title: Development and evaluation of a thermosensitive vaginal gel containing raltegravir+efavirenz loaded nanoparticles for HIV prophylaxis.
abstract: The objective of this investigation was to develop a thermosensitive vaginal gel containing raltegravir+efavirenz loaded PLGA nanoparticles (RAL+EFV-NPs) for pre-exposure prophylaxis of HIV. RAL+EFV-NPs were fabricated using a modified emulsion-solvent evaporation method and characterized for size and zeta potential. The average size and surface charge of RAL+EFV-NP were 81.8±6.4 nm and -23.18±7.18 mV respectively. The average encapsulation efficiency of raltegravir and efavirenz was 55.5% and 98.2% respectively. Thermosensitive vaginal gel containing RAL+EFV-NPs was successfully prepared using a combination of Pluronic F127 (20% w/v) and Pluronic F68 (1% w/v). Incorporation RAL+EFV-NPs in the gel did not result in nanoparticle aggregation and RAL+EFV-NPs containing gel showed thermogelation at 32.5°C. The RAL+EFV-NPs were evaluated for inhibition of HIV-1(NL4-3) using TZM-bl indicator cells. The EC(90) of RAL+EFV-NPs was lower than raltegravir+efavirenz (RAL+EFV) solution but did not reach significance. Compared to control HeLa cells without any treatment, RAL+EFV-NPs or blank gel were not cytotoxic for 14 days in vitro. The intracellular levels of efavirenz in RAL+EFV-NPs treated HeLa cells were above the EC(90) for 14 days whereas raltegravir intracellular concentrations were eliminated within 6 days. Transwell experiments of NPs-in-gel demonstrated rapid transfer of fluorescent nanoparticles from the gel and uptake in HeLa cells within 30 min. These data demonstrate the potential of antiretroviral NP-embedded vagina gels for long-term vaginal pre-exposure prophylaxis of heterosexual HIV-1 transmission.
authors.affiliation: School of Pharmacy and Health Professions, Creighton University, Omaha, NE 68178, USA.
authors.forename: Abhijit A
authors.initials: AA
authors.lastname: Date
authors.forename: Annemarie
authors.initials: A
authors.lastname: Shibata
authors.forename: Michael
authors.initials: M
authors.lastname: Goede
authors.forename: Bridget
authors.initials: B
authors.lastname: Sanford
authors.forename: Krista
authors.initials: K
authors.lastname: La Bruzzo
authors.forename: Michel
authors.initials: M
authors.lastname: Belshan
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Destache
mesh_terms: D000480:Alkynes; D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology*; D048588:Benzoxazines / Q000737:chemistry / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D003521:Cyclopropanes; D004337:Drug Carriers / Q000008:administration & dosage / Q000737:chemistry; D004353:Drug Evaluation, Preclinical; D005782:Gels / Q000737:chemistry / Q000494:pharmacology*; D015658:HIV Infections / Q000517:prevention & control / Q000821:virology; D015497:HIV-1 / Q000187:drug effects*; D006367:HeLa Cells; D006801:Humans; D019344:Lactic Acid / Q000737:chemistry; D008826:Microbial Sensitivity Tests; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D010587:Phagocytosis; D020442:Poloxamer / Q000737:chemistry; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011760:Pyrrolidinones / Q000737:chemistry / Q000494:pharmacology*; D000068898:Raltegravir Potassium; D013696:Temperature; D013997:Time Factors
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D004337:Drug Carriers; D005782:Gels; D011760:Pyrrolidinones; D020442:Poloxamer; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D000068898:Raltegravir Potassium; C098320:efavirenz