthalmic Drug Delivery by pH-Triggered Drug-Eluting Contact Lenses with Large-Pore Mesoporous Silica Nanoparticles

Drug-eluting contact lenses (DCLs) have attracted considerable attention as potential therapeutic ophthalmic drug delivery devices. In this study, we propose, fabricate, and investigate pH-triggered DCLs that are combined with large-pore mesoporous silica nanoparticles (LPMSNs). Compared to reference DCLs, LPMSN-laden DCLs can prolong the residence time of glaucoma drugs in an artificial lacrimal fluid (ALF) environment at pH 7.4. Additionally, LPMSN-laden DCLs do not require drug preloading and are compatible with current contact lens manufacturing processes. LPMSN-laden DCLs soaked at pH 6.5 exhibit better drug loading than reference DCLs due to their specific adsorption. The sustained and extended release of glaucoma drugs by LPMSN-laden DCLs was successfully monitored in ALF, and the drug release mechanism was further explained. We also evaluated the cytotoxicity of LPMSN-laden DCLs, and qualitative and quantitative results showed no cytotoxicity. Our experimental results demonstrate that LPMSNs are excellent nanocarriers that have the potential to be used as safe and stable nanocarriers for the delivery of glaucoma drugs or other drugs. pH-triggered LPMSN-laden DCLs can significantly improve drug loading efficiency and control prolonged drug release, indicating that they have great potential for future biomedical applications.

High-Capacity Mesoporous Silica Nanocarriers of siRNA for Applications in Retinal Delivery.

The main cause of subretinal neovascularisation in wet age-related macular degeneration (AMD) is an abnormal expression in the retinal pigment epithelium (RPE) of the vascular endothelial growth factor (VEGF). Current approaches for the treatment of AMD present considerable issues that could be overcome by encapsulating anti-VEGF drugs in suitable nanocarriers, thus providing better penetration, higher retention times, and sustained release. In this work, the ability of large pore mesoporous silica nanoparticles (LP-MSNs) to transport and protect nucleic acid molecules is exploited to develop an innovative LP-MSN-based nanosystem for the topical administration of anti-VEGF siRNA molecules to RPE cells. siRNA is loaded into LP-MSN mesopores, while the external surface of the nanodevices is functionalised with polyethylenimine (PEI) chains that allow the controlled release of siRNA and promote endosomal escape to facilitate cytosolic delivery of the cargo. The successful results obtained for VEGF silencing in ARPE-19 RPE cells demonstrate that the designed nanodevice is suitable as an siRNA transporter.

A robust ROS generation nanoplatform combating periodontitis via sonodynamic/chemodynamic combination therapy

Periodontitis is a popular bacteria-induced chronic disease with the absence of effective and noninvasive therapeutic strategies. Sonodynamic therapy (SDT), proved to be promising against infections of bacteria especially multidrug-resistant species by producing reactive oxygen species (ROS), has been considered as tremendous potential in antibacterial application for periodontitis treatment. However, the low quantum yield of ROS remains a significant challenge for SDT. In this study, a novel nano-sonosensitizer was prepared for robust ROS generation via growing TiO2 on dendritic large pore mesoporous silica nanoparticles (DLMSNs) followed by deposition of Ag (DT-Ag) and modifying with the quaternary ammonium chitosan (DT-Ag-CS+). In vitro antibacterial effects of DT-Ag-CS+ were investigated in porphyromonas gingivalis (P. gingivalis) which is a well-recognized periodontal pathogenic bacterium, and in vivo anti-periodontitis effects were evaluated using Wistar rats with ligature-induced periodontitis. The obtained DT-Ag-CS+ exhibited excellent SDT and chemodynamic therapy (CDT) performances both in vitro and in vivo, owing to the deposition of noble metal Ag, and greater chance to penetrate into bacterial cells due to the highly positive-charged CS+ on the surface of DT-Ag. Altogether, a multifunctional DT-Ag-CS+ nano-sonosensitizer has shown promising clinical application for combining SDT and CDT against periodontitis.

