Pharmacokinetics, Biodistribution, and Toxicity of Folic Acid-Coated Antiretroviral Nanoformulations

ABSTRACT The drug delivery platform for folic acid (FA)-coated nanoformulated ritonavir (RTV)-boosted atazanavir (FA-nanoATV/r) using poloxamer 407 was developed to enhance cell and tissue targeting for a range of antiretroviral drugs. Such formulations would serve to extend the drug half-life while improving the pharmacokinetic profile and biodistribution to reservoirs of human immunodeficiency virus (HIV) infection. To this end, we now report enhanced pharmacokinetics and drug biodistribution with limited local and systemic toxicities of this novel nanoformulation. The use of FA as a targeting ligand for nanoATV/r resulted in plasma and tissue drug concentrations up to 200-fold higher compared to equimolar doses of native drug. In addition, ATV and RTV concentrations in plasma from mice on a folate-deficient diet were up to 23-fold higher for mice administered FA-nanoATV/r than for mice on a normal diet. Compared to earlier nanoATV/r formulations, FA-nanoATV/r resulted in enhanced and sustained plasma and tissue ATV concentrations. In a drug interaction study, ATV plasma and tissue concentrations were up to 5-fold higher in mice treated with FA-nanoATV/r than in mice treated with FA-nanoATV alone. As observed in mice, enhanced and sustained plasma concentrations of ATV were observed in monkeys. NanoATV/r was associated with transient local inflammation at the site of injection. There were no systemic adverse reactions associated with up to 10 weeks of chronic exposure of mice or monkeys to FA-nanoATV/r.

[1]  H. Gendelman,et al.  Macrophage folate receptor-targeted antiretroviral therapy facilitates drug entry, retention, antiretroviral activities and biodistribution for reduction of human immunodeficiency virus infections. , 2013, Nanomedicine : nanotechnology, biology, and medicine.

[2]  W. Spreen,et al.  Long-acting injectable antiretrovirals for HIV treatment and prevention , 2013, Current opinion in HIV and AIDS.

[3]  Han Liu,et al.  Functional proteome of macrophage carried nanoformulated antiretroviral therapy demonstrates enhanced particle carrying capacity. , 2013, Journal of proteome research.

[4]  T. Schacker,et al.  Overcoming pharmacologic sanctuaries , 2013, Current opinion in HIV and AIDS.

[5]  H. Gendelman,et al.  Preclinical Pharmacokinetics and Tissue Distribution of Long-Acting Nanoformulated Antiretroviral Therapy , 2013, Antimicrobial Agents and Chemotherapy.

[6]  M. Takeda-Morishita,et al.  Analysis of the pharmacokinetic boosting effects of ritonavir on oral bioavailability of drugs in mice. , 2013, Drug metabolism and pharmacokinetics.

[7]  J. Meza,et al.  Pharmacodynamic and antiretroviral activities of combination nanoformulated antiretrovirals in HIV-1-infected human peripheral blood lymphocyte-reconstituted mice. , 2012, The Journal of infectious diseases.

[8]  H. Gendelman,et al.  Long-acting nanoformulated antiretroviral therapy elicits potent antiretroviral and neuroprotective responses in HIV-1-infected humanized mice , 2012, AIDS.

[9]  W. McCormick.  Summary Report from the Human Immunodeficiency Virus and Aging Consensus Project: Treatment Strategies for Clinicians Managing Older Individuals with the Human Immunodeficiency Virus , 2012, Journal of the American Geriatrics Society.

[10]  H. Gendelman,et al.  Comparative manufacture and cell-based delivery of antiretroviral nanoformulations , 2011, International journal of nanomedicine.

[11]  H. Gendelman,et al.  UPLC-MS/MS quantification of nanoformulated ritonavir, indinavir, atazanavir, and efavirenz in mouse serum and tissues. , 2011, Journal of chromatography. B, Analytical technologies in the biomedical and life sciences.

[12]  H. Gendelman,et al.  Nanoformulated Antiretroviral Drug Combinations Extend Drug Release and Antiretroviral Responses in HIV-1-Infected Macrophages: Implications for NeuroAIDS Therapeutics , 2010, Journal of Neuroimmune Pharmacology.

[13]  A. Bergamaschi,et al.  Host hindrance to HIV-1 replication in monocytes and macrophages , 2010, Retrovirology.

[14]  A. Puig-Kröger,et al.  Folate receptor beta is expressed by tumor-associated macrophages and constitutes a marker for M2 anti-inflammatory/regulatory macrophages. , 2009, Cancer research.

[15]  H. Gendelman,et al.  NanoART synthesis, characterization, uptake, release and toxicology for human monocyte-macrophage drug delivery. , 2009, Nanomedicine.

[16]  H. Gendelman,et al.  NanoART, neuroAIDS and CNS drug delivery. , 2009, Nanomedicine.

[17]  H. Gendelman,et al.  Macrophage Delivery of Nanoformulated Antiretroviral Drug to the Brain in a Murine Model of NeuroAIDS1 , 2009, The Journal of Immunology.

[18]  P. Low,et al.  A functional folate receptor is induced during macrophage activation and can be used to target drugs to activated macrophages. , 2009, Blood.

[19]  J. Reddy,et al.  Impact of High and Low Folate Diets on Tissue Folate Receptor Levels and Antitumor Responses Toward Folate-Drug Conjugates , 2008, Journal of Pharmacology and Experimental Therapeutics.

[20]  H. Gendelman,et al.  The Promise and Perils of CNS Drug Delivery: A Video Debate , 2008, Journal of Neuroimmune Pharmacology.

[21]  Dianne Langford,et al.  HIV and antiretroviral therapy in the brain: neuronal injury and repair , 2008, Nature Reviews Neuroscience.

[22]  H. Gendelman,et al.  Nanomedicine in the diagnosis and therapy of neurodegenerative disorders. , 2007, Progress in polymer science.

[23]  S. Dandekar.  Pathogenesis of HIV in the gastrointestinal tract , 2007, Current HIV/AIDS reports.

[24]  H. Gendelman,et al.  Development of a macrophage-based nanoparticle platform for antiretroviral drug delivery. , 2006, Blood.

[25]  R. Rathbun,et al.  Current HIV treatment guidelines--an overview. , 2006, Current pharmaceutical design.

[26]  G. Anabwani,et al.  Nutrition and HIV/AIDS in sub-Saharan Africa: an overview. , 2005, Nutrition.

[27]  R. Zeldin,et al.  Pharmacological and therapeutic properties of ritonavir-boosted protease inhibitor therapy in HIV-infected patients. , 2003, The Journal of antimicrobial chemotherapy.

[28]  W. Muller,et al.  The contribution of monocyte infection and trafficking to viral persistence, and maintenance of the viral reservoir in HIV infection , 2003, Journal of leukocyte biology.

[29]  Neff Walker,et al.  The global impact of HIV/AIDS , 2001, Nature.

[30]  P. Low,et al.  Tumor-selective radiopharmaceutical targeting via receptor-mediated endocytosis of gallium-67-deferoxamine-folate. , 1996, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.