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）：寻找新型抗AIDS治疗剂的搜索主要集中于干扰HIV生命周期特定阶段的药物的发展。这种有针对性的药理方法导致治疗剂在体外非常低剂量的情况下非常有效。然而，由于人体迅速清除，细胞摄取/保留率差和其他生物药物因素，它们的体内有效性通常会降低。使用生物材料的药物递送技术已被有效地用于患者中，以通过改变诸如处置（即身体分布，代谢或排泄物）之类的生物药物特性来增强非AIDS药物的药理活性。生物药物靶向靶向促进药物靶点部位（例如受体或酶）的递送，并且与药理学靶向相辅相成。令人惊讶的是，即使有临床证据表明，剂量和给药频率的降低会导致副作用降低，患者的依从率和更好的治疗结果，但很少有生物制药靶向措施为改善HIV感染的治疗。因此，这种竞争性更新应用的长期目标是设计，合成，表征和评估新型的聚合物药物携带者和大分子药物共轭物，从而通过改善其递送，药物代动力学和药物学来改善其抗AID毒品生物效能。因此，为了实现以下特定目的，将合成和表征新颖的生物缀合物：目标1；确定聚合物支架拓扑和效应子对体内处置，脑摄取，蛋白质结合，靶细胞摄取和保留和抗HIV活性的影响。目的2：评估细胞靶向以改善细胞内药物的递送，特别是探索：（a）使用包括FMLF和甘露糖在内的多重亲和力配体进行巨噬细胞靶向，以及（B）使用Icosahedral T7 Phage Phage Displays技术鉴定出新型的表面识别肽的脑靶向转铁蛋白受体（TFR）。目标3：使用病毒进入抑制的双重机制评估靶向T细胞，结合细胞表面药物递送。具体而言，（a）使用噬菌体显示鉴定新型的CD4识别肽，（b）研究与CXCR4病毒coecector的TAT偶联物结合，并且（C）评估单独靶向并与HIV蛋白酶抑制剂组合评估受体（CD4） - 感染者（CXCR4）双靶标。我们针对巨噬细胞和T细胞的策略涉及将识别肽用于HIV-1用来结合并进入细胞的某些相同受体。设计生物缀合物来利用病毒感染途径的一个重要优点是，即使是一种药物，也可以引起多种类型的药物动力学反应。药物输送和靶向方法引起的多种活动补充了药理学方法，并应改善生物效能和患者结局。