Biomimetic nanotherapeutics based on oxygen supply and ultrasmall Cu-Se-Au alloy nanoparticles for boosting radio-photothermal ablation of breast cancer

Radiotherapy (RT) is one of the important tools for clinical treatment of breast cancer. Currently, some nanoradiosensitizers have been developed for augmenting the therapeutic efficiency of RT. However, some limitations still exist for their further applications, such as oxygen dependence in hypoxic tumors, nonideal selectivity for tumors, and inevasible damages to normal tissues. To resolve these problems, a biomimetic nanoplatform was developed for efficient co-loading and precise co-delivery of oxygen and nanoradiosensitizer by taking advantage of large pore volumes and easy surface modification of dendritic large pore mesoporous silica nanoparticles (DLMSNs). The outer surfaces of DLMSNs were modified with citric acid for attaching firmly and chelating stably with ultrasmall Cu-Se-Au alloy nanoparticles possessing distinct radiosensitizing and photothermal conversion performances. The inner surfaces of DLMSNs were modified with perfluorosilane for loading perfluorohexane that has extraordinary oxygen-carrying capability to alleviate tumor hypoxia. White blood cells membranes were wrapped onto the surfaces of the resultant DLMSNs for promoting co-delivery of therapeutic agents targeting to tumor and reducing injuries to normal tissues. Biomimetic nanotherapeutic system thus prepared showed powerful suppression effects against breast cancer both in vitro and in vivo by intelligently integrating tumor-targeted delivery, oxygen supply, radiosensitizing and photothermal ablation.

Pathogen infection-responsive nanoplatform targeting macrophage endoplasmic reticulum for treating life-threatening systemic infection.

Systemic infections caused by life-threatening pathogens represent one of the main factors leading to clinical death. In this study, we developed a pathogen infection-responsive and macrophage endoplasmic reticulum-targeting nanoplatform to alleviate systemic infections. The nanoplatform is composed of large-pore mesoporous silica nanoparticles (MSNs) grafted by an endoplasmic reticulum-targeting peptide, and a pathogen infection-responsive cap containing the reactive oxygen species-cleavable boronobenzyl acid linker and bovine serum albumin. The capped MSNs exhibited the capacity to high-efficiently load the antimicrobial peptide melittin, and to rapidly release the cargo triggered by H2O2 or the pathogen-macrophage interaction system, but had no obvious toxicity to macrophages. During the interaction with pathogenic Candida albicans cells and macrophages, the melittin-loading nanoplatform MSNE+MEL+TPB strongly inhibited pathogen growth, survived macrophages, and suppressed endoplasmic reticulum stress together with pro-inflammatory cytokine secretion. In a systemic infection model, the nanoplatform efficiently prevented kidney dysfunction, alleviated inflammatory symptoms, and protected the mice from death. This study developed a macrophage organelle-targeting nanoplatform for treatment of life-threatening systemic infections.Electronic Supplementary MaterialSupplementary material (N2 adsorption curves of the initial synthesized MSNs, FT-IR spectra of MSN, and MSNE, MEL release from the FITC-MEL-loading MSNE + TPB induced by different concentration of H2O2, viability of NIH3T3 cells, and DC2.4 cells after treatment of free MEL or the used nanoparticles, effect of MEL on C. albicans growth and macrophage death during the interaction between C. albicans and macrophages, effect of MEL and the nanoparticles on S. aureus growth and macrophage death during the interaction between S. aureus and macrophages, quantification of GRP78 (a) and activated Caspase-3, flow cytometry analysis of kidney non-macrophages with the Alexa Fluor 594 signal, survival curve of the infected mice treated by MEL or MSNE + MEL, kidney burden, blood urea levels and serum TNF-α levels in the infected mice) is available in the online version of this article at 10.1007/s12274-022-4211-z.

