Involvement of lysosomal exocytosis in the excretion of mesoporous silica nanoparticles and enhancement of the drug delivery effect by exocytosis inhibition.

The exocytosis of phosphonate modified mesoporous silica nanoparticles (P-MSNs) is demonstrated and lysosomal exocytosis is identified as the mechanism responsible for this event. Regulation of P-MSN exocytosis can be achieved by inhibiting or accelerating lysosomal exocytosis. Slowing down P-MSN exocytosis enhances the drug delivery effect of CPT-loaded P-MSNs by improving cell killing.

Surface defects on plate-shaped silver nanoparticles contribute to its hazard potential in a fish gill cell line and zebrafish embryos.

We investigated and compared nanosize Ag spheres, plates, and wires in a fish gill epithelial cell line (RT-W1) and in zebrafish embryos to understand the mechanism of toxicity of an engineered nanomaterial raising considerable environmental concern. While most of the Ag nanoparticles induced N-acetyl cysteine sensitive oxidative stress effects in RT-W1, Ag nanoplates were considerably more toxic than other particle shapes. Interestingly, while Ag ion shedding and bioavailability failed to comprehensively explain the high toxicity of the nanoplates, cellular injury required direct particle contact, resulting in cell membrane lysis in RT-W1 as well as red blood cells (RBC). Ag nanoplates were also considerably more toxic in zebrafish embryos in spite of their lesser ability to shed Ag into the exposure medium. To elucidate the "surface reactivity" of Ag nanoplates, high-resolution transmission electron microscopy was performed and demonstrated a high level of crystal defects (stacking faults and point defects) on the nanoplate surfaces. Surface coating with cysteine was used to passivate the surface defects and demonstrated a reduction of toxicity in RT-W1 cells, RBC, and zebrafish embryos. This study demonstrates the important role of crystal defects in contributing to Ag nanoparticle toxicity in addition to the established roles of Ag ion shedding by Ag nanoparticles. The excellent correlation between the in vitro and in vivo toxicological assessment illustrates the utility of using a fish cell line in parallel with zebrafish embryos to perform a predictive environmental toxicological paradigm.

Targeted intracellular delivery of antituberculosis drugs to Mycobacterium tuberculosis-infected macrophages via functionalized mesoporous silica nanoparticles.

Delivery of antituberculosis drugs by nanoparticles offers potential advantages over free drug, including the potential to target specifically the tissues and cells that are infected by Mycobacterium tuberculosis, thereby simultaneously increasing therapeutic efficacy and decreasing systemic toxicity, and the capacity for prolonged release of drug, thereby allowing less-frequent dosing. We have employed mesoporous silica nanoparticle (MSNP) drug delivery systems either equipped with a polyethyleneimine (PEI) coating to release rifampin or equipped with cyclodextrin-based pH-operated valves that open only at acidic pH to release isoniazid (INH) into M. tuberculosis-infected macrophages. The MSNP are internalized efficiently by human macrophages, traffic to acidified endosomes, and release high concentrations of antituberculosis drugs intracellularly. PEI-coated MSNP show much greater loading of rifampin than uncoated MSNP and much greater efficacy against M. tuberculosis-infected macrophages. MSNP were devoid of cytotoxicity at the particle doses employed for drug delivery. Similarly, we have demonstrated that the isoniazid delivered by MSNP equipped with pH-operated nanovalves kill M. tuberculosis within macrophages significantly more effectively than an equivalent amount of free drug. These data demonstrate that MSNP provide a versatile platform that can be functionalized to optimize the loading and intracellular release of specific drugs for the treatment of tuberculosis.

Mechanized silica nanoparticles: a new frontier in theranostic nanomedicine.

Medicine can benefit significantly from advances in nanotechnology because nanoscale assemblies promise to improve on previously established therapeutic and diagnostic regimes. Over the past decade, the use of delivery platforms has attracted attention as researchers shift their focus toward new ways to deliver therapeutic and/or diagnostic agents and away from the development of new drug candidates. Metaphorically, the use of delivery platforms in medicine can be viewed as the "bow-and-arrow" approach, where the drugs are the arrows and the delivery vehicles are the bows. Even if one possesses the best arrows that money can buy, they will not be useful if one does not have the appropriate bow to deliver the arrows to their intended location. Currently, many strategies exist for the delivery of bioactive agents within living tissue. Polymers, dendrimers, micelles, vesicles, and nanoparticles have all been investigated for their use as possible delivery vehicles. With the growth of nanomedicine, one can envisage the possibility of fabricating a theranostic vector that could release powerful therapeutics and diagnostic markers simultaneously and selectively to diseased tissue. In our design of more robust theranostic delivery systems, we have focused our attention on using mesoporous silica nanoparticles (SNPs). The payload "cargo" molecules can be stored within this robust domain, which is stable to a wide range of chemical conditions. This stability allows SNPs to be functionalized with stimulus-responsive mechanically interlocked molecules (MIMs) in the shape of bistable rotaxanes and psuedorotaxanes to yield mechanized silica nanoparticles (MSNPs). In this Account, we chronicle the evolution of various MSNPs, which came about as a result of our decade-long collaboration, and discuss advances in the synthesis of novel hybrid SNPs and the various MIMs which have been attached to their surfaces. These MIMs can be designed in such a way that they either change shape or shed off some of their parts in response to a specific stimulus, such as changes in redox potential, alterations in pH, irradiation with light, or the application of an oscillating magnetic field, allowing a theranostic payload to be released from the nanopores to a precise location at the appropiate time. We have also shown that these integrated systems can operate not only within cells, but also in live animals in response to pre-existing biological triggers. Recognizing that the theranostics of the future could offer a fresh approach to the treatment of degenerative diseases including cancer, we aim to start moving out of the chemical domain and into the biological one. Some MSNPs are already being tested in biological systems.

