Sequential delivery of synergistic drugs by silica nanocarriers for enhanced tumour treatment.

Herein hybrid silica nanoparticles have been engineered to direct the sequential delivery of multiple chemotherapeutic drugs in response to external stimuli such as variations in pH. The nanocarriers consist of conventional MCM-41-type nanoparticles, which have been functionalised with an organic ligand (or stalk) grafted onto the external surface. The stalk is designed to "recognise" a complementary molecule, which serves as a "cap" to block the pores of the nanoparticles. First, camptothecin is introduced into the pores by diffusion prior to capping the pore apertures via molecular recognition. The cap, which is a derivative of 5-fluorouracil, serves as a second cytotoxic drug for synergistic chemotherapy. In vitro tests revealed that negligible release of the drugs occurred at pH 7.4, thus avoiding toxic side effects in the blood stream. In contrast, the stalk/cap complex is destabilised within the endolysosomal compartment (pH 5.5) of cancer cells, where release of the drugs was demonstrated. Furthermore, this environmentally responsive system exhibited a synergistic effect of the two drugs, where the pH-triggered release of the cytotoxic cap followed by diffusion-controlled release of the drug cargo within the pores led to essentially complete elimination of breast cancer cells.

Protocells: Modular Mesoporous Silica Nanoparticle-Supported Lipid Bilayers for Drug Delivery.

Mesoporous silica nanoparticle-supported lipid bilayers, termed 'protocells,' represent a potentially transformative class of therapeutic and theranostic delivery vehicle. The field of targeted drug delivery poses considerable challenges that cannot be addressed with a single 'magic bullet'. Consequently, the protocell has been designed as a modular platform composed of interchangeable biocompatible components. The mesoporous silica core has variable size and shape to direct biodistribution and a controlled pore size and surface chemistry to accommodate diverse cargo. The encapsulating supported lipid bilayer can be modified with targeting and trafficking ligands as well as polyethylene glycol (PEG) to effect selective binding, endosomal escape of cargo, drug efflux prevention, and potent therapeutic delivery, while maintaining in vivo colloidal stability. This review describes the individual components of the platform, including the mesoporous silica nanoparticle core and supported lipid bilayer, their assembly (by multiple techniques) into a protocell, and the combined, often synergistic, performance of the protocell based on in vitro and in vivo studies, including the assessment of biocompatibility and toxicity. In closing, the many emerging variations of the protocell theme and the future directions for protocell research are commented on.

Ligand-targeted theranostic nanomedicines against cancer.

Nanomedicines have significant potential for cancer treatment. Although the majority of nanomedicines currently tested in clinical trials utilize simple, biocompatible liposome-based nanocarriers, their widespread use is limited by non-specificity and low target site concentration and thus, do not provide a substantial clinical advantage over conventional, systemic chemotherapy. In the past 20years, we have identified specific receptors expressed on the surfaces of tumor endothelial and perivascular cells, tumor cells, the extracellular matrix and stromal cells using combinatorial peptide libraries displayed on bacteriophage. These studies corroborate the notion that unique receptor proteins such as IL-11Rα, GRP78, EphA5, among others, are differentially overexpressed in tumors and present opportunities to deliver tumor-specific therapeutic drugs. By using peptides that bind to tumor-specific cell-surface receptors, therapeutic agents such as apoptotic peptides, suicide genes, imaging dyes or chemotherapeutics can be precisely and systemically delivered to reduce tumor growth in vivo, without harming healthy cells. Given the clinical applicability of peptide-based therapeutics, targeted delivery of nanocarriers loaded with therapeutic cargos seems plausible. We propose a modular design of a functionalized protocell in which a tumor-targeting moiety, such as a peptide or recombinant human antibody single chain variable fragment (scFv), is conjugated to a lipid bilayer surrounding a silica-based nanocarrier core containing a protected therapeutic cargo. The functionalized protocell can be tailored to a specific cancer subtype and treatment regimen by exchanging the tumor-targeting moiety and/or therapeutic cargo or used in combination to create unique, theranostic agents. In this review, we summarize the identification of tumor-specific receptors through combinatorial phage display technology and the use of antibody display selection to identify recombinant human scFvs against these tumor-specific receptors. We compare the characteristics of different types of simple and complex nanocarriers, and discuss potential types of therapeutic cargos and conjugation strategies. The modular design of functionalized protocells may improve the efficacy and safety of nanomedicines for future cancer therapy.

Hybrid mesoporous silica nanoparticles with pH-operated and complementary H-bonding caps as an autonomous drug-delivery system.

Mesoporous silica nanoparticles (MSNPs) are functionalized with molecular-recognition sites by anchoring a triazine or uracil fragment on the surface. After loading these MSNPs with dyes (propidium iodide or rhodamine B) or with a drug (camptothecin, CPT) they are capped by the complementary fragments, uracil and adenine, respectively, linked to the bulky cyclodextrin ring. These MSNPs are pH-sensitive and indeed, the dye release was observed at acidic pH by continuously monitored fluorescence spectroscopy studies. On the other hand, no dye leakage occurred at neutral pH, hence meeting the non-premature requirement to minimize side effects. In vitro studies were performed and confocal microscopy images demonstrate the internalization of the MSNPs and also dye release in the cells. To investigate the drug-delivery performance, the cytotoxicity of CPT-loaded nanoparticles was tested and cell death was observed. A remarkably lower amount of loaded CPT in the MSNPs (more than 40 times less) proved to be as efficient as free CPT. These results not only demonstrate the drug release after pore opening under lysosomal pH, but they also show the potential use of these MSNPs to significantly decrease the amount of the administered drug.

A designed 5-fluorouracil-based bridged silsesquioxane as an autonomous acid-triggered drug-delivery system.

Two new prodrugs, bearing two and three 5-fluorouracil (5-FU) units, respectively, have been synthesized and were shown to efficiently treat human breast cancer cells. In addition to 5-FU, they were intended to form complexes through H-bonds to an organo-bridged silane prior to hydrolysis-condensation through sol-gel processes to construct acid-responsive bridged silsesquioxanes (BS). Whereas 5-FU itself and the prodrug bearing two 5-FU units completely leached out from the corresponding materials, the prodrug bearing three 5-FU units was successfully maintained in the resulting BS. Solid-state NMR ((29) Si and (13) C) spectroscopy show that the organic fragments of the organo-bridged silane are retained in the hybrid through covalent bonding and the (1) H NMR spectroscopic analysis provides evidence for the hydrogen-bonding interactions between the prodrug bearing three 5-FU units and the triazine-based hybrid matrix. The complex in the BS is not affected under neutral medium and operates under acidic conditions even under pH as high as 5 to deliver the drug as demonstrated by HPLC analysis and confirmed by FTIR and (13) C NMR spectroscopic studies. Such functional BS are promising materials as carriers to avoid the side effects of the anticancer drug 5-FU thanks to a controlled and targeted drug delivery.