Pifithrin-μ incorporated in gold nanoparticle amplifies pro-apoptotic unfolded protein response cascades to potentiate synergistic glioblastoma therapy.

Abstract

Conventional radiotherapy has a pivotal role in the treatment of glioblastoma; nevertheless, its clinical utility has been limited by radiation resistance. There is emerging evidence that upregulated heat shock protein A5 (HSPA5) in cancer cells maintains or restores the homeostasis of a cellular microenvironment and results in cancer resistance in various treatments. Therefore, we describe a bioresponsive nanoplatform that can deliver a HSPA5 inhibitor (pifithrin-μ, PES) and radiosensitizer (gold nanosphere, AuNS), to expand the synergistic photothermal therapy and radiotherapy, as well as to monitor the progression of cancer therapy using computer tomography/magnetic resonance imaging. The nanoplatform (PES-Au@PDA, 63.3 ± 3.1 nm) comprises AuNS coated with the photothermal conversion agent polydopamine (PDA) for enhanced radiotherapy and photothermal therapy, as well as PES (loading efficiency of PES approximately 40%), a small molecular inhibitor against HSPA5 to amplify the pro-apoptotic unfolded protein response (UPR). The reported nanoplatform enables hyperthermia-responsive release of PES. Results from in vitro and in vivo studies demonstrate that PES-Au@PDA can specially activate pro-apoptotic UPR cascades, leading to remarkably improved radiotherapy and photothermal therapy efficiencies. Considered together, a versatile theranostic nanosystem is reported for promoting the synergistic radiophotothermal therapy by selectively activating pro-apoptotic UPR cascade pathways.

• Authors: Haitao Zhu, Xiongfeng Cao, Xiaojie Cai, Ying Tian, Dongqing Wang, Jianchen Qi, Zhaogang Teng, Guangming Lu, Qianqian Ni, Shouju Wang, Longjiang Zhang
• Journal: Biomaterials (Biomaterials) Vol. 232 Pg. 119677 (02 2020) ISSN: 1878-5905 [Electronic] Netherlands
• PMID: 31865193 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.

Chemical References

• 2-phenylacetylenesulfonamide
• Endoplasmic Reticulum Chaperone BiP
• HSPA5 protein, human
• Sulfonamides
• Gold

Topics

• Brain Neoplasms (drug therapy)
• Endoplasmic Reticulum Chaperone BiP
• Glioblastoma (drug therapy)
• Gold
• Humans
• Hyperthermia, Induced
• Metal Nanoparticles
• Phototherapy
• Sulfonamides
• Tumor Microenvironment
• Unfolded Protein Response