Cell Membrane-camouflaged Multi-functional Dendritic Large Pore Mesoporous Silica Nanoparticles for Combined Photothermal Therapy and Radiotherapy of Cancer

Cell Membrane-camouflaged Multi-functional Dendritic Large Pore Mesoporous Silica Nanoparticles for Combined Photothermal Therapy and Radiotherapy of Cancer

Leukocyte/platelet hybrid membrane-camouflaged dendritic large pore mesoporous silica nanoparticles co-loaded with photo/chemotherapeutic agents for triple negative breast cancer combination treatment

Triple-negative breast cancer (TNBC) is an aggressive subset of breast cancer and currently lacks effective therapeutic targets. As two main phototherapeutic methods, photothermal therapy (PTT) and photodynamic therapy (PDT) show many advantages in TNBC treatment, and their combination with chemotherapy can achieve synergistic therapeutic effects. In the present study, a biomimetic nanoplatform was developed based on leukocyte/platelet hybrid membrane (LPHM) and dendritic large pore mesoporous silicon nanoparticles (DLMSNs). A near infrared (NIR) fluorescent dye IR780 and a chemotherapeutic drug doxorubicin (DOX) were co-loaded into the large pores of DLMSNs to prepare DLMSN@DOX/IR780 (DDI) nanoparticles (NPs), followed by camouflage with LPHM to obtain LPHM@DDI NPs. Through the mediation of LPHM, LPHM@DDI NPs showed an excellent TNBC-targeting ability and very high PTT/PDT performances in vitro and in vivo. Upon NIR laser irradiation, LPHM@DDI NPs exhibited synergistic cytotoxicity and apoptosis-inducing activity in TNBC cells, and effectively suppressed tumor growth and recurrence in TNBC mice through tumor ablation and anti-angiogenesis. These synergistic effects were sourced from the combination of PTT/PDT and chemotherapy. Altogether, this study offers a promising biomimetic nanoplatform for efficient co-loading and targeted delivery of photo/chemotherapeutic agents for TNBC combination treatment.

Monodispersed large-mesopore mesoporous silica nanoparticles enabled by sulfuric acid assisted hydrothermal process

Abstract In this work, it is demonstrated that monodispersed large-pore mesoporous silica nanoparticles (ML-MSNs) can be prepared by a sulfuric acid assisted hydrothermal process (SAH). The strategy is based on a SAH process enabled transformation from conventionally prepared MSNs with small mesopores (~2.6 nm) into large-mesopore ML-MSNs (over 10 nm) and high surface area (exceeding 500 m2g-1) in a rather green and controllable manner. A synergistic effect of ethanol employed in the synthesis step and more importantly the hydrothermal treatment process step in ethanolic sulfuric acid solution at high temperature is newly acknowledged in such SAH process, as manifested by different techniques. Such process enables reliable control over porous structures by varying the SAH condition. Moreover, ML-MSNs with tuneable mesostructures are shown to allow rational control over loading and release performance of water-insoluble drug molecules of Indomethacin.

Benzene-Bridged Organosilica Modified Mesoporous Silica Nanoparticles via an Acid-Catalysis Approach.

Surface functionalization of mesoporous silica nanoparticles is important for their applications but fairly challenging using benzene-bridged organosilane as the precursor through the postsynthesis approach. Herein, we report an acid-catalysis approach for the postmodification of benzene-bridged organosilica onto the surface of large-pore mesoporous silica nanoparticles. By using HCl (∼1 M) as the acid catalyst in a tetrahydrofuran solvent, the self-assembly of the bridged organosilica precursor is avoided, while surface modification of mesoporous silica nanoparticles is promoted with controllable organic contents and retained large pore sizes. This strategy can also be applied to the postmodification of organosilica with end benzene groups. The strategy developed in this study is expected to be applied for the postmodification of other organosilica precursors with various functions.

