Enhancing Intestinal & Brain Uptake of Anti-AIDS Drugs

增强肠道

• 批准号: 7846456
• 负责人: Patrick J. Sinko
• 金额: $ 4.66万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-05 至 2010-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7846456
• 关键词: Adverse effects; Affinity; Anti-HIV Agents; Antiviral Agents; Bacteriophage T7; Bacteriophages; Binding; Biocompatible Materials; Biological Products; Brain; CD4 Antigens; CXCR4 gene; Cell surface; Cells; Clinical; Complement; Dose; Drug Carriers; Drug Delivery Systems; Drug Kinetics; Effectiveness; Elements; Enzymes; Excretory function; Frequencies; Grant; HIV; HIV Infections; HIV Protease Inhibitors; HIV-1; In Vitro; Intestines; Lead; Life Cycle Stages; Ligands; Link; Mannose; Metabolism; Outcome; Pathway interactions; Patients; Peptides; Phage Display; Pharmaceutical Preparations; Pharmacodynamics; Polymers; Property; Protein Binding; Research Personnel; Site; Staging; Surface; T-Lymphocyte; Techniques; Technology; Therapeutic; Therapeutic Agents; Transferrin Receptor; Viral; Virus Diseases; base; biocompatible polymer; compliance behavior; design; drug development; improved; in vivo; macrophage; novel; programs; receptor; response; scaffold; uptake

DESCRIPTION (provided by applicant): The search for novel anti-AIDS therapeutic agents has principally focused on the development of drugs that interfere with specific stages of the HIV life cycle. This targeted pharmacological approach has resulted in therapeutic agents that are extremely effective at very low doses in vitro. However, their in vivo effectiveness is often reduced as a result of rapid body clearance, poor cellular uptake/retention and other biopharmaceutical factors. Drug delivery technologies using biomaterials have been effectively used in patients to enhance the pharmacological activity of non-AIDS drugs by changing biopharmaceutical properties such as disposition (i.e., body distribution, metabolism or excretion). Biopharmaceutical targeting facilitates the delivery of drugs to pharmacological target sites such as receptors or enzymes and is complementary to pharmacological targeting. Surprisingly, there are very few biopharmaceutical targeting efforts being undertaken to improve the treatment of HIV infection even though there is clinical proof that reductions in the dose and frequency of administration result in reduced side effects, higher patient compliance rates and better therapeutic outcomes. Therefore, the long-term objectives of this competing renewal application are to design, synthesize, characterize and evaluate novel polymeric drug carriers and macromolecular drug conjugates to enhance anti-AIDS drug bioefficacy by improving their delivery, pharmacokinetics, and pharmacodynamics. Therefore, novel bioconjugates will be synthesized and characterized in order to achieve the following specific aims: Aim 1; To determine the effect of the polymeric scaffold topology and effectors on in vivo disposition, brain uptake, protein binding, target cell uptake & retention, and anti-HIV activity. Aim 2: To evaluate cell targeting to improve intracellular drug delivery, specifically to explore: (a) Macrophage targeting using multiplex affinity ligands including fMLF and mannose, and (b) Brain targeting of transferrin receptor (TfR) using novel surface recognition peptides identified using an icosahedral T7 Phage Display technique. Aim 3: To assess T-cell targeting utilizing the dual mechanisms of viral entry inhibition combined with cell surface drug delivery. Specifically, we will (a) identify novel CD4 recognition peptides using Phage Display, (b) investigate Tat-conjugate binding to the CXCR4 viral coreceptor, and (c) assess receptor (CD4)-coreceptor (CXCR4) dual targeting alone and in combination with an HIV protease inhibitor. Our strategies to target macrophages and T-cells involve the use of recognition peptides for some of the same receptors used by HIV-1 to bind to and enter cells. A significant advantage of designing bioconjugates to utilize the viral infection pathway is that multiple types of pharmacodynamic responses can be elicited using even a single drug. The multiplicity of activities resulting from drug delivery and targeting approaches complements pharmacological approaches and should result in improved bioefficacy and patient outcomes.

描述（由申请人提供）：对新型抗艾滋病治疗剂的研究主要集中在开发干扰HIV生命周期特定阶段的药物。这种靶向药理学方法已经产生了在体外以非常低的剂量极其有效的治疗剂。然而，由于快速的身体清除、差的细胞摄取/保留和其他生物制药因素，它们的体内有效性经常降低。使用生物材料的药物递送技术已经有效地用于患者，以通过改变生物制药性质如处置（即，身体分布、代谢或排泄）。生物药物靶向有助于将药物递送至药理学靶位点，例如受体或酶，并且是药理学靶向的补充。令人惊讶的是，很少有生物制药靶向努力正在进行，以改善艾滋病毒感染的治疗，即使有临床证据表明，减少剂量和频率的管理导致减少副作用，更高的患者依从率和更好的治疗结果。因此，这一竞争性更新申请的长期目标是设计、合成、表征和评估新型聚合物药物载体和大分子药物缀合物，以通过改善其递送、药代动力学和药效学来增强抗艾滋病药物的生物功效。因此，新的生物缀合物将被合成和表征，以实现以下具体目标：目的1;确定聚合物支架拓扑结构和效应器对体内处置、脑摄取、蛋白结合、靶细胞摄取和保留以及抗HIV活性的影响。目标二：评价细胞靶向以改善细胞内药物递送，特别是探索：（a）使用包括fMLF和甘露糖的多重亲和配体的巨噬细胞靶向，和（B）使用二十面体T7噬菌体展示技术鉴定的新型表面识别肽的转铁蛋白受体（TfR）脑靶向。目的3：利用病毒进入抑制结合细胞表面药物递送的双重机制评估T细胞靶向。具体而言，我们将（a）使用噬菌体展示鉴定新型CD 4识别肽，（B）研究Tat-缀合物与CXCR 4病毒辅助受体的结合，以及（c）评估单独和与HIV蛋白酶抑制剂组合的受体（CD 4）-辅助受体（CXCR 4）双重靶向。我们针对巨噬细胞和T细胞的策略涉及使用识别肽来识别HIV-1用于结合和进入细胞的一些相同受体。设计利用病毒感染途径的生物缀合物的显著优点是，即使使用单一药物也可以引起多种类型的药效学应答。药物递送和靶向方法产生的多种活动补充了药理学方法，并应导致生物功效和患者结局的改善。