title: Prevention ofK-Ras- andPten-mediated intravaginal tumors by treatment with camptothecin-loaded PLGA nanoparticles.
abstract: Primary squamous cell carcinoma of the vagina is an uncommon disease that often exhibits few symptoms before reaching an advanced stage. Topical intravaginal therapies for resolving precancerous and cancerous vaginal lesions have the potential to be non-invasive and safer alternatives to existing treatment options. Two factors limit the testing of this approach: lack of a preclinical intravaginal tumor model and absence of safe and effective topical delivery systems. In this study, we present both an inducible genetic model of vaginal squamous cell carcinoma in mice and a novel topical delivery system. Tumors were generated via activation of oncogenicK-Rasand inactivation of tumor suppressorPteninLSL-K-RasG12D/+PtenloxP/loxPmice. This was accomplished by exposing the vaginal epithelium to a recombinant adenoviral vector expressing Cre recombinase (AdCre). As early as 3 weeks after AdCre exposure exophytic masses protruding from the vagina were observed; these were confirmed to be squamous cell carcinoma by histology. We utilized this model to investigate an anticancer therapy based on poly(lactic-co-glycolic acid) (PLGA) nanoparticles loaded with camptothecin (CPT); our earlier work has shown that PLGA nanoparticles can penetrate the vaginal epithelium and provide sustained CPT release. Particles were lavaged into the vaginal cavity of AdCre-infected mice. None of the mice receiving CPT nanoparticles developed tumors. These results demonstrate a novel topical strategy to resolve precancerous and cancerous lesions in the female reproductive tract.
authors.affiliation: Department of Biomedical Engineering, Yale University, New Haven, CT 06520, USA.
authors.forename: Jeremy S
authors.initials: JS
authors.lastname: Blum
authors.affiliation: Department of Biomedical Engineering, Yale University, New Haven, CT 06520, USA.
authors.forename: Caroline E
authors.initials: CE
authors.lastname: Weller
authors.affiliation: Section of Comparative Medicine, Yale University School of Medicine, New Haven, CT 06510, USA.
authors.forename: Carmen J
authors.initials: CJ
authors.lastname: Booth
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT 06511, USA.
authors.forename: Imran A
authors.initials: IA
authors.lastname: Babar
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT 06511, USA.
authors.forename: Xianping
authors.initials: X
authors.lastname: Liang
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT 06511, USA.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Slack
authors.affiliation: Department of Biomedical Engineering, Yale University, New Haven, CT 06520, USA.
authors.forename: W Mark
authors.initials: WM
authors.lastname: Saltzman
keywords: Camptothecin; Drug delivery; Inducible tumor model; KRAS; PTEN; Polymer nanoparticles; Vaginal squamous cell carcinoma