11 results on '"James R. Hilaire"'
Search Results
2. Rod-shape theranostic nanoparticles facilitate antiretroviral drug biodistribution and activity in human immunodeficiency virus susceptible cells and tissues
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Dhruvkumar Soni, Wenting Zhang, Brendan M. Ottemann, Jatin Machhi, JoEllyn M McMillan, Kristen N. Sikora, R. Lee Mosley, Jered C. Garrison, Insiya Mukadam, Howard E. Gendelman, Bhavesh D. Kevadiya, James R. Hilaire, Mahmudul Hasan, Laura Castellanos, Sarella Anandakumar, Jonathan Herskovitz, Benson J Edagwa, and Richard W. Vachet
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Drug ,Biodistribution ,media_common.quotation_subject ,Single photon emission computed tomography ,Cell ,Human immunodeficiency virus (HIV) ,Medicine (miscellaneous) ,HIV Infections ,Spleen ,Long acting antiretroviral therapy ,02 engineering and technology ,Lutetium ,010402 general chemistry ,medicine.disease_cause ,01 natural sciences ,Theranostic Nanomedicine ,Mice ,chemistry.chemical_compound ,Drug Delivery Systems ,Pharmacokinetics ,Multimodal imaging ,medicine ,Animals ,Tissue Distribution ,Pharmacology, Toxicology and Pharmaceutics (miscellaneous) ,Cells, Cultured ,media_common ,Radioisotopes ,Mice, Inbred BALB C ,Chemistry ,Macrophages ,Rilpivirine ,Laser ablation inductively coupled plasma mass spectrometry ,021001 nanoscience & nanotechnology ,3. Good health ,0104 chemical sciences ,Drug biodistribution ,medicine.anatomical_structure ,Lymphatic system ,HIV-1 ,Biophysics ,Nanoparticles ,Reverse Transcriptase Inhibitors ,Radiopharmaceuticals ,0210 nano-technology ,Research Paper - Abstract
Human immunodeficiency virus theranostics facilitates the development of long acting (LA) antiretroviral drugs (ARVs) by defining drug-particle cell depots. Optimal drug formulations are made possible based on precise particle composition, structure, shape and size. Through the creation of rod-shaped particles of defined sizes reflective of native LA drugs, theranostic probes can be deployed to measure particle-cell and tissue biodistribution, antiretroviral activities and drug retention. Methods: Herein, we created multimodal rilpivirine (RPV) 177lutetium labeled bismuth sulfide nanorods (177LuBSNRs) then evaluated their structure, morphology, configuration, chemical composition, biological responses and adverse reactions. Particle biodistribution was analyzed by single photon emission computed tomography (SPECT/CT) and laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) imaging. Results: Nanoformulated RPV and BSNRs-RPV particles showed comparable physicochemical and cell biological properties. Drug-particle pharmacokinetics (PK) and biodistribution in lymphoid tissue macrophages proved equivalent, one with the other. Rapid particle uptake and tissue distribution were observed, without adverse reactions, in primary blood-derived and tissue macrophages. The latter was seen within the marginal zones of spleen. Conclusions: These data, taken together, support the use of 177LuBSNRs as theranostic probes as a rapid assessment tool for PK LA ARV measurements.
