Amphiphilic Polymeric Nanoparticles Modified with a Protease-Resistant Peptide Shuttle for the Delivery of SN-38 in Diffuse Intrinsic Pontine Glioma
| Autor: | Bukchin A, Sanchez-Navarro M, Carrera A, Resa-Pares C, Castillo-Ecija H, Balaguer-Lluna L, Teixidó M, Gene-Olaciregui N, Giralt E, Carcaboso AM, Sosnik A |
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| Rok vydání: | 2021 |
| Předmět: | |
| Zdroj: | ACS Applied Nano Materials r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu instname |
| ISSN: | 2574-0970 |
| Popis: | 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 similar to 200 nm (intensity distribution) and a zeta-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 similar to 84-88% of the DIPG cells in suspension, indicating that they reach a concentration above the inhibitory concentration 50 of the drug. Finally, the brain accumulation of the drug-loaded nanoparticles upon intravenous injection to Hsd:ICR mice was preliminarily characterized by light sheet fluorescence microscopy. As opposed to unmodified SN-38-loaded nanoparticles, the modified counterparts bind the brain blood vessels and accumulate in the cerebral parenchyma to a large extent. These results confirm the potential of this nanotechnology platform to deliver anticancer agents to the brain in DIPG and other brain tumors with fully conserved BBB. |
| Databáze: | OpenAIRE |
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