Abstract
To adequately reduce new HIV infections, development of highly effective pre-exposure prophylaxis (PrEP) against HIV infection in women is necessary. Cellulose acetate phthalate (CAP) is a pHsensitive polymerwithHIV-1 entry inhibitory properties. Dolutegravir (DTG) is an integrase strand transfer inhibitor with potent antiretroviral activity. DTG delivered in combination with CAP may significantly improve current PrEP against HIV. In the present study, the development of DTG-loaded CAP nanoparticles incorporated in thermosensitive (TMS) gel at vaginal pH 4.2 and seminal fluid pH 7.4 is presented as proof-of-concept for improved PrEP. Water-oil-in-water homogenization was used to fabricate DTG-loaded CAP nanoparticles (DTG-CAP-NPs). Size, polydispersity, andmorphological analyses illustrate thatDTG-CAP-NPswere smooth and spherical, ≤200 nmin size, and monodispersed with a polydispersity index PDI ≤0.2. The drug encapsulation (EE%) and release profile of DTG-CAP-NPs was determined by HPLC analysis. The EE% of DTG in DTG-CAP-NPs was evaluated to be ~70%. The thermal sensitivity of the TMS gel was optimized and the pH dependency was evaluated by rheological analysis. DTG release studies in TMS gel revealed that DTG-CAP-NPs were stable in TMS gel at pH 4.2 while DTG-CAP-NPs in TMS gel at pH 7.4 rapidly release DTG (≥80% release within 1 h). Cytotoxicity studies using vaginal cell lines revealed that DTG-CAP-NPs were relatively non-cytotoxic at concentration <1 μg/mL. Confocal microscopic studies illustrate that ≥98% cells retained DTG-CAP-NPs intracellularly over seven days. Antiretroviral drug loaded nanocellulose fabrications in TMS gel delivered intravaginally may enhance both microbicidal and antiretroviral drug efficacy and may present a novel option for female PrEP against HIV.
| Original language | English (US) |
|---|---|
| Article number | 423 |
| Journal | Polymers |
| Volume | 9 |
| Issue number | 9 |
| DOIs | |
| State | Published - Sep 7 2017 |
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All Science Journal Classification (ASJC) codes
- Chemistry(all)
- Polymers and Plastics
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Cellulose acetate phthalate and antiretroviral nanoparticle fabrications for HIV pre-exposure prophylaxis. / Mandal, Subhra; Khandalavala, Karl; Pham, Rachel; Bruck, Patrick; Varghese, Marisa; Kochvar, Andrew; Monaco, Ashley; Prathipati, Pavan Kumar; Destache, Christopher J.; Shibata, Annemarie.
In: Polymers, Vol. 9, No. 9, 423, 07.09.2017.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Cellulose acetate phthalate and antiretroviral nanoparticle fabrications for HIV pre-exposure prophylaxis
AU - Mandal, Subhra
AU - Khandalavala, Karl
AU - Pham, Rachel
AU - Bruck, Patrick
AU - Varghese, Marisa
AU - Kochvar, Andrew
AU - Monaco, Ashley
AU - Prathipati, Pavan Kumar
AU - Destache, Christopher J.
AU - Shibata, Annemarie
PY - 2017/9/7
Y1 - 2017/9/7
N2 - To adequately reduce new HIV infections, development of highly effective pre-exposure prophylaxis (PrEP) against HIV infection in women is necessary. Cellulose acetate phthalate (CAP) is a pHsensitive polymerwithHIV-1 entry inhibitory properties. Dolutegravir (DTG) is an integrase strand transfer inhibitor with potent antiretroviral activity. DTG delivered in combination with CAP may significantly improve current PrEP against HIV. In the present study, the development of DTG-loaded CAP nanoparticles incorporated in thermosensitive (TMS) gel at vaginal pH 4.2 and seminal fluid pH 7.4 is presented as proof-of-concept for improved PrEP. Water-oil-in-water homogenization was used to fabricate DTG-loaded CAP nanoparticles (DTG-CAP-NPs). Size, polydispersity, andmorphological analyses illustrate thatDTG-CAP-NPswere smooth and spherical, ≤200 nmin size, and monodispersed with a polydispersity index PDI ≤0.2. The drug encapsulation (EE%) and release profile of DTG-CAP-NPs was determined by HPLC analysis. The EE% of DTG in DTG-CAP-NPs was evaluated to be ~70%. The thermal sensitivity of the TMS gel was optimized and the pH dependency was evaluated by rheological analysis. DTG release studies in TMS gel revealed that DTG-CAP-NPs were stable in TMS gel at pH 4.2 while DTG-CAP-NPs in TMS gel at pH 7.4 rapidly release DTG (≥80% release within 1 h). Cytotoxicity studies using vaginal cell lines revealed that DTG-CAP-NPs were relatively non-cytotoxic at concentration <1 μg/mL. Confocal microscopic studies illustrate that ≥98% cells retained DTG-CAP-NPs intracellularly over seven days. Antiretroviral drug loaded nanocellulose fabrications in TMS gel delivered intravaginally may enhance both microbicidal and antiretroviral drug efficacy and may present a novel option for female PrEP against HIV.
AB - To adequately reduce new HIV infections, development of highly effective pre-exposure prophylaxis (PrEP) against HIV infection in women is necessary. Cellulose acetate phthalate (CAP) is a pHsensitive polymerwithHIV-1 entry inhibitory properties. Dolutegravir (DTG) is an integrase strand transfer inhibitor with potent antiretroviral activity. DTG delivered in combination with CAP may significantly improve current PrEP against HIV. In the present study, the development of DTG-loaded CAP nanoparticles incorporated in thermosensitive (TMS) gel at vaginal pH 4.2 and seminal fluid pH 7.4 is presented as proof-of-concept for improved PrEP. Water-oil-in-water homogenization was used to fabricate DTG-loaded CAP nanoparticles (DTG-CAP-NPs). Size, polydispersity, andmorphological analyses illustrate thatDTG-CAP-NPswere smooth and spherical, ≤200 nmin size, and monodispersed with a polydispersity index PDI ≤0.2. The drug encapsulation (EE%) and release profile of DTG-CAP-NPs was determined by HPLC analysis. The EE% of DTG in DTG-CAP-NPs was evaluated to be ~70%. The thermal sensitivity of the TMS gel was optimized and the pH dependency was evaluated by rheological analysis. DTG release studies in TMS gel revealed that DTG-CAP-NPs were stable in TMS gel at pH 4.2 while DTG-CAP-NPs in TMS gel at pH 7.4 rapidly release DTG (≥80% release within 1 h). Cytotoxicity studies using vaginal cell lines revealed that DTG-CAP-NPs were relatively non-cytotoxic at concentration <1 μg/mL. Confocal microscopic studies illustrate that ≥98% cells retained DTG-CAP-NPs intracellularly over seven days. Antiretroviral drug loaded nanocellulose fabrications in TMS gel delivered intravaginally may enhance both microbicidal and antiretroviral drug efficacy and may present a novel option for female PrEP against HIV.
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U2 - 10.3390/polym9090423
DO - 10.3390/polym9090423
M3 - Article
AN - SCOPUS:85029124852
VL - 9
JO - Polymers
JF - Polymers
SN - 2073-4360
IS - 9
M1 - 423
ER -