Polymeric nanomedicine for overcoming resistance mechanisms in hedgehog and Myc-amplified medulloblastoma.

Abstract

Chemoresistance and inadequate therapeutics transport across the blood brain barrier (BBB) remain the major barriers to treating medulloblastoma (MB). Hedgehog (Hh) and IGF/PI3K pathways regulate tumor cell proliferation and resistance in MB. Current Hh inhibitors are effective initially to treat SHH-MB but acquire resistance. Herein, we showed that Hh inhibitor MDB5 and BRD4/PI3K dual inhibitor SF2523 synergistically inhibited the proliferation of DAOY and HD-MB03 cells when used in combination. Treatment of these MB cells with the combination of MDB5 and SF2523 significantly decreased colony formation and expression of MYCN, p-AKT, and cyclin D1 but significantly increased in Bax expression, compared to individual drugs. We used our previously reported copolymer mPEG-b-PCC-g-DC copolymer, which showed 8.7 ± 1.0 and 6.5 ± 0.1% loading for MDB5 and SF2523 when formulated into nanoparticles (NPs). There was sustained drug release from NPs, wherein 100% of MDB5 was released in 50 h, but only 60% of SF2523 was released in 80 h. Targeted NPs prepared by mixing 30:70 ratio of COG-133-PEG-b-PBC and mPEG-b-PCC-g-DC copolymer delivered a significantly higher drug concentration in the cerebellum at 6 and 24h after intravenous injection into orthotopic SHH-MB tumor-bearing NSG mice. Moreover, systemic administration of COG-133-NPs loaded with MDB5 and SF2523 resulted in decreased tumor burden compared to non-targeted drug-loaded NPs, without any hepatic toxicity. In conclusion, our nanomedicine of MDB5 and SF2523 offers a novel therapeutic strategy to treat chemoresistant MB.

• Authors: Virender Kumar, Qiyue Wang, Bharti Sethi, Feng Lin, Vinod Kumar, Donald W Coulter, Yuxiang Dong, Ram I Mahato
• Journal: Biomaterials (Biomaterials) Vol. 278 Pg. 121138 (11 2021) ISSN: 1878-5905 [Electronic] Netherlands
• PMID: 34634662 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Elsevier Ltd. All rights reserved.

Chemical References

• Benzene Derivatives
• Hedgehog Proteins
• MDB5
• Morpholines
• Nuclear Proteins
• Pyrans
• Pyridines
• SF2523
• Transcription Factors

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Benzene Derivatives
• Cell Line, Tumor
• Cerebellar Neoplasms (drug therapy, genetics)
• Drug Synergism
• Hedgehog Proteins
• Medulloblastoma (drug therapy, genetics)
• Mice
• Morpholines
• Nanomedicine
• Nuclear Proteins
• Phosphatidylinositol 3-Kinases
• Pyrans
• Pyridines
• Transcription Factors