title: 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 μm) 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.
authors.affiliation: 3B's Research Group-Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Avepark-Parque de Ciência e Tecnologia, Barco GMR 4805-017, Portugal; ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors.forename: Alexandre A
authors.initials: AA
authors.lastname: Barros
authors.affiliation: ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal; Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal.
authors.forename: Carlos
authors.initials: C
authors.lastname: Oliveira
authors.affiliation: 3B's Research Group-Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Avepark-Parque de Ciência e Tecnologia, Barco GMR 4805-017, Portugal; ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors.forename: Rui L
authors.initials: RL
authors.lastname: Reis
authors.affiliation: ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal; Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal.
authors.forename: Estevão
authors.initials: E
authors.lastname: Lima
authors.affiliation: 3B's Research Group-Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Avepark-Parque de Ciência e Tecnologia, Barco GMR 4805-017, Portugal; ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal. Electronic address: aduarte@dep.uminho.pt.
authors.forename: Ana Rita C
authors.initials: ARC
authors.lastname: Duarte
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D004317:Doxorubicin / Q000008:administration & dosage* / Q000493:pharmacokinetics; D054855:Drug-Eluting Stents; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D017239:Paclitaxel / Q000008:administration & dosage* / Q000493:pharmacokinetics; D010539:Permeability; D013552:Swine; D014513:Ureter / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D004317:Doxorubicin; D017239:Paclitaxel
keywords: biodegradable polymers; doxorubicin permeability; paclitaxel; upper tract urothelial carcinoma; ureteral stents