Pathogen Infection-Responsive Nanoplatform Targeting Macrophage Endoplasmic Reticulum for Alleviating Sepsis

Pathogen-induced sepsis represents the main cause of infection-related death, and is becoming a great threat to human health. In this study, we developed a pathogen infection-responsive and macrophage endoplasmic reticulum-targeting nanoplatform to alleviate sepsis. The nanoplatform is composed of large-pore mesoporous silica nanoparticles (MSNs) grafted by an endoplasmic reticulum-targeting peptide (ERP), and a pathogen infection-responsive cap (TPB) containing the reactive oxygen species (ROS)-cleavable boronobenzyl acid linker (TSPBA) and bovine serum albumin (BSA). The TPB-capped MSNs exhibited the capacity to highly load the antimicrobial peptide melittin (MEL), and to rapidly release the cargo triggered by H2O2 or the pathogen-macrophage interaction system. During the interaction between pathogenic C. albicans cells and macrophages, the MEL-loading nanoplatform MSNE+MEL+TPB strongly inhibited pathogen growth, survived macrophages, and suppressed endoplasmic reticulum stress and secretion of pro-inflammatory cytokines. In a systemic infection model, the nanoplatform efficiently protected the mice from death, prevented kidney dysfunction and alleviated sepsis symptoms. This study developed an efficient multifunctional nanoplatform for treatment of sepsis. Funding Information: This work was supported by National Natural Science Foundation of China (3217010793, 31870139), Natural Science Foundation of Tianjin (19JCZDJC33800), and Tianjin Synthetic Biotechnology Innovation Capacity Improvement Project (TSBICIP-KJGG-006). Declaration of Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Ethics Approval Statement: All animal experiments were approved by the Animal Care and Use Committee at Nankai University.

Large scale synthesis of self-assembled shuttlecock-shaped silica nanoparticles with minimized drag as advanced catalytic nanomotors

• Large scale synthesis of shuttlecock-shaped silica nanoparticles (SSNs) were reported. • Assembly behavior of two surfactants were finely controlled to direct the growth. • SSNs exhibited minimized drag force in motion in fluid. • SSNs based nanomotors showed high diffusibility and lipid degradation activity. The catalytic performance of nanomotors is highly dependent on their interaction with substrates, for which the motion dynamics of the nanomotors needs to be carefully manipulated via materials design. Herein, we report a facile one-step self-assembly strategy for hundred-gram scale synthesis of shuttlecock-shaped silica nanoparticles as advanced catalytic nanomotors. These asymmetric nanoparticles have a streamline conical morphology with ultra-large opening in one side. The shuttlecock-mimetic morphology endows the nanoparticles with minimized drag force during fluid motion and consequently high diffusibility, while the large open cavity ensures efficient encapsulation of lipase (a model enzyme) to provide propulsive force. These unique features collectively result in superior diffusibility, leading to significantly improved catalytic performance compared with conventional large pore mesoporous silica nanoparticles with a spherical morphology. This research provides a new conceptual design and synthetic strategy to develop high-performance nanomotors.

An Intelligent Biomimetic Nanoplatform for Holistic Treatment of Metastatic Triple-Negative Breast Cancer via Photothermal Ablation and Immune Remodeling.

