Hilliard L Kutscher1,2, Faithful Makita-Chingombe2,3, Sara DiTursi2, Ajay Singh1, Admire Dube4, Charles C Maponga2,3, Gene D Morse2, Jessica L Reynolds5. 1. The Institute for Lasers, Photonics and Biophotonics, University at Buffalo, Buffalo, NY, USA. 2. Translational Pharmacology Research Core, New York State Center of Excellence in Bioinformatics and Life Sciences; School of Pharmacy and Pharmaceutical Sciences; University at Buffalo, Buffalo, NY, USA. 3. School of Pharmacy, University of Zimbabwe, Harare, Zimbabwe. 4. Department of Pharmaceutics, University of the Western Cape, South Africa. 5. Department of Medicine, School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo NY, USA.
Abstract
OBJECTIVE: To reduce the amount of the antiretroviral (ARV) nevirapine necessary to achieve therapeutic concentrations using macrophage targeted nanoparticles. METHODS: Core-shell nanoparticles were prepared from FDA approved, biodegradable and biocompatible polymers, with poly(lactic-co-glycolic) acid (PLGA) as the core and chitosan (CS) as the shell using a water/oil/water method. Nevirapine was encapsulated in the core of the nanoparticles. β-glucan (GLU) was adsorbed to the surface of the nanoparticle. Macrophage uptake and intracellular nevirapine concentrations were determined by fluorescence imaging and ultra-performance liquid chromatography/mass spectroscopy (UPLC-MS). Optical imaging was employed to characterize the biodistribution of nanoparticles following intravenous injection in CD-1 mice. RESULTS: We synthesized spherical shaped 190 nm GLU-CS-PLGA nanoparticles that provide controlled release of nevirapine. In THP-1 macrophage the uptake of PLGA and CS- PLGA nanoparticles was less compared to targeted GLU-CS-PLGA nanoparticles. THP-1 macrophage were dosed with free nevirapine (10 μg/well) and GLU-CS- PLGA nanoparticles containing 1/10 the concentration of free nevirapine (1 μg nevirapine/well). The intracellular concentration of nevirapine was the same for both nanoparticles and free nevirapine at 2 and 24 hrs. No significant change in THP-1 macrophage viability was observed in the presence of nanoparticles relative to the control. Ex vivo imaging demonstrates that nanoparticles are predominantly found in the liver and kidney and at 24 hr there is still a large amount of nanoparticles in the body. CONCLUSION: These data demonstrate that the total dose of nevirapine delivered by GLU-CS-PLGA nanoparticles can be greatly reduced, to limit side effects, while still providing maximal ARV activity in a known cellular reservoir.
OBJECTIVE: To reduce the amount of the antiretroviral (ARV) nevirapine necessary to achieve therapeutic concentrations using macrophage targeted nanoparticles. METHODS: Core-shell nanoparticles were prepared from FDA approved, biodegradable and biocompatible polymers, with poly(lactic-co-glycolic) acid (PLGA) as the core and chitosan (CS) as the shell using a water/oil/water method. Nevirapine was encapsulated in the core of the nanoparticles. β-glucan (GLU) was adsorbed to the surface of the nanoparticle. Macrophage uptake and intracellular nevirapine concentrations were determined by fluorescence imaging and ultra-performance liquid chromatography/mass spectroscopy (UPLC-MS). Optical imaging was employed to characterize the biodistribution of nanoparticles following intravenous injection in CD-1 mice. RESULTS: We synthesized spherical shaped 190 nm GLU-CS-PLGA nanoparticles that provide controlled release of nevirapine. In THP-1 macrophage the uptake of PLGA and CS- PLGA nanoparticles was less compared to targeted GLU-CS-PLGA nanoparticles. THP-1 macrophage were dosed with free nevirapine (10 μg/well) and GLU-CS- PLGA nanoparticles containing 1/10 the concentration of free nevirapine (1 μg nevirapine/well). The intracellular concentration of nevirapine was the same for both nanoparticles and free nevirapine at 2 and 24 hrs. No significant change in THP-1 macrophage viability was observed in the presence of nanoparticles relative to the control. Ex vivo imaging demonstrates that nanoparticles are predominantly found in the liver and kidney and at 24 hr there is still a large amount of nanoparticles in the body. CONCLUSION: These data demonstrate that the total dose of nevirapine delivered by GLU-CS-PLGA nanoparticles can be greatly reduced, to limit side effects, while still providing maximal ARV activity in a known cellular reservoir.
Authors: Jessica L Reynolds; Wing Cheung Law; Supriya D Mahajan; Ravikumar Aalinkeel; Bindukumar Nair; Donald E Sykes; Manoj J Mammen; Ken-Tye Yong; Rui Hui; Paras N Prasad; Stanley A Schwartz Journal: J Immunol Date: 2012-03-19 Impact factor: 5.422
Authors: Janet A Willment; Hsi-Hsien Lin; Delyth M Reid; Philip R Taylor; David L Williams; Simon Y C Wong; Siamon Gordon; Gordon D Brown Journal: J Immunol Date: 2003-11-01 Impact factor: 5.422
Authors: Admire Dube; Jessica L Reynolds; Wing-Cheung Law; Charles C Maponga; Paras N Prasad; Gene D Morse Journal: Nanomedicine Date: 2013-12-10 Impact factor: 5.307