In this work, hollow mesoporous silica nanoparticles (HMSNs) with three pore sizes were manufactured to control the drug release rate, and the biological roles of these HMSNs were evaluated in multidrug-resistant (MDR) cancer cells. As novel pore-size-controllable inorganic materials, HMSNs showed negligible cytotoxicity and efficient cellular uptake toward drug-sensitive MCF-7 and drug-resistant MCF-7/ADR cells. Doxorubicin (DOX)-loaded HMSNs (DMSNs) not only demonstrated effective drug loading and a pH-responsive drug release character but also exhibited pore-size-dependent and sustained drug release performance in both in vitro and intracellular drug release experiments. In addition, DMSNs exhibited pore-size-dependent anticancer activity against MCF-7/ADR cells. DMSNs with larger pore size could mediate more cellular uptake of DOX and faster intracellular drug release, which led to more intracellular drug accumulation and stronger MDR-reversal effects. The MDR-overcoming mechanism could be due to the efficient cellular uptake, P-gp inhibition, and ATP depletion. These results demonstrate that HMSNs could be a very promising drug delivery system for pore-size-controllable drug release and cancer MDR reversion.

This work evaluates the cytotoxicity of spherical mesoporous silica (MS) nano- and microparticles and investigates the effects of particle size, concentration, biodegradation products of MS, residual surfactant, and surfactant removal by extraction and calcination on the cytotoxicity. The results from the intracellular localization of spherical MS nano- and microparticles with different sizes reveal the mechanism for their cytotoxicity and that the smaller particles in nanoscale are more easily endocytosed and consequently located within lysosomes.

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A novel drug‐formulation protocol is developed to solve the delivery problem of hydrophobic drug molecules by using inorganic mesoporous silica nanocapsules (IMNCs) as an alternative to traditional organic emulsions and liposomes while preserving the advantages of inorganic materials. The unique structures of IMNCs are engineered by a novel fluoride‐silica chemistry based on a structural difference‐based selective etching strategy. The prepared IMNCs combine the functions of organic nanoemulsions or nanoliposomes with the properties of inorganic materials. Various spherical nanostructures can be fabricated simply by varying the synthetic parameters. The drug loading amount of a typical highly hydrophobic anticancer drug‐camptothecin (CPT) in IMNCs reaches as high as 35.1 wt%. The intracellular release of CPT from carriers is demonstrated in situ. In addition, IMNCs can play the role of organic nanoliposome (multivesicular liposome) in co‐encapsulating and co‐delivering hydrophobic (CPT) and hydrophilic (doxorubicin, DOX) anticancer drugs simultaneously. The co‐delivery of multi‐drugs in the same carrier and the intracellular release of the drug combinations enables a drug delivery system with efficient enhanced chemotherapeutic effect for DOX‐resistant MCF‐7/ADR cancer cells. The special IMNCs‐based “inorganic nanoemulsion”, as a proof‐of‐concept, can also be employed successfully to encapsulate and deliver biocompatible hydrophobic perfluorohexane (PFH) molecules for high intensity focused ultrasound (HIFU) synergistic therapy ex vivo and in vivo. Based on this novel design strategy, a wide range of inorganic material systems with similar “inorganic nanoemulsion or nanoliposome” functions will be developed to satisfy varied clinical requirements.

Multidrug resistance (MDR) is one of the major obstacles for successful chemotherapy in cancer. One of the effective approaches to overcome MDR is to use nanoparticle-mediated drug delivery to increase drug accumulation in drug resistant cancer cells. In this work, we first report that the performance and mechanism of an inorganic engineered delivery system based on mesoporous silica nanoparticles (MSNs) loading doxorubicin (DMNs) to overcome the MDR of MCF-7/ADR (a DOX-resistant and P-glycoprotein (P-gp) over-expression cancer cell line). The experimental results showed that DMNs could enhance the cellular uptake of doxorubicin (DOX) and increase the cell proliferation suppression effect of DOX against MCF-7/ADR cells. The IC(50) of DMNs against MCF-7/ADR cells was 8-fold lower than that of free DOX. However, an improved effect of DOX in DMNs against MCF-7 cells (a DOX-sensitive cancer cell line) was not found. The increased cellular uptake and nuclear accumulation of DOX delivered by DMNs in MCF-7/ADR cells was confirmed by confocal laser scanning microscopy, and could result from the down-regulation of P-gp and bypassing the efflux action by MSNs themselves. The cellular uptake mechanism of DMNs indicated that the macropinocytosis was one of the pathways for the uptake of DMNs by MCF-7/ADR cells. The in vivo biodistribution showed that DMNs induced a higher accumulation of DOX in drug resistant tumors than free DOX. These results suggested that MSNs could be an effective delivery system to overcome multidrug resistance.

Recent advances in the understanding of molecular recognition and protein–ligand interactions have facilitated rapid development of potent and selective ligands for therapeutically relevant targets. Over the past two decades, a variety of useful approaches and emerging techniques have been developed to promote the identification and optimization of leads that have high potential for generating new therapeutic agents. Intriguingly, the innovation of a fragment-based drug design (FBDD) approach has enabled rapid and efficient progress in drug discovery. In this critical review, we focus on the construction of fragment libraries and the advantages and disadvantages of various fragment-based screening (FBS) for constructing such libraries. We also highlight the deconstruction–reconstruction strategy by utilizing privileged fragments of reported ligands.