Biodegradable and Biocompatible Chitosan-Protein Nanoparticles in Drug Delivery

纳米粒子疗法，基于天然和合成聚合物与水溶性聚合物，提供了新的途径，以改善癌症药物输送。这有助于药物的溶解度，通过长循环增加治疗过程，并通过实现渗透性和保留效应增强对肿瘤的吸收。在用于药物输送系统的天然阳离子聚合物中，壳聚糖因其具有生物相容性、可生物降解性和多用途性而引起了纳米生物医学技术领域的极大兴趣。壳聚糖及其衍生物具有良好的性能，可作为药物传递工具安全使用。利用壳聚糖及其衍生物作为药物载体的主要目的是提高治疗药物（多肽、蛋白质、抗原和质粒dna）在体内的生物利用度。然而，壳聚糖只溶于酸性溶液，不溶于中性pH，这给药物载体配方带来了主要问题。为了提高壳聚糖的溶解度和亲和力，需要对聚合物结构进行修饰。壳聚糖-蛋白结合将增加聚合物在生理pH值下的溶解度，并将显著提高壳聚糖在药物传递系统中的效率。

Nanoparticle therapeutics, based on natural and synthetic polymers with water-soluble polymers, offer new routes to improve cancer drug delivery. This aids the drug solubility, increases the therapeutic process through long circulation and enhances the uptake into tumors by achieving the permeability and retention effect. Among natural cationic polymers used in drug delivery systems, chitosan has attracted a major interest in the nanobiomedical technology sector since it is a biocompatible, biodegradable and versatile polymer. Chitosan and its derivatives have the desired properties for safe use as pharmaceutical drug delivery tools. The principal interest in using chitosan and its derivatives as a pharmaceutical carrier is to enhance the bioavailability of therapeutic drugs (peptides, proteins, antigens and plasmid DNAs) in vivo. However, chitosan is only soluble in acidic solution and not at neutral pH, which causes a major problem for drug-carrier formulation. Modifications of polymer structure are needed, in order to increase chitosan solubility and affinity. Chitosan-protein conjugation will increase polymer solubility in physiological pH and will enhance markedly chitosan efficiency in a drug delivery system. In this proposal chitosan nanoparticles of different sizes (15, 50, 100 and 200 KDa) will be conjugated with different transporter proteins, such as human and bovine serum albumins and beta-lactoglobulin. Since selected proteins are different in hydrophobicity, chitosan-protein nanoparticles will be more selective towards hydrophilic and hydrophobic drugs. Encapsulation of several anticancer drugs such as doxorubicin, daunorubicin, idarubicin, tamoxifen, 4-hydrotamoxifen and endoxifen with chitosan-protein nanocapsules will be carried out using multiple spectroscopic methods and thermodynamic analysis in combination with TEM, SEM, AFM microscopic imaging, resonance light scattering (RLS)/zeta potential and molecular modeling. The effects of polymer size and molecular weight on drug-nanoparticle encapsulation will be evaluated. Control and release of the drug will be monitored and the efficiency of each conjugate in drug delivery will be determined. This study is important, as non-covalent association of carrier and drug is one of the most significant molecular aspects that dictate the encapsulation efficacy and drug release efficiency. The generated information will facilitate a more rational chitosan design, resolving problems in drug delivery system; meanwhile it will advance novel and emerging technologies toward clinical investigation. The proposal is multidisciplinary and provides our students with important knowledge related to drug delivery, enabling them to be highly competitive in the job market.