Comparative Biophysical Properties of Tenofovir-Loaded, Thiolated and Nonthiolated Chitosan Nanoparticles Intended for HIV Prevention

Meng, Jianing; Zhang, Tao; Agrahari, Vivek; Ezoulin, Miezan J.; Youan, Bi‐Botti C.

doi:10.2217/nnm.13.136

Cited by 48 publications

(27 citation statements)

References 69 publications

(76 reference statements)

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“…Cytotoxicity studies conducted on glycol CS hydrogels with progesterone revealed no significant influence on the viability of human vaginal epithelial cells [15]. It has also been reported that tenofovir-loaded, thiolated and nonthiolated CS nanoparticles had no cytotoxic effect on vaginal epithelial cells [61]. In contrast, Depani et al, found that CS/glycerol phosphate gels exhibit dose-dependent cytotoxicity on mouse fibroblasts L-929 cells [29].…”

Section: K0mentioning

confidence: 97%

“…As a result, CS has been widely used in biomedical applications (e.g., for the development of scaffolds for skin transplantation or wound dressings) and as diet supplement. Despite the fact that CS is widely used as a drug delivery carrier and has been extensively studied for topical [59,60] and vaginal [61] drug delivery, its safety profile has still not been fully evaluated. The polymer biocompatibility can be influenced by the purity and the source of the material used, the particle size, degree of deacetylation, concentration, dosage form and the route of administration [58].…”

Section: In Vitro Cytotoxicity Evaluationmentioning

confidence: 99%

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The Effect of β-Glycerophosphate Crosslinking on Chitosan Cytotoxicity and Properties of Hydrogels for Vaginal Application

et al. 2015

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Mucoadhesive gelling systems based on chitosan and chitosan/β-glycerophosphate (β-GP) were developed in order to increase clotrimazole residence time in the vaginal cavity. Ex vivo mucoadhesiveness using porcine vaginal mucosa followed with mechanical, viscoelastic, and swelling properties of prepared hydrogels were evaluated. Drug-free, sterile, unmodified, and β-GP crosslinked chitosan were investigated for the in vitro cytotoxicity in CRL 2616 human vaginal mucosa cells using MTT assay, fluorescent microscopy, and flow cytometry analysis. Chitosan/β-GP hydrogels exhibited pseudoplastic and thixotropic properties. Ionic interaction between β-GP and chitosan improved mechanical properties of hydrogels in terms of hardness, cohesiveness, and compressibility. The hydrogels' ability to interact with porcine vaginal mucosa (measured as force of detachment and work of adhesion) was comparable to those obtained with reference mucoadhesive gel Replens™. Surprisingly, greater mucoadhesive properties were noticed for chitosan/β-GP hydrogels. The cytotoxic effect of unmodified and β-GP crosslinked chitosan was hardly affected by chitosan molecular weight, exhibited mainly through inducing apoptosis, and was found to be significantly lower in the presence of chitosan/β-GP. Furthermore, the higher amount of β-GP was used to crosslink chitosan, the lower cytotoxic effect was observed.

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Section: K0mentioning

confidence: 97%

Section: In Vitro Cytotoxicity Evaluationmentioning

confidence: 99%

The Effect of β-Glycerophosphate Crosslinking on Chitosan Cytotoxicity and Properties of Hydrogels for Vaginal Application

et al. 2015

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“…However, TDF has considerable water solubility (13.4 mg/ml at 25°C), and it is well known that hydrophilic drugs are not easy to encapsulate into nanoparticles. There have been few attempts to encapsulate TFV or TDF in PLGA nanoparticles (27,28). None of these investigations were able to achieve greater than 10% encapsulation of TFV or TDF in the nanoparticles.…”

Section: Discussionmentioning

confidence: 99%

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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“…Despite efforts to partially substitute water by non-solvents, such as ethanol, optimized association efficiencies have been usually less than around 25%, thus resulting in poor drug loading, usually no more than up to 2% [100][101].…”

Section: Prevention Of Hiv Transmissionmentioning

confidence: 99%

Polymer-based nanocarriers for vaginal drug delivery

Neves

Nunes

Machado

et al. 2015

Advanced Drug Delivery Reviews

113

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The vaginal delivery of various drugs is well described and its relevance established in current medical practice. Alongside recent advances and achievements in the fields of pharmaceutical nanotechnology and nanomedicine, there is an increasing interest in the potential use of different nanocarriers for the delivery of old and new pharmacologically active molecules with either therapeutic or prophylactic purposes. Nanosystems of polymeric nature in particular have been investigated over the last years and their interactions with mucosal fluids and tissues, as well as genital tract biodistribution upon vaginal administration, are now better understood. While different applications have been envisioned, most of the current research is focusing in the development of nano-formulations with the potential to inhibit the vaginal transmission of HIV upon sexual intercourse. The present work focuses its discussion on the potential and perils of polymer-based nanocarriers for the vaginal administration of different pharmacologically active molecules.

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Comparative Biophysical Properties of Tenofovir-Loaded, Thiolated and Nonthiolated Chitosan Nanoparticles Intended for HIV Prevention

Cited by 48 publications

References 69 publications

The Effect of β-Glycerophosphate Crosslinking on Chitosan Cytotoxicity and Properties of Hydrogels for Vaginal Application

The Effect of β-Glycerophosphate Crosslinking on Chitosan Cytotoxicity and Properties of Hydrogels for Vaginal Application

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

Polymer-based nanocarriers for vaginal drug delivery

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