Enhancing Intestinal & Brain Uptake of Anti-AIDS Drugs

描述(由申请人提供)：寻找新的抗艾滋病治疗药物主要集中在干扰艾滋病毒生命周期特定阶段的药物的开发。这种有针对性的药理学方法已经导致了在体外非常低剂量下非常有效的治疗剂。然而，由于体内清除速度快、细胞摄取/保留能力差以及其他生物制药因素，它们在体内的有效性往往会降低。使用生物材料的药物释放技术已被有效地用于患者，通过改变生物药物的性质，如体内分布、代谢或排泄，增强非艾滋病药物的药理活性。生物药物靶向有助于将药物输送到受体或酶等药理靶点，是对药理靶向的补充。令人惊讶的是，尽管有临床证据表明，减少给药剂量和频率会减少副作用，提高患者依从性和更好的治疗结果，但为改善艾滋病毒感染的治疗而进行的靶向生物制药努力很少。因此，这一竞争性更新应用的长期目标是设计、合成、表征和评价新型聚合物药物载体和大分子药物结合物，以通过改善它们的给药、药代动力学和药效学来增强抗艾滋病药物的生物有效性。因此，我们将合成和表征新型的生物结合物，以达到以下特定的目的：目的1：确定聚合物支架的拓扑结构和效应器对体内处置、脑摄取、蛋白质结合、靶细胞摄取和滞留以及抗HIV活性的影响。目的：评价细胞靶向改善细胞内药物传递的作用，特别是探索：(A)使用包括FMLF和甘露糖在内的多重亲和配体的巨噬细胞靶向，以及(B)使用利用二十面体T7噬菌体展示技术鉴定的新的表面识别肽来脑靶向转铁蛋白受体(TFR)。目的：利用病毒进入抑制和细胞表面药物传递的双重机制，评价T细胞靶向性。具体地说，我们将(A)使用噬菌体展示技术识别新的CD4识别多肽，(B)研究TAT与CXCR4病毒共受体的结合，以及(C)单独评估受体(CD4)-辅助受体(CXCR4)双靶向以及与HIV蛋白酶抑制剂联合使用。我们针对巨噬细胞和T细胞的策略包括使用识别肽识别HIV-1用来结合和进入细胞的一些相同的受体。设计生物偶联物来利用病毒感染途径的一个显著优势是，即使使用一种药物也可以引起多种类型的药效反应。药物传递和靶向方法产生的多种活动是对药理学方法的补充，应该会导致更好的生物疗效和患者结果。

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.