Engineered biomimetic cisplatin-polyphenol nanocomplex for chemo-immunotherapy of glioblastoma by inducing pyroptosis.

in Journal of nanobiotechnology by Xinyan Hao, Yucheng Tang, Wenjie Xu, Ming Wang, Jiayi Liu, Yongjiang Li, Jun He, Yanjin Peng, Pengcheng Sun, Dehua Liao, Xiongbin Hu, Tiantian Tang, Min Zhou, Ruyue Han, Jiemin Wang, João Conde, Daxiong Xiang, Junyong Wu

TLDR

  • The study combines cisplatin with nanocomplexes to induce anti-tumor immune activation and overcome immune escape in GBM, with potent in vitro and in vivo results demonstrating improved tumor targeting and immune cell activation.
  • The findings suggest a potential therapeutic strategy against GBM, which warrants further investigation and optimization.

Abstract

Glioblastoma multiforme (GBM) is characterized by pronounced immune escape and resistance to chemotherapy-induced apoptosis. Preliminary investigations revealed a marked overexpression of gasdermin E (GSDME) in GBM. Notably, cisplatin (CDDP) demonstrated a capacity of inducing pyroptosis by activating caspase-3 to cleave GSDME, coupled with the release of proinflammatory factors, indicating the potential as a viable approach of inducing anti-tumor immune activation. For the effective delivery of CDDP, the CDDP-polyphenol nanocomplexes were prepared, and catalase and copper ions were incorporated to fortify structural integrity, enhance glutathione (GSH) responsiveness, and ameliorate tumor hypoxia. Additionally, BV2 microglial cells were engineered to overexpress programmed death-1 (PD-1), and the membrane is employed for nanocomplex coating, effectively blocking the CDDP-induced upregulation of programmed death ligand 1 (PD-L1). Furthermore, the angiopep-2 peptide was modified to efficiently cross the blood brain barrier and specifically target GBM cells. In vitro analyses confirmed potent cytotoxicity and characteristic induction of pyroptosis. In vivo assays corroborated the enhancement of tumor targeting, culminating in an obvious suppression of tumor proliferation. A notable activation of immune cells was observed within tumors and lymph nodes, indicative of a synergistic effect of chemotherapy and immunotherapy, underscoring its potential as a safe and efficacious therapeutic strategy against GBM.

Overview

  • The study investigates the use of cisplatin (CDDP) in combination with nanocomplexes to induce anti-tumor immune activation and overcome immune escape in glioblastoma multiforme (GBM).
  • The researchers prepared CDDP-polyphenol nanocomplexes, incorporated catalase and copper ions, and modified the angiopep-2 peptide to target GBM cells.
  • The primary objective is to evaluate the potential of this therapeutic strategy in enhancing tumor targeting, inducing pyroptosis, and activating immune cells against GBM.

Comparative Analysis & Findings

  • In vitro analyses showed potent cytotoxicity and characteristic induction of pyroptosis by CDDP-polyphenol nanocomplexes
  • In vivo assays demonstrated enhanced tumor targeting, leading to suppression of tumor proliferation and activation of immune cells within tumors and lymph nodes.
  • A notable activation of immune cells was observed, indicating a synergistic effect of chemotherapy and immunotherapy in treating GBM.

Implications and Future Directions

  • The study highlights the potential of CDDP-polyphenol nanocomplexes as a safe and efficacious therapeutic strategy against GBM, particularly in overcoming immune escape and chemoresistance.
  • Further studies are needed to investigate the mechanistic underpinnings of the observed synergistic effect and to optimize the delivery of CDDP-polyphenol nanocomplexes across the blood-brain barrier.
  • The incorporation of PD-1-overexpressing BV2 microglial cells may be a promising approach to enhance immunotherapy in GBM, warranting further exploration.
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