Glutathione-Scavenging Poly(disulfide amide) Nanoparticles for the Effective Delivery of Pt(IV) Prodrugs and Reversal of Cisplatin Resistance.

Despite the broad antitumor spectrum of cisplatin, its therapeutic efficacy in cancer treatment is compromised by the development of drug resistance in tumor cells and systemic side effects. A close correlation has been drawn between cisplatin resistance in tumor cells and increased levels of intracellular thiol-containing species, especially glutathione (GSH). The construction of a unique nanoparticle (NP) platform composed of poly(disulfide amide) polymers with a high disulfide density for the effective delivery of Pt(IV) prodrugs capable of reversing cisplatin resistance through the disulfide-group-based GSH-scavenging process, as described herein, is a promising route by which to overcome limitations associated with tumor resistance. Following systematic screening, the optimized NPs (referred to as CP5 NPs) showed a small particle size (76.2 nm), high loading of Pt(IV) prodrugs (15.50% Pt), a sharp response to GSH, the rapid release of platinum (Pt) ions, and notable apoptosis of cisplatin-resistant A2780cis cells. CP5 NPs also exhibited long blood circulation and high tumor accumulation after intravenous injection. Moreover, in vivo efficacy and safety results showed that CP5 NPs effectively inhibited the growth of cisplatin-resistant xenograft tumors with an inhibition rate of 83.32% while alleviating serious side effects associated with cisplatin. The GSH-scavenging nanoplatform is therefore a promising route by which to enhance the therapeutic index of Pt drugs used currently in cancer treatment.

Development of multinuclear polymeric nanoparticles as robust protein nanocarriers.

One limitation of current biodegradable polymeric nanoparticles is their inability to effectively encapsulate and sustainably release proteins while maintaining protein bioactivity. Here we report the engineering of PLGA-polycation nanoparticles with a core-shell structure that act as a robust vector for the encapsulation and delivery of proteins and peptides. The optimized nanoparticles can load high amounts of proteins (>20 % of nanoparticles by weight) in aqueous solution without organic solvents through electrostatic interactions by simple mixing, thereby forming nanospheres in seconds with diameters <200 nm. The relationship between nanosphere size, surface charge, PLGA-polycation composition, and protein loading is also investigated. The stable nanosphere complexes contain multiple PLGA-polycation nanoparticles, surrounded by large amounts of protein. This study highlights a novel strategy for the delivery of proteins and other relevant molecules.

Quantum Ensembles of Silicon Nanoparticles: Discrimination of Static and Dynamic Photoluminescence Quenching Processes.

Porous silicon photoluminescence is characterized by a broad emission band that displays unusually long (tens to hundreds of micro-seconds), wavelength-dependent emissive lifetimes. The photoluminescence is associated with quantum confinement of excitons in silicon nanocrystallites contained within the porous matrix, and the broad emission spectrum derives from the wide distribution of nanocrystallite sizes in the material. The longer emissive lifetimes in the ensemble of quantum-confined emitters correspond to the larger nanocrystallites, with their longer wavelengths of emission. The quenching of this photoluminescence by aromatic, redox-active molecules aminochrome (AMC), dopamine, adrenochrome, sodium anthraquinone-2-sulfonate, benzyl viologen dichloride, methyl viologen dichloride hydrate, and ethyl viologen dibromide is studied, and dynamic and static quenching mechanisms are distinguished by the emission lifetime analysis. Because of the dependence of the emission lifetime on emission wavelength from the silicon nanocrystallite ensemble, a pronounced blue shift is observed in the steady-state emission spectrum upon exposure to dynamic-type quenchers. Conversely, static-type quenching systems show uniform quenching across all emission wavelengths. Thus, the difference between static and dynamic quenching mechanisms is readily distinguished by ratiometric photoluminescence spectroscopy. The application of this concept to imaging of AMC, the oxidized form of the neurotransmitter dopamine that is of interest for its role in neurodegenerative diseases, is demonstrated. It is found that static electron acceptors result in no ratiometric contrast, while AMC shows a strong contrast, allowing ready visualization in a 2-D imaging experiment.

Poly(ester amide)-based hybrid hydrogels for efficient transdermal insulin delivery.

Transdermal drug delivery is an attractive, non-invasive treatment. It can avoid first-pass hepatic metabolism and provides the possibility of self-administration. Hydrogels are promising biomaterials due to their important qualities such as biocompatibility and biodegradability. Recently, there has been tremendous growth in the area of hydrogels for transdermal drug delivery. In this work, a new kind of arginine-based poly(ester amide) (Arg-PEA) and polyethylene glycol diacrylamide (PEG-DA) hybrid hydrogel was developed for transdermal drug delivery. The hydrogels not only possess excellent swelling capacity, but also have good mechanical properties, which were then evaluated as drug delivery agents using insulin as a model system. Cytotoxicity testing and in vivo skin irritation tests demonstrated that the hydrogels were biocompatible. Finally, the results indicated that the prepared hydrogels could not only perform transdermal drug delivery, but also might regulate blood glucose levels in a mouse model with streptozotocin-induced diabetes.

Biomimetic Shells Endow Sub-50 nm Nanoparticles with Ultrahigh Paclitaxel Payloads for Specific and Robust Chemotherapy.

