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Prevention of K-Ras- and Pten-mediated intravaginal tumors by treatment with camptothecin-loaded PLGA nanoparticles

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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 oncogenic K-Ras and inactivation of tumor suppressor Pten in LSL-K-Ras G12D/+ Pten loxP/loxP mice. 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.

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Acknowledgments

The authors thank Gordon Terwilliger (Yale University, New Haven, CT) for his technical assistance in retrieving and preparing tissue samples and Dr. Daniela Dinulescu (Boston, MA) for supplying primer sequences for recombination analysis. J.S.B was supported through a National Institutes of Health postdoctoral fellowship (F32 AI072942) and I.A.B. was supported through a Gilliam Fellowship from Howard Hughes Medical Institute. This work was supported by grants to W.M.S. from the National Institutes of Health (R01 EB000487) and to F.J.S. from the James S. McDonnell Foundation.

Ethical standards

All experiments performed in this manuscript are in compliance with the current laws of the State of Connecticut and the United States of America.

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Authors and Affiliations

  1. Department of Biomedical Engineering, Yale University, New Haven, CT, 06520, USA

    Jeremy S. Blum, Caroline E. Weller & W. Mark Saltzman

  2. Section of Comparative Medicine, Yale University School of Medicine, New Haven, CT, 06510, USA

    Carmen J. Booth

  3. Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT, 06511, USA

    Imran A. Babar, Xianping Liang & Frank J. Slack

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  1. Jeremy S. Blum
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Correspondence to W. Mark Saltzman.

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Blum, J.S., Weller, C.E., Booth, C.J. et al. Prevention of K-Ras- and Pten-mediated intravaginal tumors by treatment with camptothecin-loaded PLGA nanoparticles. Drug Deliv. and Transl. Res. 1, 383–394 (2011). https://doi.org/10.1007/s13346-011-0038-y

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