Biodegradable and Biocompatible Chitosan-Protein Nanoparticles in Drug Delivery

基于天然和合成聚合物与水溶性聚合物的纳米颗粒治疗剂提供了改善癌症药物递送的新途径。这有助于药物溶解度，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肿瘤的摄取。在用于药物递送系统的天然阳离子聚合物中，壳聚糖由于其生物相容性、生物可降解性和多功能性而在纳米生物医学技术领域引起了人们的极大兴趣。壳聚糖及其衍生物具有安全用作药物递送工具的期望性质。使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（肽、蛋白质、抗原和质粒DNA）在体内的生物利用度。然而，壳聚糖仅溶于酸性溶液而不溶于中性pH，这导致药物载体制剂的主要问题。需要对聚合物结构进行改性，以增加壳聚糖的溶解性和亲和力。壳聚糖-蛋白质缀合将增加聚合物在生理pH下的溶解度，并将显著增强壳聚糖在药物递送系统中的效率。在该提案中，不同尺寸（15、50、100和200 KDa）的壳聚糖纳米颗粒将与不同的转运蛋白（例如人和牛血清白蛋白和β-乳球蛋白）缀合。由于所选蛋白质的疏水性不同，壳聚糖-蛋白质纳米颗粒将对亲水性和疏水性药物更具选择性。将使用多种光谱方法和热力学分析结合TEM、SEM、AFM显微成像、共振光散射（RLS）/zeta电位和分子建模来进行几种抗癌药物如阿霉素、柔红霉素、伊达比星、他莫昔芬、4-氢他莫昔芬和内昔芬与壳聚糖-蛋白质纳米胶囊的包封。将评估聚合物尺寸和分子量对药物纳米颗粒包封的影响。将监测药物的控制和释放，并确定每种缀合物在药物递送中的效率。*这项研究是重要的，因为载体和药物的非共价缔合是决定包封功效和药物释放效率的最重要的分子方面之一。所产生的信息将有助于更合理地设计壳聚糖，解决药物递送系统中的问题，同时将推动新的和新兴的技术走向临床研究。该提案是多学科的，为我们的学生提供与药物输送相关的重要知识，使他们能够在就业市场上具有很强的竞争力。

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.******