2. Academic Validation
  3. Synergistic Proteolysis Targeting Chimera Chemotherapy Conjugate for Potent Non-small Cell Lung Cancer Treatment

Synergistic Proteolysis Targeting Chimera Chemotherapy Conjugate for Potent Non-small Cell Lung Cancer Treatment

  • ACS Appl Mater Interfaces. 2025 Dec 17;17(50):67595-67608. doi: 10.1021/acsami.5c18202.
Qixin Zhao 1,  Rui Zeng 2,  Tao Bi 1 3,  Xuemei Yang 1,  Ting Wang 1,  Lei Chen 1,  Juan Huang 1,  Xiyu Dai 1,  Houping Xu 4,  Qin Sun 1 3 4,  Zengjin Liu 1 3 4
Affiliations

Affiliations

  • 1 Drug Research Center of Integrated Traditional Chinese and Western Medicine, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou 646000, Sichuan, China.
  • 2 Department of Emergency Medicine, Fushun People's Hospital, Zigong 643000, China.
  • 3 Luzhou Key Laboratory of Research and Development of Medical Institution Preparations and Large-Scale Health Products, Luzhou 646000, Sichuan, China.
  • 4 Institute of Integrated Chinese and Western Medicine, Southwest Medical University, Luzhou 646000, Sichuan, China.
PMID: 41348354 DOI: 10.1021/acsami.5c18202
Abstract

Nonsmall cell lung Cancer (NSCLC) exhibits high malignancy, low survival rates, and unfavorable prognosis. As a primary chemotherapy agent for NSCLC, gemcitabine (GEM) suppresses RNA/DNA synthesis to trigger Cancer cell Apoptosis. Nevertheless, GEM therapy is limited by systemic toxicity and suboptimal efficacy. Combining GEM with Other small-molecule kinase inhibitors frequently enhances therapeutic outcomes. Bromodomain-containing protein 4 (BRD4), a critical epigenetic regulator implicated in transcriptional control, shows strong associations with tumor progression. This study demonstrates that BRD4 degradation via the PROTAC molecule MZ1 potentiates NSCLC susceptibility to GEM. To enable codelivery, a GSH-responsive nano prodrug, BT-GEM/MZ1@NP, was strategically engineered. Compared to GEM or MZ1 monotherapy, BT-GEM/MZ1@NP demonstrated a more potent antitumor profile fostering a synergistic therapeutic through Ferroptosis induction. In vivo assessment substantiated significantly enhanced tumor regression with Ferroptosis promotion. These findings nominate BT-GEM/MZ1@NP as a promising clinical candidate for NSCLC therapy.

Keywords

BT-GEM/MZ1@NP; GEM; MZ1; NSCLC; cancer; cell; ferroptosis; therapeutic; tumor.

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