Enhancing Intestinal & Brain Uptake of Anti-AIDS Drugs

描述（由申请人提供）：对新型抗艾滋病治疗药物的研究主要集中在开发干扰艾滋病毒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极低剂量下非常有效的治疗药物。然而，由于体内清除速度快、细胞吸收/保留能力差和其他生物制药因素，它们的体内有效性往往会降低。利用生物材料的给药技术已经被有效地应用于患者身上，通过改变处置（即身体分布、代谢或排泄）等生物制药特性来增强非艾滋病药物的药理活性。生物制药靶向促进药物递送到诸如受体或酶的药理学靶点，并且是药理学靶向的补充。令人惊讶的是，尽管有临床证据表明，减少给药剂量和频率可以减少副作用，提高患者依从率和改善治疗效果，但很少有针对生物制药的努力来改善艾滋病毒感染的治疗。因此，这项竞争性更新申请的长期目标是设计、合成、表征和评估新的高分子药物载体和大分子药物偶联物，通过改善它们的递送、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，新的生物偶联物将被合成和表征，以实现以下具体目标：目标1；确定聚合物支架拓扑结构和效应器对体内配置、脑摄取、蛋白质结合、靶细胞摄取和保留以及抗hiv活性的影响。目的2：评估细胞靶向性以改善细胞内药物递送，具体探索：(a)使用包括fMLF和甘露糖在内的多重亲和配体靶向巨噬细胞，以及(b)使用使用二十面体T7噬菌体展示技术鉴定的新型表面识别肽靶向转铁蛋白受体（TfR）。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来评估t细胞靶向性。具体而言，我们将(a)使用噬菌体展示技术鉴定新的CD4识别肽，(b)研究tat与CXCR4病毒辅助受体的结合，以及(c)评估受体(CD4)-辅助受体（CXCR4）单独靶向和与HIV蛋白酶抑制剂联合靶向。我们针对巨噬细胞和t细胞的策略包括使用识别肽来识别HIV-1使用的一些相同的受体，以结合并进入细胞。利用病毒感染途径设计生物偶联物的一个显著优势是，即使使用一种药物也可以引起多种类型的药效学反应。由药物递送和靶向方法引起的活动的多样性补充了药理学方法，并应导致改善的生物功效和患者预后。

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.