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.
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