Bioinspired Diselenide‐Bridged Mesoporous Silica Nanoparticles for Dual‐Responsive Protein Delivery

Controlled delivery of protein therapeutics remains a challenge. Here, the inclusion of diselenide‐bond‐containing organosilica moieties into the framework of silica to fabricate biodegradable mesoporous silica nanoparticles (MSNs) with oxidative and redox dual‐responsiveness is reported. These diselenide‐bridged MSNs can encapsulate cytotoxic RNase A into the 8–10 nm internal pores via electrostatic interaction and release the payload via a matrix‐degradation controlled mechanism upon exposure to oxidative or redox conditions. After surface cloaking with cancer‐cell‐derived membrane fragments, these bioinspired RNase A‐loaded MSNs exhibit homologous targeting and immune‐invasion characteristics inherited from the source cancer cells. The efficient in vitro and in vivo anti‐cancer performance, which includes increased blood circulation time and enhanced tumor accumulation along with low toxicity, suggests that these cell‐membrane‐coated, dual‐responsive degradable MSNs represent a promising platform for the delivery of bio‐macromolecules such as protein and nucleic acid therapeutics.     

Mesoporous Silica Nanoparticles for Intracellular Controlled Drug Delivery

The application of nanotechnology in the field of drug delivery has attracted much attention in the latest decades. Recent breakthroughs on the morphology control and surface functionalization of inorganic‐based delivery vehicles, such as mesoporous silica nanoparticles (MSNs), have brought new possibilities to this burgeoning area of research. The ability to functionalize the surface of mesoporous‐silica‐based nanocarriers with stimuli‐responsive groups, nanoparticles, polymers, and proteins that work as caps and gatekeepers for controlled release of various cargos is just one of the exciting results reported in the literature that highlights MSNs as a promising platform for various biotechnological and biomedical applications. This review focuses on the most recent progresses in the application of MSNs for intracellular drug delivery. The latest research on the pathways of entry into live mammalian and plant cells together with intracellular trafficking are described. One of the main areas of interest in this field is the development of site‐specific drug delivery vehicles; the contribution of MSNs toward this topic is also summarized. In addition, the current research progress on the biocompatibility of this material in vitro and in vivo is discussed. Finally, the latest breakthroughs for intracellular controlled drug release using stimuli‐responsive mesoporous‐silica‐based systems are described.     

Mesoporous Silica Nanoparticles: Synthesis,Biocompatibility and Drug Delivery

In the past decade, mesoporous silica nanoparticles (MSNs) have attracted more and more attention for their potential biomedical applications. With their tailored mesoporous structure and high surface area, MSNs as drug delivery systems (DDSs) show significant advantages over traditional drug nanocarriers. In this review, we overview the recent progress in the synthesis of MSNs for drug delivery applications. First, we provide an overview of synthesis strategies for fabricating ordered MSNs and hollow/rattle‐type MSNs. Then, the in vitro and in vivo biocompatibility and biotranslocation of MSNs are discussed in relation to their chemophysical properties including particle size, surface properties, shape, and structure. The review also highlights the significant achievements in drug delivery using mesoporous silica nanoparticles and their multifunctional counterparts as drug carriers. In particular, the biological barriers for nano‐based targeted cancer therapy and MSN‐based targeting strategies are discussed. We conclude with our personal perspectives on the directions in which future work in this field might be focused.     

