Delivery of SN-38 in pediatric solid tumors

Abstract

A new combined microdialysis – tumor homogenate method for the determination of compartmental (vascular, extra- and intracellular) SN-38 distribution in patient-derived xenografts (PDX) generated from pediatric solid tumors from fresh tumor samples from patients of Sant Joan de Deu Barcelona Hospital was developed. SN-38 in late-stage (chemoresistant) tumors presented limited distribution into the intracellular compartment while drug distribution into this compartment was significantly higher in early-stage (sensitive) models when SN-38 was administered as its prodrug irinotecan. Furthermore, two polymeric drug delivery systems were developed for the local and systemic administration of SN-38. Poly(lactic) acid electrospun nanofiber matrices with microcrystals of SN-38 were developed for the local administration of SN-38. Matrices showed maintained release of SN-38 over 48 h with local distribution and efficacy delaying tumor growth over PDX models. Dialysates showed limited SN-38 diffusion from the matrices through the tumor tissue, suggesting this therapy could only be useful for the local tumor control after successful surgery of the tumor or where only microscopic tumor seeds are left. Systemic administration of SN-38 was possible by encapsulating the drug into poly(lactic-co-glycolic) acid with polyethylene glycol nanoparticles, which were decorated with 3F8 monoclonal antibody, an anti-GD2 antibody that recognizes the ganglioside GD2 overexpressed on the surface of neuroblastoma cells surface for active targeting. Nanoparticles released SN-38 over 2 days and tumor exposition to SN-38 was increased when compared with the administration of an equimolar dose of irinotecan, and that was correlated with improved efficacy over the conventional irinotecan where 10 administrations of the drug had reduced efficacy compared to the direct administration of SN-38 in the targeted nanoparticles. Both nanofiber matrices and nanoparticles showed to be good platforms for SN-38 administration reducing systemic exposition by localizing SN-38 at the tumor microenvironment and significantly delaying tumor growth as shown in the efficacy studies. Thus, polymeric local drug delivery systems strategy should be of high interest for the potential future treatment of chemoresistant tumors.