@article {18880, title = {Drug-eluting biodegradable ureteral stents: as a new approach for urothelial tumors of upper urinary tract cancer}, journal = {TERMSTEM}, year = {2016}, month = {2016-10-27 00:00:00}, address = {Guimaraes, Portugal}, abstract = {

Upper urinary tract urothelial carcinoma (UTUC) accounts for 5-10\% of urothelial carcinomas and is a disease that has not been as widely studied as carcinoma of the bladder. To avoid the problems of conventional therapies, such as the need for frequent drug-instillation due to poor drug retention, we developed a biodegradable ureteral stent (BUS) impregnated by supercritical CO2 (scCO2) with the most commonly used anti-cancer drugs, namely paclitaxel, epirubicin, doxorubicin, and gemcitabine. The release kinetics of anti-cancer therapeutics from drug-eluting stents was measured in artificial urine solution (AUS). The in vitro release showed a faster release in the first 72h for the four anti-cancer drugs, after this time a plateau was achieved and finally the stent degraded after 9 days. Regarding the amount of impregnated drugs by scCO2, gemcitabine showed the highest amount of loading (19.57{\textmu}gdrug /mgpolymer), while the lowest amount was obtained for paclitaxel (0.067{\textmu}gdrug /mgpolymer). A urothelial cancer cell line (T24) was exposed to graded concentrations (0.01 to 2000 ng/ml) of each drug for 4 and 72h to determine the sensitivities of the cells to each drug (IC50). The direct and indirect contact study of the BUS with the T24 and HUVEC cells confirmed the anti-tumoral effect of the BUS impregnated with the four anti-cancer drugs tested, reducing around 75\% of the viability of the T24 cell line after 72h and demonstrating minimal cytotoxic effect on HUVECs. We used three different setups to study the permeability: a synthetic membrane, HUVECs monolayer and an ex vivo porcine ureter. Permeability profiles, were measured during 8 hours, for paclitaxel (MW=853,91g/mol) and doxorubicin (MW=543,52g/mol). The drugs per se have shown to have a different profile and as expected, increasing the complexity of the membrane to be permeated, the permeability decreased, being the synthetic membrane more permeable and the ex vivo ureter tissue less permeable. Molecular weight has shown to influence the permeability of each drug and a higher percentage for doxorubicin (26\%) and lower for paclitaxel (18\%) was observed across the ex vivo ureter. The permeability (P), diffusion (D) and partition (Kd) coefficients of paclitaxel and doxorubicin through the permeable setups were calculated. Finally, we showed that paclitaxel and doxorubicin drugs released from the BUS were able to across the different permeable setups inclusive across the ex vivo porcine ureter with a permeability of 3\% for paclitaxel and 11\% for doxorubicin. The estimated amount of drugs remains in the ex vivo ureter tissue shown to be between 12-23\%.

}, keywords = {Durg-eluting, stent, uretel}, author = {Barros, A. A. and Oliveira, C. and Reis, R. L. and Lima, E. and Duarte, A. R. C.} }