Novel Mucoadhesive Celecoxib-Loaded Cubosomal Sponges: Anticancer Potential and Regulation of Myeloid-Derived Suppressor Cells in Oral Squamous Cell Carcinoma

Oral squamous-cell carcinoma (OSCC) is a widespread health problem. Myeloid-derived suppressor cells (MDSCs) are major tumor microenvironment (TME) population that govern many carcinogenesis aspects by establishing immunosuppressive milieu favoring tumor aggressiveness and treatment resistance. Cyclooxygenase-2 (COX-2) regulates MDSCs activity, hence, COX-2-selective inhibition by celecoxib (CXB) showed good anticancer effect at relatively high doses with possible subsequent cardiovascular complications. Therefore, targeted CXB delivery to MDSCs may represent a promising OSCC treatment strategy. Novel mucoadhesive-cubosomal buccal sponges were prepared for MDSCs targeting and were evaluated for their in-vitro quality attributes, ex-vivo mucoadhesion using buccal chicken-mucosa. Optimally-selected formulation showed considerable uptake by CD33+/11b+MDSCs in human OSCC cell-line (SCC-4) when quantitatively analyzed by flow-cytometry and examined using confocal-laser microscope. Optimum formulations loaded with low CXB doses (12 mg) were promoted to in-vivo studies via local application, using 4-nitroquinoline-1-oxide-induced OSCC in rats, and compared to their corresponding CXB gels. SP16 revealed the highest ability to decrease MDSC activation, recruitment and TME-immunosuppression in the isolated tumors. Consequently, SP16 exerted the greatest capacity to reduce histologic tumor grade, the OSCC-specific serum tumor markers levels, cancer hallmarks and stemness markers. CXB-loaded cubosomal sponges preferentially target MDSCs with noticeable anticancer potential and may exemplify novel mucoadhesive nanocarriers for OSCC treatment.