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- 2020
3. Sequential LASER ART and CRISPR Treatments Eliminate HIV-1 in a Subset of Infected Humanized Mice
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Santhi Gorantla, James R. Hilaire, Won Bin Young, Shohreh Amini, JoEllyn M McMillan, Brady Sillman, Chen Chen, Hang Su, Mary G. Banoub, Kamel Khalili, Howard E. Gendelman, Prasanta K. Dash, Jennifer Gordon, Larisa Y. Poluektova, Nagsen Gautam, Martina Donadoni, Rahsan Sariyer, Pietro Mancuso, Saumi Mathews, Rafal Kaminski, Monalisha Elango, R. Lee Mosley, Tricia H. Burdo, Jeffrey M. Jacobson, Benson J Edagwa, Taha Mohseni Ahooyi, Pasquale Ferrante, Jake A. Robinson, Zhiyi Lin, Ramona Bella, Ilker Kudret Sariyer, and Aditya N. Bade
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0301 basic medicine ,CRISPR-Cas9 genome editing ,Adoptive cell transfer ,Anti-HIV Agents ,Science ,General Physics and Astronomy ,HIV Infections ,02 engineering and technology ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Virus ,Article ,03 medical and health sciences ,Mice ,In vivo ,Virus latency ,medicine ,Animals ,Humans ,lcsh:Science ,Subgenomic mRNA ,Gene Editing ,Multidisciplinary ,General Chemistry ,Group-specific antigen ,021001 nanoscience & nanotechnology ,medicine.disease ,Antivirals ,Virology ,Adoptive Transfer ,Combined Modality Therapy ,Long terminal repeat ,3. Good health ,Virus Latency ,030104 developmental biology ,medicine.anatomical_structure ,Treatment Outcome ,DNA, Viral ,HIV-1 ,lcsh:Q ,Bone marrow ,CRISPR-Cas Systems ,0210 nano-technology - Abstract
Elimination of HIV-1 requires clearance and removal of integrated proviral DNA from infected cells and tissues. Here, sequential long-acting slow-effective release antiviral therapy (LASER ART) and CRISPR-Cas9 demonstrate viral clearance in latent infectious reservoirs in HIV-1 infected humanized mice. HIV-1 subgenomic DNA fragments, spanning the long terminal repeats and the Gag gene, are excised in vivo, resulting in elimination of integrated proviral DNA; virus is not detected in blood, lymphoid tissue, bone marrow and brain by nested and digital-droplet PCR as well as RNAscope tests. No CRISPR-Cas9 mediated off-target effects are detected. Adoptive transfer of human immunocytes from dual treated, virus-free animals to uninfected humanized mice fails to produce infectious progeny virus. In contrast, HIV-1 is readily detected following sole LASER ART or CRISPR-Cas9 treatment. These data provide proof-of-concept that permanent viral elimination is possible., Here, the authors show that sequential treatment with long-acting slow-effective release ART and AAV9- based delivery of CRISPR-Cas9 results in undetectable levels of virus and integrated DNA in a subset of humanized HIV-1 infected mice. This proof-of-concept study suggests that HIV-1 elimination is possible.
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- 2019
4. Europium sulfide nanoprobes predict antiretroviral drug delivery into HIV-1 cell and tissue reservoirs
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Javier Seravalli, James R. Hilaire, Yutong Liu, Brendan M. Ottemann, Jatin Machhi, JoEllyn M McMillan, Anandakumar Sarella, Bhavesh D. Kevadiya, Mahmudul Hasan, Christopher Woldstad, Insiya Mukadam, Howard E. Gendelman, and Jonathan Herskovitz
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Drug ,Male ,Biodistribution ,Single Photon Emission Computed Tomography Computed Tomography ,Anti-HIV Agents ,media_common.quotation_subject ,antiretroviral ,nanotheranostics ,Biomedical Engineering ,Medicine (miscellaneous) ,Nanoprobe ,HIV Infections ,Sulfides ,Cell Line ,chemistry.chemical_compound ,Mice ,Europium ,medicine ,Animals ,Humans ,Pharmacology, Toxicology and Pharmaceutics (miscellaneous) ,media_common ,Drug Carriers ,Mice, Inbred BALB C ,medicine.diagnostic_test ,Reverse-transcriptase inhibitor ,business.industry ,Rilpivirine ,Magnetic resonance imaging ,Mononuclear phagocyte system ,molecular imaging ,Magnetic Resonance Imaging ,digestive system diseases ,chemistry ,SPECT-CT ,Delayed-Action Preparations ,Cancer research ,HIV-1 ,Nanoparticles ,Molecular imaging ,business ,Biotechnology ,medicine.drug ,Research Paper - Abstract
