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Prodrug Formulations Create Sustained Release Antiretrovirals

前药制剂可产生持续释放的抗逆转录病毒药物

基本信息

批准号：
10205973
负责人：
Benson Edagwa
金额：
$ 75.71万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10205973
关键词：
AIDS prevention Adherence Adverse effects Adverse event Animal Model Animals Anti-Retroviral Agents Area Binding Proteins Bioavailable Biological Assay Biological Testing Blood CD34 gene CD4 Positive T Lymphocytes Cell Count Cell model Cells Chemistry Collaborations Critiques Data Set Dendritic Cells Development Dose Drug Combinations Drug Formulations Drug Interactions Drug Kinetics Drug Targeting Drug Transport Drug resistance Drug toxicity Effectiveness Excipients Excretory function FDA approved Female Formulation Frequencies Funding Genitourinary system Goals Guidelines Gut associated lymphoid tissue HIV HIV-1 Half-Life Human Hydrolysis Immunologics Immunologist Immunology Inbred BALB C Mice Individual Infection Injections Integrase Integrase Inhibitors Intramuscular Injections Laboratories Lamivudine Lipids Lymphoid Measures Medicine Metabolic Metabolism Monitor Mononuclear Mus Muscle Neuraxis Nucleosides Outcome Pathway interactions Phagocytes Pharmaceutical Preparations Pharmacodynamics Pharmacology Phase Plasma Polymers Prevention Prevention strategy Prodrugs Production Property Publishing RNA-Directed DNA Polymerase Regimen Research Reverse Transcriptase Inhibitors Safety Scheme Sex Differences Site T-Lymphocyte Tenofovir Test Result Testing Therapeutic Time Tissues Toxic effect Toxicology Translating Treatment Protocols Viral Viral Load result Viral reservoir Virus Virus Diseases abacavir antiretroviral therapy aqueous base biomaterial compatibility chemical stability clinically relevant cytotoxicity design drug distribution drug efficacy emtricitabine expectation experimental study humanized mouse improved inhibitor/antagonist lipophilicity lymphoid organ macrophage male monocyte mouse model nanocrystal nanomedicine particle pharmacokinetics and pharmacodynamics pre-exposure prophylaxis product development reconstitution response scale up screening side effect success surfactant therapy outcome tool trafficking transmission process treatment strategy uptake virology

项目摘要

Abstract This proposal seeks funds to translate existing antiretroviral drugs (ARVs) into scalable long acting medicines. A step-wise approach is offered with defined “go no go” criteria. The first is conversion of nucleoside reverse transcriptase and an integrase inhibitor(s) into lipophilic prodrug nanocrystals. These conversions are designed for simple, safe and scalable productions under current good manufacturing practices. Following the production of ARV nanocrystals, the second step will optimize CD4+ T cell uptake while sustaining drug depots in macrophages. ARV release from prodrugs will occur by controlled hydrolysis enabling sustained antiretroviral potency. The third will facilitate distribution of prodrug nanocrystals into lymphoid, gut associated lymphoid tissue, genitourinary and central nervous system tissues. The fourth, will complete tests designed to limit off target toxicity (S Cohen) by screening pro-, native- and nanocrystal- drug formulations in cell and tissue assays. These extended toxicology tests will serves to investigate any or no adverse events that follow increased ARV levels in cells and tissues. Our goal is the production of safe well-tolerated long acting slow effective release antiretroviral therapies with “putative” dosing intervals of up to once every six months. The design will offer maximal effectiveness for pre-exposure prophylaxis and treatment regimens. The specific aims are supported by extensive published data sets. To accomplish the proposed research, a partnership was made between a medicinal and polymer chemist (B Edagwa) and a virologist, cell biologist, and immunologist (H Gendelman). This collaboration will accelerate transformation of short- to long-acting ARVs. Biological testing will follow product development in cell and animal models. Formulation safety will be realized by continuous testing of replicate short-acting native ARV formulations in good laboratory and current good manufacturing practice facilities. The pathway for ARV nanocrystal development will move forward by sequential Go No Go criteria. Drug choices, formulation stability, drug combinations, tissue and cell targeting, toxicology, pharmacokinetics (PK), and pharmacodynamics (PD) profiles follow the action plan. Several have “reached” drug manufacture. The outcome of these experiments can reduce drug toxicities, improve regimen adherence, and provide enhanced viral prevention into tissue reservoirs. The research builds on an already strong track record in cell-targeted nanomedicines. Antiretroviral responses and endosomal trafficking will be tested. PK and PD mouse screens (S Gorantla) will validate the findings. Overall, our long-term goal is to transform existing antiretroviral treatment regimens into long acting therapies.

抽象的该提案寻求资金将现有的抗逆转录病毒药物（ARV）转化为可扩展的长效药物。提供了一种分步方法，并定义了“不进行”标准。第一个是核苷反向转换转录酶和整合酶抑制剂进入亲脂性前药纳米晶体中。这些转换的设计在当前的良好制造实践下实现简单、安全和可扩展的生产。继生产抗逆转录病毒纳米晶体，第二步将优化 CD4+ T 细胞的摄取，同时维持药物巨噬细胞中的贮库。前药中的抗逆转录病毒药物通过受控水解释放，从而实现持续的抗逆转录病毒效力。第三个将促进前药纳米晶体分布到淋巴、肠道相关的区域。淋巴组织、泌尿生殖系统和中枢神经系统组织。第四，将完成旨在通过筛选细胞和纳米晶体药物制剂来限制脱靶毒性（S Cohen）组织测定。这些扩展的毒理学测试将用于调查随后发生的任何不良事件或没有不良事件细胞和组织中的抗病毒药物水平增加。我们的目标是生产安全、耐受性良好、长效、缓慢的药物有效释放抗逆转录病毒疗法，“推定”给药间隔可达每六个月一次。这设计将为暴露前预防和治疗方案提供最大的有效性。具体目标得到广泛发布的数据集的支持。为了完成拟议的研究，建立了伙伴关系由药物和高分子化学家 (B Edagwa) 与病毒学家、细胞生物学家和免疫学家合作（H·詹德曼）。此次合作将加速短效抗逆转录病毒药物向长效抗逆转录病毒药物的转变。生物产品开发后将在细胞和动物模型中进行测试。制剂安全将通过以下方式实现在良好的实验室和当前良好的条件下对复制的短效天然抗逆转录病毒制剂进行连续测试制造实践设施。抗逆转录病毒纳米晶的开发之路将向前推进连续的 Go No Go 标准。药物选择、制剂稳定性、药物组合、组织和细胞靶向、毒理学、药代动力学 (PK) 和药效学 (PD) 概况遵循行动计划。有几个有 “达到”药品制造。这些实验的结果可以降低药物毒性，改善治疗方案粘附性，并增强病毒进入组织储存库的能力。该研究建立在已经在细胞靶向纳米药物方面拥有良好的记录。抗逆转录病毒反应和内体贩运将是已测试。 PK 和 PD 鼠标屏幕 (S Gorantla) 将验证研究结果。总体而言，我们的长期目标是将现有的抗逆转录病毒治疗方案转变为长效疗法。