2. Academic Validation
  3. Genetically Engineered Membrane-Coated Nanoparticles for Enhanced Prostate-Specific Membrane Antigen Targeting and Ferroptosis Treatment of Castration-Resistant Prostate Cancer

Genetically Engineered Membrane-Coated Nanoparticles for Enhanced Prostate-Specific Membrane Antigen Targeting and Ferroptosis Treatment of Castration-Resistant Prostate Cancer

  • Adv Sci (Weinh). 2024 Jul 1:e2401095. doi: 10.1002/advs.202401095.
Yu Li 1 2,  Hongji Li 1,  Keying Zhang 1,  Chao Xu 1,  Jingwei Wang 3,  Zeyu Li 1,  Yike Zhou 1,  Shaojie Liu 1,  Xiaolong Zhao 1,  Zhengxuan Li 1,  Fa Yang 1,  Wei Hu 1,  Yuming Jing 1,  Peng Wu 1,  Jingliang Zhang 1,  Changhong Shi 4,  Rui Zhang 5,  Wenkai Jiang 2,  Nianzeng Xing 6,  Weihong Wen 7,  Donghui Han 1 8,  Weijun Qin 1
Affiliations

Affiliations

  • 1 Department of Urology, Xijing Hospital, Air Force Medical University, No.127 Western Changle Road, Xi'an, Shaanxi, 710032, China.
  • 2 State Key Laboratory of Oral, Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Key Laboratory of Stomatology, Department of Operative Dentistry and Endodontics, School of Stomatology, Air Force Medical University, No.145 Western Changle Road, Xi'an, Shaanxi, 710032, China.
  • 3 Department of Medicine Chemistry and Pharmaceutical Analysis, School of Pharmacy, Air Force Medical University, No.169 Western Changle Road, Xi'an, Shaanxi, 710032, China.
  • 4 Division of Cancer Biology, Laboratory Animal Center, Air Force Medical University, No.169 Western Changle Road, Xi'an, Shaanxi, 710032, China.
  • 5 The State Key Laboratory of Cancer Biology, Department of Immunology, Air Force Medical University, No.169 Western Changle Road, Xi'an, Shaanxi, 710032, China.
  • 6 State Key Laboratory of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Department of Urology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
  • 7 Institute of Medical Research, Northwestern Polytechnical University, Xi'an, Shaanxi, 710072, China.
  • 8 National Translational Science Center for Molecular Medicine, Department of Cell Biology, Air Force Medical University, No.169 Western Changle Road, Xi'an, Shaanxi, 710032, China.
PMID: 38946578 DOI: 10.1002/advs.202401095
Abstract

Conventional androgen deprivation therapy (ADT) targets the Androgen Receptor (AR) inhibiting prostate Cancer (PCa) progression; however, it can eventually lead to recurrence as castration-resistant PCa (CRPC), which has high mortality rates and lacks effective treatment modalities. The study confirms the presence of high Glutathione Peroxidase 4 (GPX4) expression, a key regulator of Ferroptosis (i.e., iron-dependent program cell death) in CRPC cells. Therefore, inducing Ferroptosis in CRPC cells might be an effective therapeutic modality for CRPC. However, nonspecific uptake of Ferroptosis inducers can result in undesirable cytotoxicity in major organs. Thus, to precisely induce Ferroptosis in CRPC cells, a genetic engineering strategy is proposed to embed a prostate-specific membrane antigen (PSMA)-targeting antibody fragment (gy1) in the macrophage membrane, which is then coated onto mesoporous polydopamine (MPDA) nanoparticles to produce a biomimetic nanoplatform. The results indicate that the membrane-coated nanoparticles (MNPs) exhibit high specificity and affinity toward CRPC cells. On further encapsulation with the Ferroptosis inducers RSL3 and iron ions, MPDA/Fe/RSL3@M-gy1 demonstrates superior synergistic effects in highly targeted Ferroptosis therapy eliciting significant therapeutic efficacy against CRPC tumor growth and bone metastasis without increased cytotoxicity. In conclusion, a new therapeutic strategy is reported for the PSMA-specific, CRPC-targeting platform for Ferroptosis induction with increased efficacy and safety.

Keywords

PSMA; castration‐resistant prostate cancer; ferroptosis; macrophage membrane‐coated nanoparticles; tumor targeting therapy.

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