TY - JOUR
T1 - Amphiphilic Polymeric Nanoparticles Modified with a Protease-Resistant Peptide Shuttle for the Delivery of SN-38 in Diffuse Intrinsic Pontine Glioma
AU - Bukchin, Alexandra
AU - Sanchez-Navarro, Macarena
AU - Carrera, Adam
AU - Resa-Pares, Claudia
AU - Castillo-Ecija, Helena
AU - Balaguer-Lluna, Leire
AU - Teixidó, Meritxell
AU - Olaciregui, Nagore G.
AU - Giralt, Ernest
AU - Carcaboso, Angel M.
AU - Sosnik, Alejandro
N1 - Publisher Copyright:
©
PY - 2021/2/26
Y1 - 2021/2/26
N2 - 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, 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.
AB - 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, 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.
KW - amphiphilic polymeric nanoparticles
KW - diffuse intrinsic pontine glioma (DIPG)
KW - peptide shuttles
KW - targeting of the central nervous system (CNS)
UR - http://www.scopus.com/inward/record.url?scp=85100052095&partnerID=8YFLogxK
U2 - 10.1021/acsanm.0c02888
DO - 10.1021/acsanm.0c02888
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AN - SCOPUS:85100052095
VL - 4
SP - 1314
EP - 1329
JO - ACS Applied Nano Materials
JF - ACS Applied Nano Materials
IS - 2
ER -