Mesoporous Silica Nanoparticles Act as a Self‐Adjuvant for Ovalbumin Model Antigen in Mice

Immunization to the model protein antigen ovalbumin (OVA) is investigated using MCM‐41 mesoporous silica nanoparticles as a novel vaccine delivery vehicle and adjuvant system in mice. The effects of amino surface functionalization and adsorption time on OVA adsorption to nanoparticles are assessed. Amino‐functionalized MCM‐41 (AM‐41) shows an effect on the amount of OVA binding, with 2.5‐fold increase in binding capacity (72 mg OVA/g AM‐41) compared to nonfunctionalized MCM‐41 (29 mg OVA/g MCM‐41). Immunization studies in mice with a 10 μg dose of OVA adsorbed to AM‐41 elicits both antibody and cell‐mediated immune responses following three subcutaneous injections. Immunizations at a lower 2 μg dose of OVA adsorbed to AM‐41 particles results in an antibody response but not cell‐mediated immunity. The level of antibody responses following immunization with nanoformulations containing either 2 μg or 10 μg of OVA are only slightly lower than that in mice which receive 50 μg OVA adjuvanted with QuilA, a crude mixture of saponins extracted from the bark of the Quillaja saponaria Molina tree. This is a significant result, since it demonstrates that AM‐41 nanoparticles are self‐adjuvanting and elicit immune responses at reduced antigen doses in vivo compared to a conventional delivery system. Importantly, there are no local or systemic negative effects in animals injected with AM‐41. Histopathological studies of a range of tissue organs show no changes in histopathology of the animals receiving nanoparticles over a six week period. These results establish the biocompatible MCM‐41 silica nanoparticles as a new method for vaccine delivery which incorporates a self‐adjuvant effect.     

Cancer‐Cell‐Specific Induction of Apoptosis Using Mesoporous Silica Nanoparticles as Drug‐Delivery Vectors

Targeted delivery of the chemotherapeutic agent methotrexate (MTX) to cancer cells using poly(ethyleneimine)‐functionalized mesoporous silica particles as drug‐delivery vectors is reported. Due to its high affinity for folate receptors, the expression of which is elevated in cancer cells, MTX serves as both a targeting ligand and a cytotoxic agent. Enhanced cancer‐cell apoptosis (programmed cell death) relative to free MTX is thus observed at particle concentrations where nonspecific MTX‐induced apoptosis is not observed in the nontargeted healthy cell line, while corresponding amounts of free drug affect both cell lines equally. The particles remain compartmentalized in endo‐/lysosomes during the time of observation (up to 72 h), while the drug is released from the particle only upon cell entry, thereby inducing selective apoptosis in the target cells. As MTX is mainly attached to the particle surface, an additional advantage is that the presented carrier design allows for adsorption (loading) of additional drugs into the pore network for therapies based on a combination of drugs.     

A Vesicle Supra‐Assembly Approach to Synthesize Amine‐Functionalized Hollow Dendritic Mesoporous Silica Nanospheres for Protein Delivery

Intracellular delivery of proteins is a promising strategy of intervention in disease, which relies heavily on the development of efficient delivery platforms due to the cell membrane impermeability of native proteins, particularly for negatively charged large proteins. This work reports a vesicle supra‐assembly approach to synthesize novel amine‐functionalized hollow dendritic mesoporous silica nanospheres (A‐HDMSN). An amine silica source is introduced into a water–oil reaction solution prior to the addition of conventional silica source tetraethylorthosilicate. This strategy favors the formation of composite vesicles as the building blocks which further assemble into the final product. The obtained A‐HDMSN have a cavity core of ≈170 nm, large dendritic mesopores of 20.7 nm in the shell and high pore volume of 2.67 cm³ g^?1. Compared to the calcined counterpart without amine groups (C‐HDMSN), A‐HDMSN possess enhanced loading capacity to large negative proteins (IgG and β‐galactosidase) and improved cellular uptake performance, contributed by the cationic groups. A‐HDMSN enhance the intracellular uptake of β‐galactosidase by up to 5‐fold and 40‐fold compared to C‐HDMSN and free β‐galactosidase, respectively. The active form of β‐galactosidase delivered by A‐HDMSN retains its intracellular catalytic functions.     

