Polymersome drug delivery into 3D models of oral disease

Polymersomes are synthetic block co-polymers that self-assemble in aqueous solution to form membrane-enclosed nano-vesicles. They can encapsulate and carry drugs in their core and deliver them directly into the cytoplasm of cells, and so may avoid off target toxicity that often compromises the treatment of oral diseases. Objective: To generate tissue-engineered oral mucosal models (OMM) of early oral squamous cell carcinoma and bacterial infection. To use these models to assess the ability of polymersomes to penetrate and deliver their drug load into the oral mucosa. Methods: OMM were made by culturing oral keratinocytes on top of a fibroblast-populated collagen matrix or dermal scaffold for 14 d at an air-to-liquid interface and examined histologically. Polymersomes loaded with a fluorescent tracking molecule (rhodamine) were applied to OMM for increasing lengths of time. Cell viability and the penetration and retention of polymersomes were analysed by flow cytometry and confocal microscopy. OMM containing intracellular dwelling P.gingivalis were treated with polymersome-encapsulated metronidazole or metronidazole alone and the number of intracellular bacteria measured. Results: Normal OMM and OMM of oral squamous cell carcinoma were histologically similar to biopsy material. Polymersomes were able to deliver rhodamine across the OMM epithelium in a dose and time-dependent manner, and was able to penetrate almost the entire epithelium by 48h. Polymersome-encapsulated metronidazole significantly (P<0.05) reduced the number of intracellular P.gingivalis in infected OMM compared to free metronidazole controls. Conclusion: In vitro OMM of oral squamous cell carcinoma and oral infections replicate those seen in vivo and are a good model to study drug delivery across the oral mucosa. Polymersomes can penetrate and deliver molecules into the cytoplasm of cell of the oral mucosa and these nano-vesicles may offer a novel drug delivery system for use in the treatment of oral disease. Funded in part by Yorkshire Cancer Research.