Self-Oxygenating PROTAC Microneedle for Spatiotemporally-Confined Protein Degradation and Enhanced Glioblastoma Therapy.

in Advanced materials (Deerfield Beach, Fla.) by Xingyu Jiang, Yi Lai, Wenzheng Xia, Wenfang Yang, Junjue Wang, Jiaxing Pan, Qian Zhao, Feng Zhou, Shiqin Li, Shunan Zhang, Jing Gao, Yinyan Wang, Tao Zan, Zhi Ping Xu, Haijun Yu, Zhiai Xu

TLDR

  • The study presents a novel therapeutics approach for glioblastoma that combines acid- and light-activatable PROteolysis TArgeting Chimera (PROTAC) nanoparticles and self-oxygenating BSA-MnO(BM) nanoparticles, achieving efficient tumor growth inhibition and potential for precise treatment of refractory brain tumors.

Abstract

Glioblastoma (GBM) is the most aggressive subtype of primary brain tumors, which marginally respond to standard chemotherapy due to the blood-brain barrier (BBB) and the low tumor specificity of the therapeutics. Herein, a double-layered microneedle (MN) patch is rationally engineered by integrating acid and light dual-activatable PROteolysis TArgeting Chimera (PROTAC) nanoparticles and self-oxygenating BSA-MnO(BM) nanoparticles for GBM treatment. The MN is administrated at the tumor site to locally deliver the PROTAC prodrug and BM nanoparticles. The PROTAC nanoparticles are rapidly released from the outer layer of the MN and specifically activated in the acidic intracellular environment of tumor cells. Subsequently, near-infrared light activates the photosensitizer to produce singlet oxygen (O) through photodynamic therapy (PDT), thereby triggering spatiotemporally-tunable degradation of bromodomain and extraterminal protein 4 (BRD4). The BM nanoparticles, in the inner layer of the MN, serve as an oxygen supply station, and counteracts tumor hypoxia by converting hydrogen peroxide (HO) into oxygen (O), thus promoting PDT and PROTAC activation. This PROTAC prodrug-integrated MN significantly inhibits tumor growth in both subcutaneous and orthotopic GBM tumor models. This study describes the first spatiotemporally-tunable protein degradation strategy for highly efficient GBM therapy, potentially advancing precise therapy of other kinds of refractory brain tumors.

Overview

  • The study focuses on developing a new therapeutic approach for glioblastoma (GBM), the most aggressive subtype of primary brain tumors, which have a poor response to standard chemotherapy due to the blood-brain barrier and limited tumor specificity.
  • The approach involves a double-layered microneedle patch that integrates acid- and light-activatable PROteolysis TArgeting Chimera (PROTAC) nanoparticles and self-oxygenating BSA-MnO(BM) nanoparticles for local delivery and targeted treatment at the tumor site.
  • The primary objective of the study is to develop a spatiotemporally-tunable protein degradation strategy for efficient therapy of refractory brain tumors, such as GBM.

Comparative Analysis & Findings

  • The study demonstrates the efficacy of the PROTAC nanoparticles in inhibiting tumor growth in both subcutaneous and orthotopic GBM tumor models.
  • The microneedle patch showed significant inhibition of tumor growth, compared to control groups, and improved outcomes in orthotopic GBM models.
  • The combination of PROTAC nanoparticles and BM nanoparticles led to enhanced PDT and PROTAC activation, resulting in improved treatment outcomes.

Implications and Future Directions

  • The study highlights the potential of this novel therapy for precise treatment of refractory brain tumors, such as GBM, by spatiotemporally-tunable protein degradation.
  • The findings suggest that this approach could be further developed and explored for treatment of other kinds of refractory brain tumors.
  • Future studies will aim to investigate the long-term efficacy, safety, and feasibility of this novel therapy for treatment of GBM and other brain tumors.
Read Full Article