Thermosensitive Gel Containing Cellulose Acetate Phthalate-Efavirenz Combination Nanoparticles for Prevention of HIV-1 Infection

Date, Abhijit A.; Shibata, Annemarie; McMullen, Emily; Bruzzo, Krista La; Bruck, Patrick T.; Belshan, Michael; Zhou, You; Destache, Christopher J.

doi:10.1166/jbn.2015.1942

Cited by 34 publications

(49 citation statements)

References 33 publications

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“…The TMS gel was prepared by following the method we described previously, with a few modifications (13). Briefly, a 20:1 ratio of Pluronic F127 to Pluronic F68 was dissolved in PBS, pH 7.4.…”

Section: Methodsmentioning

confidence: 99%

“…However, in the presence of an ion-pairing agent, the mean EE of TDF in TDF-NPs increased to 52.9%. We have already reported characteristics of our TMS gel formulation (13). Further, we optimized the TMS gel fabrication process to incorporate TDF-NPs to obtain uniform TDF-NP-TMS gels having different concentrations of TDF (0.1%, 0.5%, and 1%, wt/vol).…”

Section: Methodsmentioning

confidence: 99%

“…Rheology has been used to study the thermogelation properties of our gel in the presence of simulated cervicovaginal fluid (11)(12)(13)(14). In the presence of simulated vaginal fluids, the optimized formulation of TMS gel was able to retain thermogelling behavior at approximately 32 to 34°C.…”

Section: Figmentioning

confidence: 99%

“…Our laboratory has been developing a nanotechnology-based gel delivery system (11)(12)(13)(14)(15)(16). Our gel delivery system incorporates a thermosensitive (TMS) gel that is liquid at room temperature and a semisolid at body temperature.…”

mentioning

confidence: 99%

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Topical Tenofovir Disoproxil Fumarate Nanoparticles Prevent HIV-1 Vaginal Transmission in a Humanized Mouse Model

Destache

Mandal

Yuan

et al. 2016

Antimicrob Agents Chemother

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e Preexposure prophylaxis (PrEP) with 1% tenofovir (TFV) vaginal gel has failed in clinical trials. To improve TFV efficacy in vaginal gel, we formulated tenofovir disoproxil fumarate nanoparticles in a thermosensitive (TMS) gel (TDF-NP-TMS gel). TDF-NPs were fabricated using poly(lactic-co-glycolic acid) (PLGA) polymer and an ion-pairing agent by oil-in-water emulsification. The efficacy of TDF-NP-TMS gel was tested in humanized bone marrow-liver-thymus (hu-BLT) mice. Hu-BLT mice in the treatment group (Rx; n ‫؍‬ 15) were administered TDF-NP-TMS gel intravaginally, having TDF at 0.1%, 0.5%, and 1% (wt/vol) concentrations, whereas the control (Ctr; n ‫؍‬ 8) group received a blank TMS gel. All Rx mice ( Presently, a total of 36.9 million people worldwide are living with HIV-1 (1). Topical preexposure prophylaxis (PrEP) currently is a promising preventative strategy (2). The basic idea is to protect the vagina (and/or rectum) from HIV-1 infection by applying gel containing antiretroviral drug(s) around the time of sexual intercourse. This topical preparation is considered a microbicide, inhibiting infection by blocking viral transmission at the mucosal surface. To date, tenofovir (TFV) is the only drug administered locally as a 1% vaginal gel shown to be effective at preventing heterosexual contraction of HIV-1 (3). TFV tissue concentrations indicate a direct relationship between levels of TFV in genitals and protection (4-7). The minimum amount of TFV in cervicovaginal fluid levels when associated with gel that shows protection against HIV-1 infection has been reported to be Ͼ1,000 ng/ml (4). This level is greater than 10 times that seen in patients receiving oral TDF and emtricitabine (4). In female macaques given 1% TFV gel, the intracellular half-life for the active metabolite, tenofovir diphosphate, is significantly shorter (averaging 25 h) in vaginal lymphocytes than peripheral PBMCs (averaging 49 h) (7). A coitally independent strategy using 1% TFV gel has not shown efficacy in several clinical trials (8,9). Based on the dramatic negative results of the Vaginal and Oral Interventions to Control the Epidemic (VOICE) trial, it is important to consider female attitudes and opinions for a vaginal gel-based prevention delivery system. A safe and effective female-controlled, discrete gel-based delivery system has the potential to prevent millions of HIV-1 infections worldwide annually.When designing female-controlled preventative delivery systems, the gel-based system should have features important for the female user. Namely, the delivery system should be (i) easy to administer; (ii) adherent to the mucosal surface once applied vaginally; (iii) low seepage; and (iv) free of side effects or cytotoxicity to the mucosal surfaces of the female genital tract (10). All of these factors, if not optimized, could diminish gel effectiveness or lead to gel aversion. Finally, a long-acting preparation would be highly desirable if it offered long-term protection from HIV-1 (11).Our laboratory has been developing a nanotechn...

