Prevention of K-Ras- and Pten-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 oncogenic K-Ras and inactivation of tumor suppressor Pten in LSL-K-RasG12D/+ PtenloxP/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.

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

“…A number of nanoparticle-based platforms, including polymeric nanoparticles, [6] and quantum dots, [7] have been developed that show potential in animal models for preventing sexually transmitted infections, [8] prophylaxis against the development of cervicovaginal tumors, [9] and improved siRNA delivery [10] . However, conventional polymeric nanoparticles, including those composed of polymers used in FDA-approved products, poly(lactic- co -glycolic acid) (PLGA) and polycaprolactone, are easily immobilized by the visocoelastic and adhesive cervicovaginal mucus (CVM) secretions coating the CV epithelium.…”

Development of quercetin nanoformulation and in vivo evaluation using streptozotocin induced diabetic rat model

“…Approaches based on nanoformulations for the delivery of potential therapeutic molecules have been reported to improve the efficacy of such molecules, which otherwise suffer from certain limitations [14][15][16][17][18]. Different delivery systems for quercetin have been reported such as nanoparticles [6], solid lipid nanoparticles [12], liposomes [19], and microemulsion [20] for various applications, such as in neurodegenerative disease, aging, etc.…”

Polymer-based nanocarriers for vaginal drug delivery

“…Drug-loaded NPs also presented low toxicity and did not induce significant pathologic changes as compared to untreated wild-type mice infected by the recombinant adenovirus [137].…”

“…Blum et al [137] obtained camptothecin-loaded PLGA NPs by a single emulsion-evaporation method using PVA as stabilizer, and tested it for the treatment of vaginal primary squamous cell carcinoma. Using an interesting new animal model of the disease (LSL-K-Ras G12D/+ Pten loxP/loxP mice exposed intravaginally to recombinant an adenoviral vector expressing Cre recombinase), these researchers showed that mice treated weekly for 5 weeks with NPs (around 160 nm) did not developed visible tumors (0 out of 6 animals).…”