POLYMERICS DELIVERY SYSTEMS FOR ANTI-RETROVIRAL AGENTS

这项第一阶段研究的目标是设计、合成、开发和 一类新型聚合物“靶向”材料的体外药效评价 AZT前药。该计划的总体目标是创造新的 将具有显著增强的抗病毒活性的抗艾滋病前药， 低毒、靶向可及、药物缓释。 第一阶段计划是基于前景看好的体外抗病毒活性。 由我们用AZT-聚合物，共轭化合物I获得，并仿照我们的 铂(反式-DACH)羧糖抗肿瘤研究进展 具有显著改善的抗肿瘤性能的络合物 与它们的单体类似物相比。 在第一阶段的研究中，AZT结合物的抗逆转录病毒特性将是 优化；例如通过增加共轭化合物中的AZT含量。活动 将使用HIV和小鼠逆转录病毒进行体外评估 T细胞、巨噬细胞和成纤维细胞感染。AST-羧基葡聚糖 将合成、评估和优化偶联物以针对药物进行定位 巨噬细胞和逆转录病毒模型系统来评估 化合物的药代动力学和动力学，以及测定 聚合物和单体载体靶向抗病毒药物的能力 特定的组织。 这种持续定点给药的方法是通过 可生物降解和生物相容的聚合物可以外推以改善 已知的抗艾滋病药物的治疗特性。

The goal of this Phase I research is to design, synthesize, develop, and evaluate the in vitro efficacy of a new class of polymeric "targeted" prodrugs of AZT. The overall objective of this program is to create new anti-AIDS prodrugs which will possess markedly enhanced antiviral activity, low toxicity, target-accessibility, and sustained drug release. The Phase I plan is based on the promising in vitro antiviral activity obtained by us with AZT-polymer, conjugate I, and is modeled after our prior work on the development of Pt(trans-DACH)carboxysaccharide antitumor complexes which exhibited substantially improved antitumor properties when compared to their monomeric analogs. In Phase I research anti-retroviral properties of AZT conjugate I will be optimized; e.g. by increasing the AZT content in the conjugate. Activity of the conjugate will be evaluated in vitro using HIV and murine retrovirus infection of T-cells, macrophages and fibroblasts. AST-carboxydextran conjugates will be synthesized, evaluated, and optimized to target the drug to macrophage cells and for retrovirus model systems to evaluate the pharmacokinetics and dynamics of the compounds as well as to determine the ability of polymeric and monomeric carriers to target antivirals to specific tissues. This approach of sustained site-specific delivery of drugs via biodegradable and biocompatible polymers can be extrapolated to improve the therapeutic properties of known anti-AIDS drugs.