Chen Qinjun, Wang Qingbing, Wang Yu, Chu Yongchao, Luo Yifan, You Haoyu, Su Boyu, Li Chao, Guo Qin, Sun Tao, Jiang Chen
Key Laboratory of Smart Drug Delivery (Ministry of Education), Minhang Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Department of Pharmaceutics, School of Pharmacy, Research Center on Aging and Medicine, Fudan University, Shanghai, 201203, P. R. China.
Department of Interventional Radiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, P. R. China.
Small. 2022 May;18(18):e2107712. doi: 10.1002/smll.202107712. Epub 2022 Mar 13.
Pancreatic ductal adenocarcinoma (PDAC) is on of the most lethal malignant tumors with relatively poor prognosis, characterized with insufficient drug penetration, low immune response and obvious drug resistances. The therapeutic inefficiency is multifactorially related to its specific tumor microenvironment (TME), which is representatively featured as rich stroma and immunosuppression. In this work, a versatile drug delivery system is developed that can coencapsulate two prodrugs modified from gemcitabine (GEM) and a signal transducer and activator of transcription 3 (STAT3) inhibitor (HJC0152), and the gradient pH variation is further sensed in the TME of PDAC to achieve a higher penetration by reversing its surficial charges. The escorted prodrugs can release GEM intracellularly, and respond to the hypoxic condition to yield the parental STAT3 inhibitor HJC0152, respectively. By inhibiting STAT3, the tumor immunosuppression microenvironment can be re-educated through the reversion of M2-like tumor associated macrophages (M2-TAMs), recruitment of cytotoxic T lymphocytes and downregulation of regulatory T cells (T s). Furthermore, cytidine deaminase (CDA) and α-smooth muscle actin (α-SMA) expression can be downregulated, plus the lipid modification of GEM, the drug resistance of GEM can be greatly relieved. Based on the above design, a synergetic therapeutic efficacy in PDAC treatment can be achieved to provide more opportunity for clinical applications.
胰腺导管腺癌（PDAC）是最致命的恶性肿瘤之一，预后相对较差，其特点是药物渗透不足、免疫反应低和明显的耐药性。治疗效率低下与它特定的肿瘤微环境（TME）多因素相关，TME的典型特征是富含基质和免疫抑制。在这项工作中，开发了一种多功能药物递送系统，该系统可以共包封两种由吉西他滨（GEM）修饰的前药和一种信号转导及转录激活因子3（STAT3）抑制剂（HJC0152），并且在PDAC的TME中进一步感知梯度pH变化，通过逆转其表面电荷来实现更高的渗透。被护送的前药可以在细胞内释放GEM，并分别响应缺氧条件产生亲本STAT3抑制剂HJC0152。通过抑制STAT3，可以通过逆转M2样肿瘤相关巨噬细胞（M2-TAMs）、募集细胞毒性T淋巴细胞和下调调节性T细胞（Ts）来重塑肿瘤免疫抑制微环境。此外，胞苷脱氨酶（CDA）和α平滑肌肌动蛋白（α-SMA）的表达可以下调，加上GEM的脂质修饰，可以大大缓解GEM的耐药性。基于上述设计，可以在PDAC治疗中实现协同治疗效果，为临床应用提供更多机会。