Metastasis is one of the main causes of failure in the treatment of triple-negative breast cancer (TNBC). Immunotherapy brings hope and opportunity to solve this challenge, while its clinical applications are greatly inhibited by the tumor immunosuppressive environment. Here, an intelligent biomimetic nanoplatform was designed based on dendritic large-pore mesoporous silica nanoparticles (DLMSNs) for suppressing metastatic TNBC by combining photothermal ablation and immune remodeling. Taking advantage of the ordered large-pore structure and easily chemically modified property of DLMSNs, the copper sulfide (CuS) nanoparticles with high photothermal conversion efficiency were in situ deposited inside the large pores of DLMSNs, and the immune adjuvant resiquimod (R848) was loaded controllably. A homogenous cancer cell membrane was coated on the surfaces of these DLMSNs, followed by conjugation with the anti-PD-1 peptide AUNP-12 through a polyethylene glycol linker with an acid-labile benzoic-imine bond. The thus-obtained AM@DLMSN@CuS/R848 was applied to holistically treat metastatic TNBC in vitro and in vivo. The data showed that AM@DLMSN@CuS/R848 had a high TNBC-targeting ability and induced efficient photothermal ablation on primary TNBC tumors under 980 nm laser irradiation. Tumor antigens thus generated and increasingly released R848 by response to the photothermal effect, combined with AUNP-12 detached from AM@DLMSN@CuS/R848 in the weakly acidic tumor microenvironment, synergistically exerted tumor vaccination, and T lymphocyte activation functions on immune remodeling to prevent TNBC recurrence and metastasis. Taken together, this study provides an intelligent biomimetic nanoplatform to enhance therapeutic outcomes in metastatic TNBC.

Design of Dendritic Large-Pore Mesoporous Silica Nanoparticles with Controlled Structure and Formation Mechanism in Dual-Templating Strategy.

Dendritic large-pore mesoporous silica nanoparticles (DLMSN) is an important biodegradable drug carrier due to its high porosity, which can be prepared by coassembly of a major template and an auxiliary template in aqueous solution, followed by hydrolysis of tetraethyl orthosilicate (TEOS). The auxiliary template is key to obtaining dendritic large-pore structures; however, how to choose the auxiliary template to obtain the desired pore structure is largely unknown. This is because the formation mechanism of DLMSN is still not clear. In this study, a series of therapeutic agent molecules were used as the auxiliary templates to study the control of the pore morphology of DLMSN. Transmission electron microscopy observation and theoretical modeling were used to study the micelle formation, and early stage silica formation was also observed. It is proposed that the silica branches and sheets formed by hydrolysis of TEOS on single micelle and micelle bundles, which formed the initial nanoparticles with spherical structures and new silica species growing on the early formed particles to form DLMSN. The fine control of pore morphology was demonstrated by using auxiliary templates with different structural characteristics, which were used for selective drug loading. This work provides a design strategy of how to choose suitable auxiliary templates for preparing DLMSN with desired pore structure for biomedical applications.

Targeted arsenite-loaded magnetic multifunctional nanoparticles for treatment of hepatocellular carcinoma

Arsenic trioxide (ATO), an FDA-approved drug for acute promyelocytic leukemia, also has great potential for treatment of solid tumors. Drug delivery powered by recent advances in nanotechnology has boosted the efficacy of many drugs, which is enlightening for applications of ATO in treating solid tumors. Herein, we reported arsenite-loaded multifunctional nanoparticles that are capable of pH-responsive ATO release for treating hepatocellular carcinoma (HCC) and real-time monitoring via magnetic resonance imaging. We fabricated these nanoparticles (designated as magnetic large-pore mesoporous silica nanoparticle (M-LPMSN)-NiAsOx) by loading nanoparticulate ATO prodrugs (NiAsOx) into the pores of large-pore mesoporous silica nanoparticles (LPMSNs) that contain magnetic iron oxide nanoparticles in the center. The surface of these nanodrugs was modified with a targeting ligand folic acid (FA) to further enhance the drug efficacy. Releasing profiles manifest the responsive discharging of arsenite in acidic environment. In vitro experiments with SMMC-7721 cells reveal that M-LPMSN-NiAsOx-FA nanodrugs have significantly higher cytotoxicity than traditional free ATO and induce more cell apoptosis. In vivo experiments with mice bearing H22 tumors further confirm the superior antitumor efficacy of M-LPMSN-NiAsOx-FA over traditional free ATO and demonstrate the outstanding imaging ability of M-LPMSN-NiAsOx-FA for real-time tumor monitoring. These targeted arsenite-loaded magnetic mesoporous silica nanoparticles integrating imaging and therapy hold great promise for treatment of HCC, indicating the auspicious potential of LPMSN-based nanoplatforms.

