Zhou Xinyu, Zhang Yiyi, Xiong Jianjun, Dai Yibin, Zhu Fangxing, Sun Hongtao, Zhu Dongwang, Huang Yingying, Tan Yiran, Zhou Xinxia, Zhao Tongchao, Zhong Laiping, Pang Yichuan, Zhou Zhihang
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.
Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, National Clinical Research Center of Stomatology, Shanghai, 200011, China.
Mater Today Bio. 2025 Jun 13;33:101964. doi: 10.1016/j.mtbio.2025.101964. eCollection 2025 Aug.
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.
在过去的一个世纪里，浅表恶性肿瘤的治疗主要局限于全身治疗。全身给药的主要缺点在于其对浅表肿瘤的杀伤作用有限，同时却可能对其他器官造成严重损害。目前，用于浅表肿瘤的经皮给药仍然很少，主要受限于肿瘤/癌前组织的低渗透性和特异性。在本研究中，我们利用阳离子化诱导的内吞作用和转胞吞作用开发了一种类似ADC的纳米药物。合成了一种负载MMAE的γ-谷氨酰转肽酶（GGT）催化的聚合物-药物偶联物，用于治疗GGT表达升高的多种癌症。本研究首次开发了一种通过经皮给药治疗浅表恶性肿瘤的偶联物，并将其命名为gaOCD（GGT酶激活口服包衣化疗药物）。鉴于其浅表性质和高GGT表达水平，口腔鳞状细胞癌（OSCC）被用作评估gaOCD疗效的代表。电中性的gaOCD可被OSCC细胞膜上高表达的GGT裂解。此外，一些阳离子化的gaOCD被邻近癌细胞胞吐并内化，从而实现深度渗透。当将该偶联物经皮应用于4NQO诱导的OSCC并在OSCC移植小鼠模型中静脉给药时，显示出有前景的抗肿瘤疗效和生物安全性。