Synthesis of biomolecule-modified mesoporous silica nanoparticles for targeted hydrophobic drug delivery to cancer cells.

Synthetic methodologies integrating hydrophobic drug delivery and biomolecular targeting with mesoporous silica nanoparticles are described. Transferrin and cyclic-RGD peptides are covalently attached to the nanoparticles utilizing different techniques and provide selectivity between primary and metastatic cancer cells. The increase in cellular uptake of the targeted particles is examined using fluorescence microscopy and flow cytometry. Transferrin-modified silica nanoparticles display enhancement in particle uptake by Panc-1 cancer cells over that of normal HFF cells. The endocytotic pathway for these particles is further investigated through plasmid transfection of the transferrin receptor into the normal HFF cell line, which results in an increase in particle endocytosis as compared to unmodified HFF cells. By designing and attaching a synthetic cyclic-RGD, selectivity between primary cancer cells (BT-549) and metastatic cancer cells (MDA-MB 435) is achieved with enhanced particle uptake by the metastatic cancer cell line. Incorporation of the hydrophobic drug Camptothecin into these two types of biomolecular-targeted nanoparticles causes an increase in mortality of the targeted cancer cells compared to that caused by both the free drug and nontargeted particles. These results demonstrate successful biomolecular-targeted hydrophobic drug delivery carriers that selectively target specific cancer cells and result in enhanced drug delivery and cell mortality.

Nanomaterials in the environment: from materials to high-throughput screening to organisms.

One of the challenges in the field of nanotechnology is environmental health and safety (EHS), including consideration of the properties of engineered nanomaterials (ENMs) that could pose dangers to the environment. Progress in the field of nanomaterial development and nanotoxicology was presented at the International Conference on the Environmental Implications of Nanotechnology at the California NanoSystems Institute (CNSI) on the UCLA campus on May 11-14, 2010. This event was cohosted by the University of California Center for the Environmental Implications of Nanotechnology (UC CEIN) and the Center for the Environmental Implications of NanoTechnology (CEINT) based at Duke University. Participants included scientists and scholars from various backgrounds, including chemistry, biology, engineering, nanomaterial science, toxicology, ecology, mathematics, sociology, and policy makers. The topics of discussion included safety evaluation of ENMs from an environmental perspective, nanotoxicology, ecotoxicology, safe design of ENMs, environmental risk assessment, public perception of nanotechnology, application of ENMs in consumer products, and many more. The UC CEIN presented data on their predictive toxicological approach to the assessment of ENM libraries, which were designed and synthesized to develop an understanding of the material properties that could lead to hazard generation at the cellular and organismal levels in the environment. This article will focus on the first metal oxide ENM library that was introduced to harmonize research activities in the UC CEIN, with particular emphasis on the safety assessment of ZnO on cells and organisms. Methods of decreasing the observed toxic effects will also be discussed as an integral component of the UC CEIN's activity in developing safer nanomaterials to lessen their environmental impacts.

Noninvasive remote-controlled release of drug molecules in vitro using magnetic actuation of mechanized nanoparticles.

Mesoporous silica nanoparticles are useful nanomaterials that have demonstrated the ability to contain and release cargos with mediation by gatekeepers. Magnetic nanocrystals have the ability to exhibit hyperthermic effects when placed in an oscillating magnetic field. In a system combining these two materials and a thermally sensitive gatekeeper, a unique drug delivery system can be produced. A novel material that incorporates zinc-doped iron oxide nanocrystals within a mesoporous silica framework that has been surface-modified with pseudorotaxanes is described. Upon application of an AC magnetic field, the nanocrystals generate local internal heating, causing the molecular machines to disassemble and allowing the cargos (drugs) to be released. When breast cancer cells (MDA-MB-231) were treated with doxorubicin-loaded particles and exposed to an AC field, cell death occurred. This material promises to be a noninvasive, externally controlled drug delivery system with cancer-killing properties.