Amphiphilic Polymeric Nanoparticles Modified with a Protease-Resistant Peptide Shuttle for the Delivery of SN-38 in Diffuse Intrinsic Pontine Glioma

作者：Alexandra Bukchin, Macarena Sánchez‐Navarro, Adam Carrera-Aubesart, Claudia Resa‐Pares, Helena Castillo‐Ecija, Leire Balaguer‐Lluna, Meritxell Teixidò, Nagore G. Olaciregui, Ernest Giralt, Ángel M. Carcaboso, Alejandro Sosnik · 发表于：ACS Applied Nano Materials · 年份：2021 · DOI：10.1021/acsanm.0c02888 · 被引用次数：24 · 研究领域：Nanoparticle-Based Drug Delivery、Glioma Diagnosis and Treatment、RNA Interference and Gene Delivery

Diffuse intrinsic pontine glioma (DIPG) is a chemo-resistant, incurable pediatric tumor of the central nervous system (CNS). The blood–brain barrier (BBB) remains intact in the course of the disease, preventing drugs from entering the brain and resulting in therapeutic failure. The topoisomerase I inhibitor SN-38 shows strong anticancer activity in a patient-derived DIPG cell line in vitro, though a low CNS bioavailability and anti-DIPG efficacy in vivo . In this work, we produced SN-38-loaded polymeric nanoparticles of an amphiphilic chitosan (CS)- g -poly(methyl methacrylate)-poly(acrylic acid) copolymer that were surface-modified with a peptide shuttle that improves transport across the BBB. Drug-loaded nanoparticles displayed a size of ∼200 nm (intensity distribution) and a ζ-potential of +16 mV. The cytocompatibility and endocytosis assayed in DIPG cells (both attached and in suspension) indicated that the nanoparticles are compatible and mainly internalized by clathrin-mediated endocytosis and that the anticancer activity of SN-38 is preserved after nanoencapsulation. In addition, a tandem permeability/anticancer activity study utilizing a coculture model of BBB endothelial cells and DIPG cell spheroids demonstrated that the modified nanoparticles cross a BBB endothelial cell monolayer to a higher extent than the unmodified counterparts and are taken up by DIPG cells. After 72 h of exposure, both SN-38-loaded nanoparticles killed ∼84-88% of the DIPG cells in suspension,...