POLYMERICS DELIVERY SYSTEMS FOR ANTI-RETROVIRAL AGENTS

抗逆转录病毒药物的聚合物递送系统

• 批准号: 3489187
• 负责人: DEVINDER S GILL
• 金额: $ 4.99万
• 依托单位: ANDRULIS RESEARCH CORPORATION
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-05-01 至 1990-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3489187
• 关键词: AIDS; HIV infections; antiAIDS agent; cell free system; chemical conjugate; dextrans; drug delivery systems; drug design /synthesis /production; drug metabolism; enzyme linked immunosorbent assay; human immunodeficiency virus; interferon inducers; macrophage; polymers; prodrugs; tissue /cell culture; zidovudine

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.

第一阶段研究的目标是设计、合成、开发和 评估一类新的聚合物“靶向” AZT的前药 该计划的总体目标是创造新的 具有显著增强的抗病毒活性的抗AIDS前药， 低毒性、靶向可及性和持续药物释放。 I期计划是基于有希望的体外抗病毒活性 由我们用AZT-聚合物，缀合物I获得，并且在我们的 开发Pt（trans-DACH）羧基多糖抗肿瘤药物的前期工作 当使用时显示出显著改善的抗肿瘤性质的络合物， 与它们的单体类似物相比。 在I期研究中，AZT偶联物I的抗逆转录病毒特性将被 优化;例如通过增加缀合物中的AZT含量。 活动 将使用HIV和鼠逆转录病毒在体外评价偶联物 T细胞、巨噬细胞和成纤维细胞的感染。 AST-羧基葡聚糖 结合物将被合成、评估和优化以靶向药物 巨噬细胞和逆转录病毒模型系统，以评估 化合物的药代动力学和动力学以及确定化合物的 聚合物和单体载体靶向抗病毒药物的能力， 特定组织 这种通过药物的持续位点特异性递送的方法 生物可降解和生物相容的聚合物可以外推，以改善 已知抗艾滋病药物的治疗特性。