Poor loading capacity and nonspecific tumor accumulation of current drug delivery system remain the critical challenges that prevent nanomedicine from maximizing therapeutic efficacy in cancer treatment. Herein, poly(ester amide) polymers composed of cationic and hydrophobic segments were formulated with a paclitaxel/human serum albumin (PTX/HSA) complex, as well as free PTX, to construct a core-shell nanoparticle (NP) platform with the interior simultaneously reserving PTX and PTX/HSA complex, while the exterior absorbing the PTX/HSA complex. Following systematic screening, the optimized NPs, namely, APP1i@e NPs, exhibited small particle size (43.95 nm), maximal PTX loading (42.23%), excellent dynamic stability (at least 1 week), and acid-triggered release. In vitro results showed that after being trafficked through caveolae-mediated endocytosis, APP1i@e NPs successfully escaped from endo-/lysosomes and then rapidly released cargos in the acidic cytosol, which continued to enhance cytotoxicity by mitochondrial control of apoptosis and suppression of microtubule dynamics. Longer circulation time and superior targeting efficiency post-intravenous injection confirmed that surface PEGylation imparted APP1i@e NPs with the ability to control their pharmacokinetics and biodistribution. The biomimetic shell design with HSA, which enlarged PTX stock and improved biosafety, made APP1i@e NPs more suitable for in vivo applications. Furthermore, in vivo safety and efficacy demonstrated that APP1i@e NPs effectively inhibited the growth of ovarian xenograft tumors, whereas significantly avoiding toxic issues associated with PTX. APP1i@e NPs with surface PEG coating and biomimetic HSA design, therefore, may provide a remarkable improvement in the therapeutic index of taxanes used in the clinic.

Evaluation of tofu as a potential tissue engineering scaffold.

Tofu not only is a delicious vegetarian food, but also shows potential biomedical applications for its high protein content and typical porous scaffold structure. Herein, two kinds of porous soybean scaffolds were developed, the first based on the traditional tofu manufacturing processes, the second modified via covalent crosslinking. The morphology, physicochemical properties and biocompatibility in vitro and in vivo were systematically investigated. A similar porous micromorphology was observed in both the tofu scaffolds and crosslinked soybean protein scaffolds. Both scaffolds exhibited good cell proliferation and cellular adherence. No obvious inflammatory response was observed after subcutaneous implantation tests for either material. These results demonstrated that the tofu scaffolds or soybean protein scaffolds fabricated by tofu processing have potential as new food-source biomaterials in tissue engineering applications.

Oriented Nanofibrous Polymer Scaffolds Containing Protein-Loaded Porous Silicon Generated by Spray Nebulization.

Oriented composite nanofibers consisting of porous silicon nanoparticles (pSiNPs) embedded in a polycaprolactone or poly(lactide-co-glycolide) matrix are prepared by spray nebulization from chloroform solutions using an airbrush. The nanofibers can be oriented by an appropriate positioning of the airbrush nozzle, and they can direct growth of neurites from rat dorsal root ganglion neurons. When loaded with the model protein lysozyme, the pSiNPs allow the generation of nanofiber scaffolds that carry and deliver the protein under physiologic conditions (phosphate-buffered saline (PBS), at 37 °C) for up to 60 d, retaining 75% of the enzymatic activity over this time period. The mass loading of protein in the pSiNPs is 36%, and in the resulting polymer/pSiNP scaffolds it is 3.6%. The use of pSiNPs that display intrinsic photoluminescence (from the quantum-confined Si nanostructure) allows the polymer/pSiNP composites to be definitively identified and tracked by time-gated photoluminescence imaging. The remarkable ability of the pSiNPs to protect the protein payload from denaturation, both during processing and for the duration of the long-term aqueous release study, establishes a model for the generation of biodegradable nanofiber scaffolds that can load and deliver sensitive biologics.

Targeted nanoparticles for head and neck cancers: overview and perspectives.

Head and neck cancer (HNC) is common in several regions and is associated with high morbidity and mortality worldwide. This review summarizes the recent progress in the development of targeted nanoparticle systems for HNC therapy. WIREs Nanomed Nanobiotechnol 2017, 9:e1469. doi: 10.1002/wnan.1469 For further resources related to this article, please visit the WIREs website.

Polymeric nanoparticles for colon cancer therapy: overview and perspectives.

Colorectal cancer (CRC) is the third-most common malignant tumour and is associated with high morbidity and mortality worldwide. This review summarizes the recent progress in the development of polymeric nanoparticle systems for colon cancer therapy.

Spatially selective photoconductive stimulation of live neurons.

Synaptic activity is intimately linked to neuronal structure and function. Stimulation of live cultured primary neurons, coupled with fluorescent indicator imaging, is a powerful technique to assess the impact of synaptic activity on neuronal protein trafficking and function. Current technology for neuronal stimulation in culture include chemical techniques or microelectrode or optogenetic based techniques. While technically powerful, chemical stimulation has limited spatial resolution and microelectrode and optogenetic techniques require specialized equipment and expertise. We report an optimized and improved technique for laser based photoconductive stimulation of live neurons using an inverted confocal microscope that overcomes these limitations. The advantages of this approach include its non-invasive nature and adaptability to temporal and spatial manipulation. We demonstrate that the technique can be manipulated to achieve spatially selective stimulation of live neurons. Coupled with live imaging of fluorescent indicators, this simple and efficient technique should allow for significant advances in neuronal cell biology.