Background: Delivery of long-acting nanoformulated antiretroviral drugs (ARVs) to human immunodeficiency virus type one cell and tissue reservoirs underlies next generation antiretroviral therapeutics. Nanotheranostics, comprised of trackable nanoparticle adjuncts, can facilitate ARV delivery through real-time drug tracking made possible through bioimaging platforms. Methods: To model HIV-1 therapeutic delivery, europium sulfide (EuS) nanoprobes were developed, characterized and then deployed to cells, tissues, and rodents. Tests were performed with nanoformulated rilpivirine (NRPV), a non-nucleoside reverse transcriptase inhibitor (NNRTI) used clinically to suppress or prevent HIV-1 infection. First, CD4+ T cells and monocyte-derived macrophages were EuS-treated with and without endocytic blockers to identify nanoprobe uptake into cells. Second, Balb/c mice were co-dosed with NRPV and EuS or lutetium177-doped EuS (177LuEuS) theranostic nanoparticles to assess NRPV biodistribution via mass spectrometry. Third, single photon emission computed tomography (SPECT-CT) and magnetic resonance imaging (MRI) bioimaging were used to determine nanotheranostic and NRPV anatomic redistribution over time. Results: EuS nanoprobes and NRPV entered cells through dynamin-dependent pathways. SPECT-CT and MRI identified biodistribution patterns within the reticuloendothelial system for EuS that was coordinate with NRPV trafficking. Conclusions: EuS nanoprobes parallel the uptake and biodistribution of NRPV. These data support their use in modeling NRPV delivery to improve treatment strategies.
- Published
- 2021
5. A year-long extended release nanoformulated cabotegravir prodrug
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Brady Sillman, Tai-Yuen Yue, Howard E. Gendelman, Nagsen Gautam, Melinda Wojtkiewicz, R. Lee Mosley, Adam M. Szlachetka, Bhagya Laxmi Dyavar Shetty, Sruthi Sravanam, Howard S. Fox, Jane L. Meza, Yazen Alnouti, James R. Hilaire, Aditya N. Bade, Tanmay A. Kulkarni, Paul L. Domanico, Benson J Edagwa, Brenda Morsey, Benjamin G. Lamberty, Gary Moore, and JoEllyn M McMillan
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Drug ,Biodistribution ,Pyridones ,media_common.quotation_subject ,Drug Compounding ,02 engineering and technology ,Pharmacology ,010402 general chemistry ,01 natural sciences ,chemistry.chemical_compound ,Mice ,Cabotegravir ,Pharmacokinetics ,Drug Stability ,Animals ,General Materials Science ,Drug Interactions ,Prodrugs ,media_common ,Mechanical Engineering ,Biological Transport ,General Chemistry ,Prodrug ,021001 nanoscience & nanotechnology ,Condensed Matter Physics ,0104 chemical sciences ,Nanostructures ,chemistry ,Anti-Retroviral Agents ,Mechanics of Materials ,Delayed-Action Preparations ,Drug delivery ,Pharmaceutics ,0210 nano-technology ,Intramuscular injection - Abstract
Long-acting cabotegravir (CAB) extends antiretroviral drug administration from daily to monthly. However, dosing volumes, injection site reactions and health-care oversight are obstacles towards a broad usage. The creation of poloxamer-coated hydrophobic and lipophilic CAB prodrugs with controlled hydrolysis and tissue penetrance can overcome these obstacles. To such ends, fatty acid ester CAB nanocrystal prodrugs with 14, 18 and 22 added carbon chains were encased in biocompatible surfactants named NMCAB, NM2CAB and NM3CAB and tested for drug release, activation, cytotoxicity, antiretroviral activities, pharmacokinetics and biodistribution. Pharmacokinetics studies, performed in mice and rhesus macaques, with the lead 18-carbon ester chain NM2CAB, showed plasma CAB levels above the protein-adjusted 90% inhibitory concentration for up to a year. NM2CAB, compared with NMCAB and NM3CAB, demonstrated a prolonged drug release, plasma circulation time and tissue drug concentrations after a single 45 mg per kg body weight intramuscular injection. These prodrug modifications could substantially improve CAB’s effectiveness. Nanoformulated long-acting cabotegravir prodrugs are shown to be capable of extending the native drug’s antiretroviral activity, biodistribution and pharmacokinetics for up to 12 months in mice and rhesus macaques.
