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 a PLGA-polycation nanoparticle platform with core-shell structure as a robust vector for the encapsulation and delivery of proteins and peptides. We demonstrate that the optimized nanoparticles can load high amounts of proteins (>20% of nanoparticles by weight) in aqueous solution by simple mixing via electrostatic interactions without organic solvents, forming nanospheres in seconds with diameter <200 nm. We also investigate the relationship between nanosphere size, surface charge, PLGA-polycation composition, and protein loading. The stable nanosphere complexes contain multiple PLGA-polycation nanoparticles, surrounded by large amounts of protein. This study highlights a novel nanoparticle platform and nanotechnology strategy for the delivery of proteins and other relevant molecules

Selective Sensing and Sustained Release: Biomedical Applications of Porous Silicon

Porous silicon has been investigated as a novel material for biomedical applications since the early 1990s. Owing to its low toxicity profile and unique properties, it has been utilized in a variety of manners, including biomedical imaging and sustained delivery applications discussed within. In the first portion of this dissertation, quantum confined domains of silicon were used as ratiometric fluorescent probes, in which the long-lived excited states were harnessed to generate wavelength-dependent quenching motifs. To further evaluate the performance of porous silicon as a biomedical imaging agent, it was then compared and contrasted against a series of luminescent silicon nanocrystals to probe which unique properties are intrinsic to all silicon nanocrystals and which are imbued during the fabrication process. Finally, porous silicon microparticles were used to sustain the delivery of hormonal progestins to develop injectable contraceptives with the goal of reducing maternal mortality rates in sub-Saharan Africa. Owing to the anisotropic dissolution of porous silicon, hydrophobic progestin molecules were able to be released from the porous particle host in a highly linear fashion and for longer periods of time than the unprotected controls. The progestins were incorporated into the porous particle via a technique known as melt casting, in which molten drug infiltrates and then recrystallizes within the porous structure. Strategies for melt casting thermally instable drugs were also explored. Particles containing segesterone acetate were found to be non-toxic and well tolerated in a cohort of adult female Sprague-Dawley rats over an extended period of time

Cyclodextrin-based host-guest supramolecular hydrogel and its application in biomedical fields

The cyclodextrin (CD) based host-guest inclusion complexation between cyclodextrins (CDs) and guest moieties has inspired the fabrication of novel supramolecular hydrogels for biomedical applications. From a topology of view, this article reviews the recent developments of two kinds of CD-based supramolecular hydrogels and their applications in biomedical fields respectively. On one hand, supramolecular hydrogels derived from CD-based poly(pseudo)rotaxanes generally displayed thixotropic and reversible properties and have been extensively developed as injectable drug delivery systems. On the other hand, supramolecular hydrogels based on the host-guest interaction between CDs and small guest moieties generally exhibited stimuli-responsive behaviors, typically the release of therapeutic agents. The development of CD-based supramolecular hydrogels provides a new platform for the design of novel biomaterials

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

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 CP<b>5</b> 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. CP<b>5</b> NPs also exhibited long blood circulation and high tumor accumulation after intravenous injection. Moreover, in vivo efficacy and safety results showed that CP<b>5</b> 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