Long-acting nanoformulated antiretroviral therapy elicits potent antiretroviral and neuroprotective responses in HIV-1-infected humanized mice
| Autor: | Larisa Y. Poluektova, Prasanta K. Dash, JoEllyn M McMillan, Yazen Alnouti, Shantanu Balkundi, Upal Roy, Howard E. Gendelman, Santhi Gorantla, R.L. Mosley, Harris A. Gelbard |
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| Rok vydání: | 2012 |
| Předmět: |
Drug
Anti-HIV Agents Pyridines media_common.quotation_subject Atazanavir Sulfate Immunology Antigens CD34 Pharmacology Article Mice Drug Delivery Systems Pharmacokinetics Mice Inbred NOD Animals Immunology and Allergy Medicine Distribution (pharmacology) media_common Dosage Forms Drug Carriers Ritonavir Dose-Response Relationship Drug business.industry Nanoart Brain Viral Load Immunohistochemistry Atazanavir Infectious Diseases Pharmacodynamics HIV-1 Nanoparticles business Oligopeptides Viral load medicine.drug |
| Zdroj: | AIDS. 26:2135-2144 |
| ISSN: | 0269-9370 |
| DOI: | 10.1097/qad.0b013e328357f5ad |
| Popis: | Objectives Long-acting nanoformulated antiretroviral therapy (nanoART) with improved pharmacokinetics, biodistribution and limited systemic toxicities will likely improve drug adherence and access to viral reservoirs. Design Atazanavir and ritonavir crystalline nanoART were formulated in a poloxamer-188 excipient by high-pressure homogenization. These formulations were evaluated for antiretroviral and neuroprotective activities in humanized NOD/scid-IL-2Rgc (NSG) mice. Methods NanoART-treated NSG mice were evaluated for drug biodistribution, pharmacodynamics and toxicity. CD34 human hematopoietic stem cells were transplanted at birth in replicate NSG mice. The mice were infected with HIV-1ADA at 5 months of age. Eight weeks later, the infected animals were treated with weekly subcutaneous injections of nanoformulated ATV and RTV. Peripheral viral load, CD4 T-cell counts and lymphoid and brain histopathology and immunohistochemistry tests were performed. Results NanoART treatments by once-a-week injections reduced viral loads more than 1000-fold and protected CD4 T-cell populations. This paralleled high ART levels in liver, spleen and blood that were in or around the human minimal effective dose concentration without notable toxicities. Importantly, examination of infected brain subregions showed that nanoART elicited neuroprotective responses with detectable increases in microtubule-associated protein-2, synaptophysin and neurofilament expression when compared to untreated virus-infected animals. Therapeutic interruptions produced profound viral rebounds. Conclusion Long-acting nanoART has translational potential with sustained and targeted efficacy and with limited systemic toxicities. Such success in drug delivery and distribution could improve drug adherence and reduce viral resistance in infected people. |
| Databáze: | OpenAIRE |
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