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- 2019
6. Optimizing the preparation and stability of decorated antiretroviral drug nanocrystals
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Yazen Alnouti, Howard E. Gendelman, Tian Zhou, James R. Hilaire, Zhiyi Lin, JoEllyn M McMillan, Diana L. Palandri, Nathan Smith, Xin Ming Liu, Pavan Puligujja, Benson J Edagwa, Mariluz Araínga, and Nagsen Gautam
- Subjects
0301 basic medicine ,Drug ,Materials science ,Pyridones ,media_common.quotation_subject ,Biomedical Engineering ,Medicine (miscellaneous) ,Nanoparticle ,HIV Infections ,Bioengineering ,Antiretroviral drug ,Nanotechnology ,02 engineering and technology ,Development ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,Drug Delivery Systems ,Folic Acid ,Cabotegravir ,nanocrystals ,Animals ,Humans ,Tissue Distribution ,General Materials Science ,media_common ,monocyte-derived macrophage ,Macrophages ,cabotegravir ,021001 nanoscience & nanotechnology ,Antiretroviral therapy ,uptake and release ,Disease Models, Animal ,030104 developmental biology ,Anti-Retroviral Agents ,Nanocrystal ,chemistry ,Folic acid ,Drug delivery ,HIV-1 ,Nanoparticles ,long-acting antiretrovirals ,0210 nano-technology ,Research Article - Abstract
Aim: While the therapeutic potential for current long-acting (LA) antiretroviral therapy (ART) is undeniable, ligand-decorated nanoformulated LA-ART could optimize drug delivery to viral reservoirs. The development of decorated ART hinges, however, on formulation processes and manufacture efficiencies. To this end, we compared manufacture and purification techniques for ligand-decorated antiretroviral drug nanocrystals. Materials & methods: Ligand-decorated nanoparticle manufacturing was tested using folic acid (FA) nanoformulated cabotegravir. Results: Direct manufacturing of FA-cabotegravir resulted in stable particles with high drug loading and monocyte–macrophage targeting. A one step ‘direct’ scheme proved superior over differential centrifugation or tangential flow filtration facilitating particle stability and preparation simplicity and efficiency. Conclusion: Direct manufacturing of FA nanoparticles provides a path toward large-scale clinical grade manufacturing of cell-targeted LA-ART., Lay abstract Folic acid (FA) decoration on the surface of nanocrystals can be achieved by mixing FA conjugated poloxamer 407 (FA-P407) and native P407 in varied ratios followed by size reduction by homogenization and differential centrifugation or tangential flow filtration to remove excess unbound polymers. The optimized manufacturing scheme is by direct homogenization with predetermined quantity of FA conjugated P407. Direct manufacturing method yields stable homogenous nanoparticles with high drug loading.
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- 2018
7. Creation of a Long-Acting Rilpivirine Prodrug Nanoformulation
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Melinda Wojtkiewicz, Nagsen Gautam, Brady Sillman, Jonathan Herskovitz, Benson J Edagwa, James R. Hilaire, Howard S. Fox, Sruthi Sravanam, Yazen Alnouti, Adam M. Szlachetka, Benjamin G. Lamberty, Howard E. Gendelman, JoEllyn M McMillan, Aditya N. Bade, Bhagya Laxmi Dyavar Shetty, and Prasanta K. Dash
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Drug ,Male ,Biodistribution ,Anti-HIV Agents ,media_common.quotation_subject ,Pharmaceutical Science ,02 engineering and technology ,Pharmaceutical formulation ,Pharmacology ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,Cabotegravir ,Medicine ,Animals ,Humans ,Prodrugs ,Tissue Distribution ,Dosing ,030304 developmental biology ,media_common ,0303 health sciences ,Mice, Inbred BALB C ,business.industry ,Macrophages ,Rilpivirine ,Prodrug ,021001 nanoscience & nanotechnology ,Macaca mulatta ,chemistry ,Delayed-Action Preparations ,HIV-1 ,Nanoparticles ,0210 nano-technology ,business ,Intramuscular injection - Abstract
Antiretroviral therapy requires lifelong daily dosing to attain viral suppression, restore immune function, and improve quality of life. As a treatment alternative, long-acting (LA) antiretrovirals can sustain therapeutic drug concentrations in blood for prolonged time periods. The success of recent clinical trials for LA parenteral cabotegravir and rilpivirine highlight the emergence of these new therapeutic options. Further optimization can improve dosing frequency, lower injection volumes, and facilitate drug-tissue distributions. To this end, we report the synthesis of a library of RPV prodrugs designed to sustain drug plasma concentrations and improved tissue biodistribution. The lead prodrug M3RPV was nanoformulated into the stable LA injectable NM3RPV. NM3RPV treatment led to RPV plasma concentrations above the protein-adjusted 90% inhibitory concentration for 25 weeks with substantial tissue depots after a single intramuscular injection in BALB/cJ mice. NM3RPV elicited 13- and 26-fold increases in the RPV apparent half-life and mean residence time compared to native drug formulation. Taken together, proof-of-concept is provided that nanoformulated RPV prodrugs can extend the apparent drug’s half-life and improve tissue biodistribution. These results warrant further development for human use.
