In vitro and ex-vivo permeability studies of paclitaxel and doxorubicin from drug-eluting biodegradable ureteral stents

Abstract

A drug-eluting biodegradable ureteral stent (BUS) has been developed as a new approach for the treatment of urothelial tumors of upper urinary tract cancer. In a previous work, this system has proven to be a good carrier for anticancer drugs as a potential effective and sustainable intravesical drug delivery system. BUS has revealed to reduce in 75% the viability of human urothelial cancer cells (T24) after 72 h of contact and demonstrated minimal cytotoxic effect on human umbilical vein endothelial cells (HUVECs) which were used as a control. In this work, we studied the permeability of the anticancer drugs, such as paclitaxel and doxorubicin, alone or released from the BUS developed. We used 3 different membranes to study the permeability: polyethersulfone (PES) membrane, HUVECs cell monolayer, and an ex vivo porcine ureter. The ureter thickness was measured (864.51 mm) and histological analysis was performed to confirm the integrity of urothelium. Permeability profiles were measured during 8 h for paclitaxel and doxorubicin. 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, with the PES being more permeable and the ex vivo ureter tissue being less permeable. The molecular weight has also 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 membranes were calculated. Finally, we showed that paclitaxel and doxorubicin drugs released from the BUS were able to remain in the ex vivo ureter and only a small amount of the drugs can across the different permeable membranes with a permeability of 3% for paclitaxel and 11% for doxorubicin. The estimated amount of paclitaxel that remains in the ex vivo ureter tissue is shown to be effective to affect the cancer cell and not affect the noncancer cells.The research leading to these results has received funding from Urology Research Grant Jaba Recordati 2015, Portuguese Urology Association, ICVS/3B’seAssociate Laboratory Research Grants, and the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement number REGPOT-CT2012-316331-POLARIS. The project “Novel smart and biomimetic materials for innovative regenerative medicine approaches” (RL1 - ABMR - NORTE-01-0124- FEDER-000016) cofinanced by North Portugal Regional Operational Programme (ON.2 e O Novo Norte), under the National Strategic Reference Framework (NSRF), through the European Regional Development Fund (ERDF) is also acknowledged. Alexandre Barros acknowledges his FCT PhD grant SFRH/BD/97203/2013. The authors would like to acknowledge Teresa Oliveira for the technical assistance on the histological analysis.info:eu-repo/semantics/publishedVersio