Vaginal Delivery of Paclitaxel via Nanoparticles with Non‐Mucoadhesive Surfaces Suppresses Cervical Tumor Growth

Abstract

Local delivery of chemotherapeutics in the cervicovaginal tract using nanoparticles may reduce adverse side effects associated with systemic chemotherapy, while improving outcomes for early stage cervical cancer. We hypothesize drug-loaded nanoparticles must rapidly penetrate cervicovaginal mucus (CVM) lining the female reproductive tract to effectively deliver their payload to underlying diseased tissues in a uniform and sustained manner. We develop paclitaxel-loaded nanoparticles, composed entirely of polymers used in FDA-approved products, which rapidly penetrate human CVM and provide sustained drug release with minimal burst effect. We further employ a mouse model with aggressive cervical tumors established in the cervicovaginal tract to compare paclitaxel-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (conventional particles , or CP) and similar particles coated with Pluronic® F127 (mucus-penetrating particles , or MPP). CP are mucoadhesive and, thus, aggregated in mucus, while MPP achieve more uniform distribution and close proximity to cervical tumors. Paclitaxel-MPP suppress tumor growth more effectively and prolong median survival of mice compared to free paclitaxel or paclitaxel-CP. Histopathological studies demonstrate minimal toxicity to the cervicovaginal epithelia, suggesting paclitaxel-MPP may be safe for intravaginal use. These results demonstrate for the first time the in vivo advantages of polymer-based MPP for treatment of tumors localized to a mucosal surface.

Precise engineering of dapivirine-loaded nanoparticles for the development of anti-HIV vaginal microbicides

“…In the 320 present study, PLGA was selected as an alternative polymeric 321 matrix for the nano-formulation of dapivirine due to its wide use322 and versatility in the preparation of drug-loaded NPs, and well 323 documented biocompatibility and safety[27]. Indeed, different 324 groups attested the suitability of PLGA NPs for active compound 325 delivery with different vaginal therapeutic purposes[28,29]. Initial 326 experiments determined the effect of increasing amounts of dapi-327 virine in the colloidal properties of NPs.…”

“…Dapivirine-loaded poly(D,L-lactic-co- 29 glycolic acid) (PLGA) NPs were produced by an emulsion-solvent evaporation method, optimized for col- 30 loidal properties using a 3-factor, 3-level Box-Behnken experimental design, and characterized for drug 31 loading, production yield, morphology, thermal behavior, drug release, in vitro cellular uptake, cyto- 32 toxicity and pro-inflammatory potential. Also, drug permeability/membrane retention in well-estab- 33 lished HEC-1-A and CaSki cell monolayer models as mediated by NPs was assessed in the absence or 34 presence of mucin.…”

Polymer-based nanocarriers for vaginal drug delivery

“…In this last case, differences in mucus samples and PEGylation protocols may justify contradictory data. The potential value of densely PEG-modified NPs in improving vaginal distribution of nanocarriers or nanosized drugs, including at collapsed mucosal folds, has been further demonstrated by Hanes and collaborators in both ex vivo [77] and animal in vivo [78][79][80] experiments. In particular, the administration of mucus-penetrating NPs in a hypotonic vehicle (water) was able to enhance mucus transport.…”

“…In addition, median survival of mice treated with mucus-penetrating NPs was 19 days, contrasting with 11 and 9 days for other treatments and control, respectively. These positive results for mucus-penetrating NPs were correlated with their ability to penetrate mucus, as well as distribute more uniformly and enhance drug retention in the cervicovaginal tract of mice than mucoadhesive NPs [80].…”

“…Yang et al [80] recently reported on the potential of two different types of NPs for the vaginal delivery control and other treatments (Figure 10). In addition, median survival of mice treated with mucus-penetrating NPs was 19 days, contrasting with 11 and 9 days for other treatments and control, respectively.…”