Ding Mengchao, Zong Qingyu, Zhang Dan, Ullah Ihsan, Zhang Xingzu, Liang Wenhua, Li Xinchun, Bulatov Emil, Yuan Youyong
School of Biomedical Sciences and Engineering, Guangzhou International Campus, South China University of Technology, Guangzhou 511442, P. R. China.
National Engineering Research Center for Tissue Restoration and Reconstruction, South China University of Technology, Guangzhou 510006, P. R. China.
ACS Nano. 2025 Jan 14;19(1):662-679. doi: 10.1021/acsnano.4c11514. Epub 2024 Dec 28.
Chemotherapy is the primary treatment option for pancreatic cancer, although nanocarrier-based drug delivery systems often struggle with multiple physiological barriers, limiting their therapeutic efficacy. Here, we developed a pH/reactive oxygen species (ROS) dual-sensitive self-adaptive nanocarrier (DAT) encapsulating camptothecin (CPT), an analog of the pancreatic chemotherapeutic drug irinotecan (CPT-11), to enhance chemotherapy outcomes in orthotopic pancreatic cancer by addressing multiple physiological barriers. The nanocarrier features a peripherally positively charged arginine (Arg) residue on DAT and is masked with an acid-labile 2,3-dimethylmaleic anhydride (DA) to improve circulation time. In the acidic tumor microenvironment (TME), DA dissociates, exposing arginine to facilitate nanocarrier binding and internalization of DAT. Subsequently, peroxynitrite (ONOO) is generated by a cascade reaction between exposed Arg and ROS, which effectively activates matrix metalloproteinases (MMPs) to degrade the dense extracellular matrix (ECM) and enhance the deep accumulation and penetration of DAT. Meanwhile, ONOO inhibits tumor metastasis by influencing mitochondrial function, preventing adenosine triphosphate (ATP) production, and inhibiting ATP-dependent tumor-derived microvesicles (TMVs). This study presents a promising strategy to develop efficient nanocarriers to address multiple physiological barriers in antipancreatic cancer therapy.
化疗是胰腺癌的主要治疗选择，尽管基于纳米载体的药物递送系统常常难以跨越多种生理屏障，从而限制了它们的治疗效果。在此，我们开发了一种pH/活性氧（ROS）双敏感自适应纳米载体（DAT），其包裹着喜树碱（CPT），后者是胰腺癌化疗药物伊立替康（CPT-11）的类似物，旨在通过克服多种生理屏障来提高原位胰腺癌的化疗效果。该纳米载体在DAT上具有外围带正电荷的精氨酸（Arg）残基，并用酸不稳定的2,3-二甲基马来酸酐（DA）进行屏蔽，以延长循环时间。在酸性肿瘤微环境（TME）中，DA解离，使精氨酸暴露，从而促进纳米载体的结合以及DAT的内化。随后，暴露的Arg与ROS之间的级联反应生成过氧亚硝酸盐（ONOO），其可有效激活基质金属蛋白酶（MMPs），以降解致密的细胞外基质（ECM），并增强DAT的深度积累和渗透。同时，ONOO通过影响线粒体功能、阻止三磷酸腺苷（ATP）生成以及抑制ATP依赖性肿瘤衍生微泡（TMVs）来抑制肿瘤转移。本研究提出了一种有前景的策略，即开发高效纳米载体以克服抗胰腺癌治疗中的多种生理屏障。
