Increased delivery of chemotherapy to the vitreous by inhibition of the blood-retinal barrier.

PACUAL PASTO G; OLACIREGUI N; OPEZZO J; CASTILLO ECIJA; CUADRADO VILANOVA; PACO S; SCHAIQUEVICH P; RIVERO EM; BRAMUGLIA G; CHANTADA G; MONTERO CARCABOSO A

JOURNAL OF CONTROLLED RELEASE

ELSEVIER SCIENCE BV

Lugar: Amsterdam; Año: 2017

0168-3659

Treatment of retinoblastoma -a pediatric cancer of the developing retina- mightbenefit from strategies to inhibit the blood-retinal barrier (BRB). The potentanticancer agent topotecan is a substrate of efflux transporters BCRP and P-gp,which are expressed at the BRB to restrict vitreous and retinal distribution ofxenobiotics. In this work we have studied vitreous and retinal distribution,tumor accumulation and antitumor activity of topotecan, using pantoprazole asinhibitor of BCRP and P-gp. We used rabbit and mouse eyes as BRB models andpatient-derived xenografts as retinoblastoma models. To validate the rabbit BRBmodel we stained BCRP and P-gp in the retinal vessels. Using intravitreousmicrodialysis we showed that the penetration of the rabbit vitreous by lactonetopotecan increased significantly upon concomitant administration of pantoprazole(P=0.0285). Pantoprazole also increased topotecan penetration of the mousevitreous, measured as the vitreous-to-plasma topotecan concentration ratio at thesteady state (P=0.0246). Pantoprazole increased topotecan antitumor efficacy and intracellular penetration in retinoblastoma in vitro, but did not enhanceintratumor drug distribution and survival in mice bearing the intraocular humantumor HSJD-RBT-2. Anatomical differences with the clinical setting likely limitedour in vivo study, since xenografts were poorly vascularized masses that loadedmost of the vitreous compartment. We conclude that pharmacological modulation of the BRB is feasible, enhances anticancer drug distribution into the vitreous and might have clinical implications in retinoblastoma.CHEMICAL COMPOUNDS INCLUDED INTHIS MANUSCRIPT: Topotecan (PubChem CID: 60700) Pantoprazole sodium (PubChem CID:15008962).