Biocompatibility,Biodistribution, and Drug‐Delivery Efficiency of Mesoporous Silica Nanoparticles for Cancer Therapy in Animals

Mesoporous silica nanoparticles (MSNs) are a promising material for drug delivery. In this Full Paper, MSNs are first shown to be well tolerated, as demonstrated by serological, hematological, and histopathological examinations of blood samples and mouse tissues after MSN injection. Biodistribution studies using human cancer xenografts are carried out with in vivo imaging and fluorescent microscopy imaging, as well as with inductively coupled plasma mass spectroscopy. The results show that MSNs preferentially accumulate in tumors. Finally, the drug‐delivery capability of MSNs is demonstrated by following tumor growth in mice treated with camptothecin‐loaded MSNs. These results indicate that MSNs are biocompatible, preferentially accumulate in tumors, and effectively deliver drugs to the tumors and suppress tumor growth.     

Safe and Effective Reversal of Cancer Multidrug Resistance Using Sericin‐Coated Mesoporous Silica Nanoparticles for Lysosome‐Targeting Delivery in Mice

Multidrug resistance (MDR) and adverse side effects are the major challenges facing cancer chemotherapy. Here, pH/protease dually responsive, sericin‐coated mesoporous silica nanoparticles (SMSNs) for lysosomal delivery of doxorubicin (DOX) to overcome MDR and reduce systemic toxicity are reported. Sericin, a natural protein from silkworm cocoons, is coated onto MSNs as a gatekeeper via pH sensitive imine linkages. The sericin shell prevents the premature leakage of encapsulated DOX from MSNs in extracellular environment. Once reaching drug‐resistant tumors, sericin's cell‐adhesive bioactivity enhances cellular uptake of SMSNs that are in turn transported into perinuclear lysosomes, thus avoiding drug efflux mediated by membrane‐bound pumps. Lysosomal acidity triggers cleavage of pH sensitive linkage between sericin and MSNs concurrently with lysosomal proteases deconstructing sericin shell. This pH/protease dual responsiveness leads to DOX burst release into cell nuclei, inducing effective cell death, thus reversing MDR. These DOX‐loaded SMSNs not only effectively kill drug‐resistant cells in vitro, but also significantly reduce the growth of DOX‐resistant MCF‐7/ADR (breast cancer cells) tumor by 70% in a preclinical animal model without eliciting systemic toxicity frequently encountered in current clinical therapeutic formulations. Thus, the dually responsive SMSNs are an effective, lysosome‐tropic, and bio‐safe delivery system for chemotherapeutics for combating MDR.     

共担载阿霉素/血红蛋白树枝状介孔硅球的制备及其生物性能研究

实体瘤中普遍存在乏氧现象, 是导致肿瘤对非手术治疗手段抗拒性增加, 降低药物疗效的重要因素。针对这一问题, 本研究采用简单的两相界面法制备了一种小尺寸(65 nm)、单分散、生物稳定性良好的可共载抗癌药物盐酸阿霉素(DOX)和载氧蛋白血红蛋白(Hb)的树枝状介孔硅纳米颗粒(DMSNs)。利用扫描电子显微镜(SEM)、透射电子显微镜(TEM)、动态光散射仪(DLS)和氮气吸附-脱附仪等对材料进行表征。结果表明, 合成的DMSNs纳米颗粒粒径均一、分散性良好, 具有较大的比表面积(654.52 m²/g)和孔容(1.26 cm³/g)以及两套孔道结构(直径2.7 nm和5.4~6.8 nm)。更重要的是, 树枝状介孔层的孔径仅需改变三乙醇胺(TEA)的用量即可调节。药物释放、流式细胞术、激光共聚焦以及细胞毒性等相关实验结果表明, DMSNs可同时装载DOX与Hb, 且具有较高的药物释放能力(75.6%)和持久的释放性能(48 h)。载入血红蛋白后, 其IC₅₀为20.6 μg/mL, 能够有效提高抗癌药物DOX的细胞致死率。因此, 这种小尺寸的树枝状介孔硅球在药物传输和肿瘤治疗方面具有潜在的应用价值。