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，并证明它们比未修饰的药物更有效。这笔赠款将继续开发与脂质挂钩的抗艾滋病毒药物，并将这些“前药物”纳入微粒中，以便将前药物靶向艾滋病毒的巨噬细胞庇护所。将前体药物掺入微粒中，为高浓度的前体药物主要输送到吞噬细胞提供了一种载体。这些微粒由一种可生物降解的共聚物组成，它保持完好的时间足够长，以防止抗病毒前体药物在被巨噬细胞吞噬之前过早释放。前体药物在巨噬细胞中释放后，通过酯酶作用于前体药物中的酯键而被激活。第二阶段的具体目标是：i)开发经济合成脂联抗HIV药物的路线并进行放大合成；2)测定含酯类前药的酶促水解率；3)将前药合并到可生物降解的微粒中；以及4)使用MAIDS模型，确定含有脂联逆转录酶抑制物(RTI)和蛋白酶抑制物(PI)药物的各种组合的微粒的治疗效果。给感染HIV的患者使用含有RTI和PI脂质前体药物的微粒具有“商业应用”中列出的潜在优势。拟议的商业应用：1)将在感染细胞和未感染细胞中建立药物储存库。2)I期试验结果表明，前药在未感染细胞中的药物浓度更稳定，毒性更低。3)由于微粒子主要靶向巨噬细胞，脂质连接前药的生物半衰期较长，以及微粒子制剂的缓释特性，药物的不良反应将会减少。

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.