USING LIPID-LINKED AZT DRUGS TO IMPROVE HIV THERAPY

在第一阶段，开发了脂质连接的Air和脂质连接的ddI，并证明比未修饰的药物更有效。这笔赠款将继续开发脂质连接的抗艾滋病毒药物，并将这些“前药”纳入微粒，以靶向艾滋病毒的巨噬细胞避难所的前药。将前药掺入微粒中提供了用于将高浓度的前药主要递送至吞噬细胞的载体。微粒由可生物降解的共聚物组成，其保持完整足够长的时间以防止抗病毒前药在被巨噬细胞摄取之前过早释放。前药在巨噬细胞中释放后，前药通过酯酶对前药中酯键的作用而活化。II期具体目标是：I）开发用于脂质连接的抗HIV药物的经济合成的路线并进行放大合成; 2）测定含酯前药的酶促水解速率; 3）将前药并入可生物降解的微粒中; 4）利用MAIDS模型，测定含有脂质连接的逆转录酶抑制剂（RTI）和蛋白酶抑制剂的各种组合的微粒的治疗功效（PI）药物。向感染艾滋病毒的患者施用含有RTI和PI脂质前药的微粒具有“商业应用”下列出的潜在优势。建议的商业应用：1）药物库将在感染和未感染的细胞中建立。2)如I期结果所示，前药将在未感染的细胞中提供更稳定和毒性更小的药物浓度。3)由于微粒主要靶向巨噬细胞、脂质连接的前药的较长生物半衰期以及微粒制剂的持续释放特性，对药物的不良反应将减少。

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.