PH responsive selective protein adsorption by carboxylic acid functionalized large pore mesoporous silica nanoparticles SBA-1

Cubic mesoporous silica nanoparticles (MSNs) with the SBA-1 moiety, functionalized with carboxylic acid (COOH) groups as well as enlarged mesopores, are successfully synthesized using tetraethyl orthosilicate (TEOS) and carboxyethylsilanetriol sodium salt (CES) as silica sources, complexes formed by polyacrylic acid (PAA) and hexadecylpyridinium chloride (CPC) as templates, and trimethylbenzene (TMB) as pore expander. The successful incorporation of organic functionalities are confirmed by 13C and 29Si solid-state NMR. The structural properties of cubic mesostructures are characterized by powder XRD, N2 adsorption-desorption isotherms, and TEM measurements. The prepared MSNs exhibit a remarkably high adsorption capacity of 1138 mg g−1 at pH 8.2 when they are used as the supports to immobilize papain. Both factors of the large pore size of the support and the favorable electrostatic attractions between the carboxylate groups on the adsorbent surface and the papain molecules play important roles in reaching such a high adsorption capacity. The immobilized papain possesses better thermal stability, pH tolerance, and heat resistance in comparison to the free papain. The materials are also used for selective adsorption of a single protein (papain) from the binary mixture of two different types of proteins (papain and hemoglobin). Our results demonstrate that proteins such as papain and hemoglobin with different isoelectric points and shapes can be effectively separated from their binary mixture by simply tuning the pH of the buffer.

Clickable Multifunctional Large-Pore Mesoporous Silica Nanoparticles as Nanocarriers

Large-pore mesoporous silica nanoparticles (LP-MSNs) with defined particle size (<200 nm) are promising carrier systems for the cellular delivery of macromolecules. Ideal nanocarriers should be adaptable in their surface properties to optimize host–guest interactions; thus, surface functionalization of the nanovehicles is highly desirable. In this study, we synthesized various monofunctional LP-MSNs by incorporating different organic groups into the silica framework via a co-condensation approach. Further, we applied a delayed co-condensation strategy to create spatially segregated core–shell bifunctional LP-MSNs. Diverse particle morphologies were obtained by adding different organosilanes to the silica precursor solution. The effect of organosilanes in the co-condensation process on particle size and pore structure formation is also discussed. Surface functional groups were then used for binding stimuli-responsive linkers. These were finally exploited for copper-free click chemistry for cargo conjugatio...

Large-Pore Functionalized Mesoporous Silica Nanoparticles as Drug Delivery Vector for a Highly Cytotoxic Hybrid Platinum-Acridine Anticancer Agent.

Large-pore mesoporous silica nanoparticles (MSN) were prepared and functionalized to serve as a highly robust and biocompatible delivery platform for platinum-acridine (PA) anticancer agents. The material showed a high loading capacity for the dicationic, hydrophilic hybrid agent [PtCl(en)(N-[acridin-9-ylaminoethyl]-N-methylpropionamidine)] dinitrate salt (P1A1) and virtually complete retention of payload at neutral pH in a high-chloride buffer. In acidic media mimicking the pH inside the cell lysosomes, rapid, burst-like release of P1A1 from the nanoparticles is observed. Coating of the materials in phospholipid bilayers resulted in nanoparticles with greatly improved colloidal stability. The lipid and carboxylate-modified nanoparticles containing 40 wt % drug caused S-phase arrest and inhibited cell proliferation in pancreatic cancer cells at submicromolar concentrations similar to carrier-free P1A1. The most striking feature of nanoparticle-delivered P1A1 was that the payload did not escape from the acidified lysosomal vesicles into the cytoplasm, but was shuttled to the nuclear membrane and released into the nucleus.