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- 2019
8. Medicinal Chemistry and Brain Drug Penetrance
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Howard E. Gendelman and James R. Hilaire
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Drug ,Degenerative Disorder ,business.industry ,media_common.quotation_subject ,Central nervous system ,Molecular neuroscience ,Blood–brain barrier ,Medicinal chemistry ,medicine.anatomical_structure ,Immune system ,Drug delivery ,medicine ,business ,Neuropharmacology ,media_common - Abstract
Recent advances in molecular neuroscience and neuropharmacology have improved our knowledge of the intricate mechanisms that define and treat infectious, immune and degenerative disorders of the brain and spinal cord. As our knowledge expands, treatment of central nervous system diseases still remains a challenge. One obstacle is drug delivery. Indeed, designed to protect the brain from toxic molecules, the blood–brain barrier also limits therapeutic drug entry into the brain. The dynamic balance between the exclusion and therapeutic delivery remains a key component to improve disease outcomes.
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- 2016
9. Macrophages, Microglia and Dendritic Cell Function
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James R. Hilaire and Howard E. Gendelman
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Cell type ,Innate immune system ,medicine.anatomical_structure ,Follicular dendritic cells ,Microglia ,Antigen presentation ,medicine ,Myeloid-derived Suppressor Cell ,Dendritic cell ,Progenitor cell ,Biology ,Cell biology - Abstract
Mononuclear phagocytes (MP; monocytes, macrophages, microglia and dendritic cells) are joined together based on common function and phenotypic properties. In regards to phagocytoic, interacellular killing, secretory, antigen presentation and mobility properties differentiating the cell types can be difficult. Ontogeny, locale and modest phenotype differences underlie differences. Similarities abound in innate immunity and protection of a steady-state homeostatic environment and engaging inflammatory responses that direct surveillance and clearance responses. A clear benefit of spanning tissue origins and species differences underlies the importance of these cells that serve as the first line of immune defense.
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- 2016
10. Development and characterization of a long-acting nanoformulated abacavir prodrug
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Yazen Alnouti, Nagsen Gautam, Benson J Edagwa, Diana L. Palandri, JoEllyn M McMillan, Dhirender Singh, Howard E. Gendelman, and James R. Hilaire
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0301 basic medicine ,Drug ,Male ,Drug Liberation ,Anti-HIV Agents ,media_common.quotation_subject ,Biomedical Engineering ,Medicine (miscellaneous) ,Bioengineering ,HIV Infections ,02 engineering and technology ,Poloxamer ,Development ,Pharmacology ,Injections, Intramuscular ,Cell Line ,03 medical and health sciences ,Mice ,Pharmacokinetics ,Abacavir ,Medicine ,Animals ,Humans ,General Materials Science ,Prodrugs ,Particle Size ,media_common ,Ritonavir ,business.industry ,Macrophages ,Prodrug ,021001 nanoscience & nanotechnology ,Dideoxynucleosides ,Bioavailability ,030104 developmental biology ,Delayed-Action Preparations ,HIV-1 ,Nanoparticles ,0210 nano-technology ,business ,Hydrophobic and Hydrophilic Interactions ,medicine.drug ,Half-Life ,Research Article - Abstract
Aim: A myristoylated abacavir (ABC) prodrug was synthesized to extend drug half-life and bioavailability. Methods: Myristoylated ABC (MABC) was made by esterifying myristic acid to the drug's 5-hydroxy-cyclopentene group. Chemical composition, antiretroviral activity, cell uptake and retention and cellular trafficking of free MABC and poloxamer nanoformulations of MABC were assessed by proton nuclear magnetic resonance and tested in human monocyte-derived macrophages. Pharmacokinetics of ABC and nanoformulated MABC were evaluated after intramuscular injection into mice. Results: MABC antiretroviral activity in monocyte-derived macrophages was comparable to native drug. Encasement of MABC into poloxamer nanoparticles extended drug bioavailability for 2 weeks. Conclusion: MABC synthesis and encasement in polymeric nanoformulations improved intracellular drug accumulation and demonstrate translational potential as part of a long-acting antiretroviral regimen.
