icon-folder.gif   Conference Reports for NATAP  
  17th International Workshop
on Clinical Pharmacology of
HIV and Hepatitis Therapy
June 8-10, 2016, Washington DC
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Development of Dolutegravir Combination Nanoparticle Fabrications for HIV Prophylaxis
  Reported by Jules Levin
17th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy, 8-10 June 2016, Washington, DC, USA
Annemarie Shibata, Ph.D.
in collaboration with Dr. Christopher Destache
Creighton University
Omaha, NE



program abstract
The numbers of individuals infected with HIV could be reduced with highly effective pre-exposure prophylaxis (PreP). Dolutegravir (DTG) is an integrase strand transfer inhibitor with potent anti-HIV activity. Cellulose acetate phthalate (CAP) is a natural polymer with HIV-1 entry inhibitory properties. Development of DTG-loaded CAP nanoparticles (DTG-CAP-NP) could serve as a novel combination for PreP.
Methods: Anoil-in-water homogenization was used to fabricate DTG-CAP-NP and CAP-NP. Pluronic F127 (2%) and organic to aqueous phase ratio of 1:1 were used for DTG-CAP-NP and CAP-NP. Encapsulation efficiency (EE) of DTG in DTG-CAP-NP was validated by HPLC. Cytotoxicity of DTG-CAP-NP was evaluated and compared to CAP-NP and DTG solution in cell lines and human Epivaginal™ tissues. Intracellular delivery of DTG to cell lines was determined by pretreatment with DTG-CAP-NP or DTG solution and cell lysates were analyzed by HPLC. To evaluate antiviral activity, TZM-bl cells were treated with DTG-CAP-NP and DTG solution for 1 or 3 days then infected with HIV-1NL-4-3. Luminescence was measured after 48 h.
Results: Mean (+ SD) size < 80.7 ± 1.7 nm and surface charge -33.67 ± 1.9 mV for DTG-CAP-NP. EE of DTG was > 26.3% in CAP-DTG-NP. DTG-CAP-NP were significantly less toxic to cell lines as compared to DTG solution and non-toxic to endocervical tissues. CAP-NP were not toxic to cell lines or Epivaginal™ tissues at concentrations as high as 100 μg/mL. DTG-CAP-NP showed complete inhibition of HIV-1 infection at a concentration equivalent to 5 ng of DTG whereas DTG solution and CAP-NP showed significantly less inhibition at this concentration (p<0.05). These data indicate synergy between DTG and CAP as well as the advantage of nanoscale fabrication.
Conclusions: DTG-CAP-NP would be a novel vaginal microbicide with greater potency than DTG in solution and may offer a sustained release PrEP option for HIV. This is the first report of DTG fabricated into a NP formulation for PReP for treatment.