Cytocompatibility, membrane disruption, and siRNA delivery using environmentally responsive cationic nanogels.

Advances in the formulation of nucleic acid-based therapeutics have rendered them a promising avenue for treating diverse ailments. Nonetheless, clinical translation of these therapies is hindered by a lack of strategies to ensure the delivery of these nucleic acids in a safe, efficacious manner with the required spatial and temporal control. To this aim, environmentally responsive hydrogels are of interest due to their ability to provide the desired characteristics of a protective carrier for siRNA delivery. Previous work in our laboratory has demonstrated the ability to synthesize nanoparticle formulations with targeted pKa, swelling, and surface PEG density. Here, a library of nanoparticle formulations was assessed on their in vitro toxicity, hemolytic capacity, siRNA loading, and gene-silencing efficacy. Successful candidates exhibited the lowest degrees of cytotoxicity, pH-dependent membrane disruption potential, the highest siRNA loading, and the highest transfection efficacies.

Advanced architectures in the design of responsive polymers for cancer nanomedicine.

In recent decades, nanoparticles have shown significant promise as an oncology treatment modality. Responsive polymers represent a promising class of nanoparticles that can trigger delivery through the exploitation of a specific stimuli. Response to a stimulus is one of the most basic processes found in living systems. As such, the desire to engineer dynamic and functional materials is becoming more prevalent in an effort to achieve precise control over our environment. The combination of controlled radical polymerization and high yielding chemistry strategies provide an excellent basis for the development of the next generation of drug delivery systems. The versatility of polymer chemistries available enables the synthesis of increasingly complex architectures with enhanced delivery specificity and control over the desired properties to interface with biological systems. This tutorial review highlights recent developments in polymer-based approaches to internally responsive nanoparticles for oncology. Presented are concise overviews of the current challenges and opportunities in cancer nanomedicine, common polymer-based architectures, and the basis for internally triggered stimuli-response relationships commonly employed in oncology applications. Examples of the chemistry used in the design of environmentally labile nanomaterials are discussed, and we outline recent advances in creating advanced bioresponsive drug delivery architectures.

Control of Cationic Nanogel PEGylation in Heterogeneous ARGET ATRP Emulsion Polymerization with PEG Macromonomers.

Crosslinked cationic nanoscale networks with hydrophobic cores are an environmentally robust alternative to self-assembled polymeric drug delivery carriers with respect to therapeutic encapsulation and stability to dilution. However, the ability to tune the degree of PEG incorporated into nanogels during synthesis is more challenging. In this work, biodegradable cationic nanogels were synthesized by ARGET ATRP emulsion polymerization in a single step. The density of PEG in the final nanogels ranged from zero to 40 wt % and was dependent on the feed concentration of PEG monomer, surfactant concentration, surfactant hydrophilic-lipophilic balance, and the ratio of cationic to nonionic surfactant. A comprehensive analysis of nanogel material properties as a function of PEG graft density is presented including analysis of composition, monomer conversion, thermal properties, size, surface charge, and degradation. This study provides a robust analysis for the synthesis of degradable cationic nanogels via a controlled radical polymerization with predictable degrees of PEGylation.

Student award for outstanding research winner in the Ph.D. category for the 2017 society for biomaterials annual meeting and exposition, april 5-8, 2017, Minneapolis, Minnesota: Characterization of protein interactions with molecularly imprinted hydrogels that possess engineered affinity for high isoelectric point biomarkers.

Molecularly imprinted polymers (MIPs) with selective affinity for protein biomarkers could find extensive utility as environmentally robust, cost-efficient biomaterials for diagnostic and therapeutic applications. In order to develop recognitive, synthetic biomaterials for prohibitively expensive protein biomarkers, we have developed a molecular imprinting technique that utilizes structurally similar, analogue proteins. Hydrogel microparticles synthesized by molecular imprinting with trypsin, lysozyme, and cytochrome c possessed an increased affinity for alternate high isoelectric point biomarkers both in isolation and plasma-mimicking adsorption conditions. Imprinted and non-imprinted P(MAA-co-AAm-co-DEAEMA) microgels containing PMAO-PEGMA functionalized polycaprolactone nanoparticles were net-anionic, polydisperse, and irregularly shaped. MIPs and control non-imprinted polymers (NIPs) exhibited regions of Freundlich and BET isotherm adsorption behavior in a range of non-competitive protein solutions, where MIPs exhibited enhanced adsorption capacity in the Freundlich isotherm regions. In a competitive condition, imprinting with analogue templates (trypsin, lysozyme) increased the adsorption capacity of microgels for cytochrome c by 162% and 219%, respectively, as compared to a 122% increase provided by traditional bulk imprinting with cytochrome c. Our results suggest that molecular imprinting with analogue protein templates is a viable synthetic strategy for enhancing hydrogel-biomarker affinity and promoting specific protein adsorption behavior in biological fluids. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 1565-1574, 2017.

Intelligent Nanoparticles for Advanced Drug Delivery in Cancer Treatment.

Treatment of cancer using nanoparticle-based approaches relies on the rational design of carriers with respect to size, charge, and surface properties. Polymer-based nanomaterials, inorganic materials such as gold, iron oxide, and silica as well as carbon based materials such as carbon nanotubes and graphene are being explored extensively for cancer therapy. The challenges associated with the delivery of these nanoparticles depend greatly on the type of cancer and stage of development. This review highlights design considerations to develop nanoparticle-based approaches for overcoming physiological hurdles in cancer treatment, as well as emerging research in engineering advanced delivery systems for the treatment of primary, metastatic, and multidrug resistant cancers. A growing understanding of cancer biology will continue to foster development of intelligent nanoparticle-based therapeutics that take into account diverse physiological contexts of changing disease states to improve treatment outcomes.