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- 2016
11. Pharmacodynamics of long-acting folic acid-receptor targeted ritonavir-boosted atazanavir nanoformulations
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Tianlei Ying, Larisa Y. Poluektova, Xin Ming Liu, Aditya N. Bade, Santhi Gorantla, Prasanta K. Dash, Hannah M. Baldridge, Gang Zhang, Howard E. Gendelman, JoEllyn M McMillan, Lindsey M. Kendrick, Yang Feng, Pavan Puligujja, Dimiter S. Dimitrov, Yanping Wang, James R. Hilaire, and Shantanu Balkundi
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Human immunodeficiency virus type one ,Male ,Pyridines ,Chemistry, Pharmaceutical ,T-Lymphocytes ,HIV Core Protein p24 ,02 engineering and technology ,Pharmacology ,Mice, Inbred NOD ,Tissue Distribution ,media_common ,0303 health sciences ,Mice, Inbred BALB C ,Nanoart ,021001 nanoscience & nanotechnology ,Flow Cytometry ,3. Good health ,Anti-Retroviral Agents ,Liver ,Mechanics of Materials ,0210 nano-technology ,Viral load ,Oligopeptides ,medicine.drug ,Long-acting nanoformulated antiretroviral therapy ,Drug ,media_common.quotation_subject ,Atazanavir Sulfate ,Biophysics ,Folic acid receptor ,Bioengineering ,Poloxamer ,Article ,Biomaterials ,03 medical and health sciences ,Pharmacokinetics ,Antigens, CD ,medicine ,Animals ,Humans ,Folate Receptor 1 ,030304 developmental biology ,Non-obese diabetic severe combined immunodeficient mice ,Ritonavir ,business.industry ,Atazanavir ,Bioavailability ,Pharmacodynamics ,Ceramics and Composites ,Nanoparticles ,business ,Spleen - Abstract
Long-acting nanoformulated antiretroviral therapy (nanoART) that target monocyte-macrophage could improve the drug’s half-life and protein binding capacities while facilitating cell and tissue depots. To this end, ART nanoparticles that target the folic acid (FA) receptor and permit cell-based drug depots were examined using pharmacokinetic and pharmacodynamic (PD) tests. FA receptor-targeted poloxamer 407 nanocrystals, containing ritonavir-boosted atazanavir (ATV/r), significantly affected several therapeutic factors: drug bioavailability increased as much as 5 times and PD activity improved as much as 100 times. Drug particles administered to human peripheral blood lymphocyte reconstituted NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ mice and infected with HIV-1ADA at a tissue culture infective dose50 of 104 infectious viral particles/ml led to ATV/r drug concentrations that paralleled FA receptor beta staining in both the macrophage-rich parafollicular areas of spleen and lymph nodes. Drug levels were higher in these tissues than what could be achieved by either native drug or untargeted nanoART particles. The data also mirrored potent reductions in viral loads, tissue viral RNA and numbers of HIV-1p24+ cells in infected and treated animals. We conclude that FA-P407 coating of ART nanoparticles readily facilitate drug carriage and facilitate antiretroviral responses.
- Published
- 2014
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