Mesoporous silica nanoparticle supported-lipid bilayers, termed ‘protocells,’ represent a potentially transformative class of therapeutic and theranostic delivery vehicles. 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 can have variable size and shape to direct biodistribution and controlled pore size and surface chemistry to accommodate diverse cargos. The encapsulating supported lipid bilayer can be modified with targeting and trafficking ligands as well as PEG to effect selective binding, endosomal escape of cargo, drug efflux prevention, and potent therapeutic delivery, while maintaining in vivo colloidal stability. This mini-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 assessment of biocompatibility and toxicity. We close by commenting on the many emerging variations of the protocell theme and the future directions for protocell research.
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 20 years, 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.
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.
In recent years, significant effort has been focused toward the synthesis of porous materials with potential applications such as for drug-delivery carriers 1À3 and for catalysis. 4 These materials consist of either organic or inorganic polymers, 5,6 among which silica meets most of the requirements as a good support: chemical inertness, thermal and mechanical stability, and also the possibility of tailoring the size and the shape of the pores and cavities inside the materials. 7À9 Mesoporous materials were obtained using surfactants as structuring agents and from this surfactant-mediated route, organic groups may be covalently anchored in two ways: (1) grafting a functional alkoxysilane on a preformed mesoporous silica (MCM-or SBA-type); and (2) co-condensation of the functional alkoxysilane with TEOS in the presence of a suitable surfactant. 10À12 Following these two methods, many forms of functional mesoporous hybrids have been synthesized and exploited for many applications. 13 For example, mechanized nanomachines have been prepared for on-demand release of cargo molecules (including drugs, dyes, biomolecules, etc.) 14 as well as easily recoverable and recyclable homogeneous catalysts supported on hybrid porous silicates which have applications in a variety of chemical processes. 15 Hybrid mesoporous silica can also be prepared via the self-assembly of organopolysilane precursors bearing a long alkylene chain. In this case, self-structuring occurs to form a purely hybrid silica without added TEOS and without any surfactant. 16,17 Complementary to these are the periodic mesoporous organosilicates (PMO) obtained from bridged silsesquioxane precursors, which are prepared with surfactants. 18,19 In the series of bridged silsesquioxanes, labile SiÀC covalently bonded ethynyl units were softly cleaved by a chemical route to afford mesoporous silica. 20 The pore sizes and distribution were dependent on both the structure of the sacrificial ethynyl templates and the reaction conditions employed. 21 Porous materials can also be obtained by molecular imprinting techniques which are used to create solid materials containing chemical functionalities that are spatially localized and fixed by interactions with the imprint molecules during the synthesis process. Subsequent removal of these template molecules leaves preformed sites for the recognition of small molecules, hence affording materials which may be suitable for applications in separation chemistry. 22 Indeed, protein-imprinted silica prepared via covalent imino group bonding showed enhanced affinity for the template protein compared to the corresponding imprinted silica obtained by entrapment of the protein with no interaction of the latter with the silica surface. 23 Using a chiral cationic surfactant in conjunction with solÀgel processing, chiral imprinted silicabased thin films were obtained, which exhibited good selectivity toward chiral alcohols. 24 Imprinted polysilsesquioxanes have also been obtained by the co-condensation of a bridged organosilane (BTSE) p...
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.
We present a general and in-depth study of the effect of dopants in hybrid inorganic/organic ZnO/PAA (polyacrylic acid) nanocomposites. These dopants vary as much by their ionic size, as by their electronic valence and some of them have been used in ZnO due to their known magnetic and/or optical properties. The chemical nature of the dopants controls their ability to incorporate into ZnO crystal lattice. Three concentrations (0.1%, 1% and 5%) of dopants were studied in order to compare the effect of the concentration with the results obtained previously in the literature. Our results confirm in the first place the trend observed in the literature, that increase in dopant concentration leads to quenching of visible luminescence for ZnO nanocrystals obtained by very different processes. However, the degradation of photoluminescence quantum yield (PL QY) is not inevitable in our nanocomposites. At low doping concentration for some dopants with a small or comparable ionic radius than Zn 2+ , PL QY can be maintained or even improved, making it possible to tune the visible emission spectrum between 2.17 eV and 2.46 eV. This opens up the prospect of synthesizing phosphors without rare earth for white LEDs, whose spectrum can be tuned to render warm or cold white light, by a chemical synthesis process with a low environmental impact.
The effect of a silica coating on the improvement of the visible light emission properties of ZnO/polyacrylic acid (PAA) nanohybrids is reported. The synthesized material consists of ZnO nanocrystals incorporated into the PAA mesospheres and then coated with silica. The silica amount can be controlled by the concentration of ammonia used in the sol-gel process as catalyst. The interaction between PAA and ammonia is crucial, the presence of the former tending to inhibit the catalytic action of the latter. We show that there is an optimum in the silica amount around the mesospheres, which leads to a drastic increase in the defect-related visible photoluminescence quantum yield of ZnO nanocrystals. A six-fold increase of the quantum yield can thus be achieved, reaching competitive values higher than 60%. This optimum is a compromise between a complete protective silica layer around the mesospheres and too thick a layer inducing inefficient absorption of excitation light by the coating.
New tetrasilylated precursors with molecular recognition properties were synthesized.pH-sensitive and loaded non porous bridged silsesquioxane nanoparticles (nano-BS) were prepared.Nano-BS were internalized into cancer cells.
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