Prodrug and conjugate drug delivery strategies for improving HIV/AIDS therapy

Abstract

Despite the wide variety of highly potent anti-HIV drugs that have been developed and made available in clinical practice over the years, eradication of HIV infection has not been achieved. Currently, HIV infection and AIDS are thought to be chronically treatable. HIV attacks host immune cells namely macrophages and CD4(+)T-cells and sequesters itself into sanctuary and reservoir sites such as the lymphoid tissues, testes, and brain. Initial drug delivery efforts with prodrugs and drug conjugates focused on improving the physicochemical (i.e. solubility), biopharmaceutic (i.e. absorption, metabolism), and pharmacokinetic (i.e. blood concentrations) properties of the parent drugs. Eradicating HIV, however, will require advanced drug delivery approaches in order to access and maintain effective drug concentrations for prolonged periods of time in sanctuary sites. The current review discusses prodrug/conjugate efforts, clinical successes and describes drug delivery challenges and approaches for eradicating HIV infection.

Figure 1

HIV life cycle. The viral stages include surface adsorption, binding to the cell surface receptors (CD4 and a chemokine coreceptor), fusion of the viral envelope to the cell membrane, capsid uncoating, reverse transcription, nuclear translocation of viral cDNA and integrase, integration of the viral cDNA into the host genome, transcription, translation, protease mediated cleavage, and viral assembly and budding (redrawn from [10] and [15]).

Figure 2

Structure of fosamprenavir. IUPAC name is [(2R, 3S)-1-[(4-aminophenyl)sulfonyl-(2-methylpropyl)amino]-3-{[(3S)-oxolan-3-yl] oxycarbonylamino}-4-phenyl-butan-2-yl]oxyphosphonic acid.

Figure 3

Metabolic conversion of fosamprenavir to amprenavir by alkaline phosphatase in the intestinal lumen.

Figure 4

Nucleoside phosphonate analogues developed for various anti-viral therapies.

Figure 5

Tenofovir disoproxil fumarate or bis(isopropyloxycarbonyloxymethyl)-(R)-9-(2-phosphonomethoxypropyl) adenine. IUPAC name is 1-(6-aminopurin-9-yl) propan-2-yloxymethylphosphonic acid.

Figure 6

Intracellular activation of tenofovir to TDP.

Figure 7

Incorporation of tenofovir into viral cDNA and mechanism of chain termination.

Figure 8

Conversion of tenofovir disoproxil fumarate to tenofovir upon intestinal absorption.

Figure 9

General design of prodrug conjugates.

Figure 10

General design of PEG nanocarriers conjugated to SQV prodrug and biotin/retro-inverso CK-Tat9 or CK(stearate)Tat9 peptides. The prodrug is attached through a reversible ester bond, whereas the cell-penetrating peptides are attached through reducible disulfide bonds. PEG is attached through stable amide bonds and biotin is attached through PEG spacer. The nanocarrier shown here releases the SQV.

Figure 11

PEG (A–C) and PEG-peptide (D) based nanocarriers developed for macrophage targeting by receptor-mediated endocytosis. The fMLF copy number was varied to obtain a nanocarrier with optimum binding properties. The molecular weight of PEG was varied to influence the molecular size of the nanocarrier whereas fluorescein molecule was attached to monitor their binding and uptake behavior.