2. Academic Validation
  3. γ-glutamyl transpeptidase-catalyzed polymer-enzyme-drug conjugate enhances penetration and suppression in oral squamous cell carcinoma via transdermal application

γ-glutamyl transpeptidase-catalyzed polymer-enzyme-drug conjugate enhances penetration and suppression in oral squamous cell carcinoma via transdermal application

  • Mater Today Bio. 2025 Jun 13:33:101964. doi: 10.1016/j.mtbio.2025.101964.
Xinyu Zhou 1 2,  Yiyi Zhang 2 3,  Jianjun Xiong 4,  Yibin Dai 4,  Fangxing Zhu 1 2,  Hongtao Sun 5,  Dongwang Zhu 4,  Yingying Huang 4,  Yiran Tan 4,  Xinxia Zhou 6,  Tongchao Zhao 4,  Laiping Zhong 4,  Yichuan Pang 7,  Zhihang Zhou 3
Affiliations

Affiliations

  • 1 Department of Oral and Maxillofacial-Head and Neck Oncology, Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China.
  • 2 Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, National Clinical Research Center of Stomatology, Shanghai, 200011, China.
  • 3 Department of Oral Pathology, Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China.
  • 4 Department of Stomatology Huashan Hospital, Fudan University, Shanghai, 200040, China.
  • 5 Shandong Cord Blood Hematopoietic Stem Cell Bank, Qilu Hospital, Jinan, 250001, China.
  • 6 Department of Clinical Immunology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China.
  • 7 Department of Nuclear Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China.
PMID: 40605992 DOI: 10.1016/j.mtbio.2025.101964
Abstract

Over the past century, the treatment of superficial malignant tumors has largely remained within systemic therapies. The major drawback of systemic administration lies in its limited killing effects specifically to superficial tumors while causing potentially severe damage to Other organs. Currently, transdermal drug administration for superficial tumors is still minimal, primarily constrained by the poor permeability and specificity in tumorous/precancerous tissue. In this study, we develop an ADC-like nano-medicine utilizing cationization-induced endocytosis and transcytosis. A γ-glutamyl transpeptidase (GGT)-catalyzed polymer-drug conjugate with MMAE payload is synthesized to treat a variety of cancers with elevated GGT expression. For the first time, this research develops a conjugate treating superficial malignant tumors by transdermal administration and names it gaOCD (GGT enzyme-activated oral coating chemotherapeutic drug). Given the superficial nature and the high GGT expression level, oral squamous cell carcinoma (OSCC) is used as a representative to evaluate the efficacy of gaOCD. The electroneutral gaOCD could be cleaved by the highly expressed GGT on OSCC cell membranes. Furthermore, some cationized gaOCD is exocytosed and internalized by neighboring Cancer cells to enable deep penetration. The conjugate demonstrates promising anti-tumor efficacy and biosafety when transdermally applied on 4NQO-induced OSCC and intravenously medicated in OSCC transplanted mouse models.

Keywords

Antibody-enzyme conjugates; GGT; Nano-medicine; Oral squamous cell carcinoma; Tumor penetration.

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