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Figmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Topical Tenofovir Disoproxil Fumarate Nanoparticles Prevent HIV-1 Vaginal Transmission in a Humanized Mouse Model

Destache

Mandal

Yuan

et al. 2016

Antimicrob Agents Chemother

Self Cite

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“…However, thermogelling and bioadhesive gels have been investigated, which could provide sustained retention and long-term protection [93]. Despite the issues concerning leakiness and messiness, hydrogels are being investigated for topical delivery of ARV drugs either by the vaginal or rectal route.…”

Section: On-demand Vaginal Rectal and Dual Compartment Dosage Formsmentioning

confidence: 99%

On-demand microbicide products: design matters

Patel

Rohan

2017

Drug Deliv. and Transl. Res.

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Sexual intercourse (vaginal and anal) is the predominant mode of HIV (human immune deficiency virus) transmission. Topical microbicides used in an on-demand format (i.e. immediately before or after sex), can be part of an effective tool kit utilized to prevent sexual transmission of HIV. The effectiveness of prevention products is positively correlated with adherence, which is likely to depend on user acceptability of the product. The development of an efficacious and acceptable product is therefore paramount for the success of an on-demand product. Acceptability of on-demand products (e.g. gels, films, and tablets) and their attributes is influenced by a multitude of user-specific factors that span behavioral, life-style, socio-economic, and cultural aspects. In addition, physicochemical properties of the drug, anatomical and physiological aspects of anorectal and vaginal compartments, issues relating to large-scale production and cost can impact product development. These factors together with user preferences determine the design space of an effective, acceptable, and feasible on-demand product. In this review, we summarize the interacting factors that together determine product choice and its target product profile.

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Pharmaceutical Approaches to HIV Treatment and Prevention

Yavuz

Morgan

Showalter

et al. 2018

Advanced Therapeutics

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Human immunodeficiency virus (HIV) infection continues to pose a major infectious disease threat worldwide. It is characterized by the depletion of CD4 + T cells, persistent immune activation, and increased susceptibility to secondary infections. Advances in the development of antiretroviral drugs and combination antiretroviral therapy have resulted in a remarkable reduction in HIV-associated morbidity and mortality. Antiretroviral therapy (ART) leads to effective suppression of HIV replication with partial recovery of host immune system and has successfully transformed HIV infection from a fatal disease to a chronic condition. Additionally, antiretroviral drugs have shown promise for prevention in HIV pre-exposure prophylaxis and treatment as prevention. However, ART is unable to cure HIV. Other limitations include drug-drug interactions, drug resistance, cytotoxic side effects, cost, and adherence. Alternative treatment options are being investigated to overcome these challenges including discovery of new molecules with increased anti-viral activity and development of easily administrable drug formulations. In light of the difficulties associated with current HIV treatment measures, and in the continuing absence of a cure, the prevention of new infections has also arisen as a prominent goal among efforts to curtail the worldwide HIV pandemic. In this review, the authors summarize currently available anti-HIV drugs and their combinations for treatment, new molecules under clinical development and prevention methods, and discuss drug delivery formats as well as associated challenges and alternative approaches for the future.

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Thermosensitive Gel Containing Cellulose Acetate Phthalate-Efavirenz Combination Nanoparticles for Prevention of HIV-1 Infection

Cited by 34 publications

References 33 publications

Topical Tenofovir Disoproxil Fumarate Nanoparticles Prevent HIV-1 Vaginal Transmission in a Humanized Mouse Model

Topical Tenofovir Disoproxil Fumarate Nanoparticles Prevent HIV-1 Vaginal Transmission in a Humanized Mouse Model

On-demand microbicide products: design matters

Pharmaceutical Approaches to HIV Treatment and Prevention

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