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. KeywordsAnti-viral; Conjugate; Fosamprenavir; HIV; Nanocarrier; Prodrug; Targeted drug delivery; Tenofovir disoproxil fumarate Since the first report in 1981, more than 67 million persons have been infected with HIV, and more than 27 million have died of AIDS [1,2]. More than 40% of new infections worldwide occur among adults in the age range of 15-24 years [3]. In fact, AIDS is now the leading cause of premature death among people 15 to 59 years of age. HIV/AIDS remains both a medical and economic challenge in developing countries especially in Sub-Saharan Africa [4]. Unfortunately, after nearly 30 years of research there are still three compelling facts driving the development of new anti-AIDS drugs and delivery systems: i) there is a lack of an effective vaccine or prophylactic agent that would provide protection for the foreseeable future, ii) there is a constant need for both less expensive and more tolerable drug therapies, and iii) the development of resistant viral strains in treatment-experienced patients continue [5]. The late Dr. Paul Janssen described four ideal characteristics of a novel anti-HIV drug. The drug must possess: i) high antiviral activity against both wild-type and mutant virus, thus a drug must be effective despite the genetic flexibility of the virus and it must anticipate resistant strains that may develop once therapy is initiated, ii) high oral bioavailability and a long elimination half-life to allow for once daily dosing, which is considered the gold standard of any therapy, iii) have minimal adverse effects, which will ultimately impact patient compliance, and iv) be easy to synthesize and formulate into dosage forms, which ultimately impact the cost of the drug for both the manufacturer and the patient [6]. However, the development of drugs that meet these criteria is an arduous * Correspondence: sinko@rutgers.edu. NIH Public AccessAuthor Manuscript J Drug Deliv Sci Technol. Author manuscript; available in PMC 2010 August 16. NIH-PA Author Manuscript NIH-P...

HIV protease inhibitors: garlic supplements and first‐pass intestinal metabolism impact on the therapeutic efficacy

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“…Namely, a sufficient penetration of HIV-PI into the infected sanctuary sites, which ensures low HIV virus load [4], can be achieved only by attaining adequate HIV-PI plasma concentrations after per oral application.…”

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