USING LIPID-LINKED AZT DRUGS TO IMPROVE HIV THERAPY

在I期，脂联Air和脂联ddI被开发出来，并被证明比未修饰的药物更有效。这笔拨款将继续开发与脂质相关的抗HIV药物，并将这些“前药”纳入微粒中，以便将前药靶向到HIV的巨噬细胞避难所。将前药结合到微粒中，为将高浓度前药主要输送到吞噬细胞提供了载体。微颗粒由可生物降解的共聚物组成，其保持完整的时间足够长，以防止抗病毒前药在巨噬细胞摄入之前过早释放。前药在巨噬细胞中释放后，前药被酯酶作用于前药的酯键而激活。第二阶段的具体目标是：1)开发经济合成脂联抗hiv药物的途径，并进行规模化合成；2)测定含酯前药酶解速率；3)将前药掺入可生物降解的微粒中；4)利用MAIDS模型，确定含有脂联逆转录酶抑制剂（RTI）和蛋白酶抑制剂（PI）药物不同组合的微颗粒的治疗效果。将含有RTI和PI的脂质前体药物的微粒用于感染HIV的患者具有“商业应用”中列出的潜在优势。建议的商业应用：1)在感染细胞和未感染细胞中建立药物库。2) I期结果表明，前药在未感染细胞中提供更稳定、毒性更小的药物浓度。3)由于微颗粒主要靶向巨噬细胞，脂联前药的生物半衰期较长，以及微颗粒制剂的缓释特性，会减少药物的不良反应。

In Phase I, lipid-linked Air and lipid-linked ddI were developed and demonstrated to be more efficacious than the unmodified drugs. This grant will continue the development of lipid-linked antiHIV drugs and incorporate these "prodrugs" into microparticles in order to target the prodrugs to the macrophage sanctuary for HIV. The incorporation of prodrugs into microparticles provides a vehicle for delivery of prodrug at a high concentration primarily to phagocytic cells. The microparticles are composed of a biodegradable copolymer, which remains intact sufficiently long to prevent the premature release of antiviral prodrugs prior to their ingestion by macrophages. After the prodrugs are released in the macrophage, the prodrug is activated by the action of esterase enzymes on the ester bond in the prodrug. The Phase II Specific Aims are: I) Develop routes for the economical synthesis of lipid-linked anti-HIV drugs and perform scaled-up synthesis; 2) Determine rates of enzymatic hydrolysis of ester-containing prodrugs; 3) Incorporate prodrugs into biodegradable microparticles; and 4) Using the MAIDS model, determine the therapeutic efficacy of microparticles containing various combinations of lipid-linked reverse transcriptase inhibitor (RTI) and protease inhibitor (PI) drugs. Administration of microparticles containing lipid prodrugs of RTI and PI to patients infected with HIV has the potential advantages listed under "Commercial Applications." PROPOSED COMMERCIAL APPLICATION: 1) Drug reservoirs would be established in both infected and uninfected cells. 2) As shown by Phase I results, the prodrugs would provide a more stable and less toxic concentration of drug in uninfected cells. 3) Adverse reactions to drugs would be reduced because of the targeting of microparticles primarily to macrophages, the longer biological half life of lipid-linked prodrugs, and the sustained release characteristics of the microparticle formulation.