Enhancing chemoimmunotherapy for colorectal cancer with paclitaxel and alantolactone via CD44-Targeted nanoparticles: A STAT3 signaling pathway modulation approach
Fu‐Gen Wu, Xingsi An, Shize Li, Chenyu Qiu, Yixuan Zhu, Zhanzheng Ye, Shengnan Song, Yunzhi Wang, Dingchao Shen, Xinyu Di, Yinsha Yao, Wanling Zhu, Xinyu Jiang, Xianbao Shi, Ruijie Chen, Longfa Kou
Abstract
Chemoimmunotherapy has the potential to enhance chemotherapy and modulate the immunosuppressive tumor microenvironment by activating immunogenic cell death (ICD), making it a promising strategy for clinical application. Alantolactone (A) was found to augment the anticancer efficacy of paclitaxel (P) at a molar ratio of 1:0.5 (P:A) through induction of more potent ICD via modulation of STAT3 signaling pathways. Nano drug delivery systems can synergistically combine natural drugs with conventional chemotherapeutic agents, thereby enhancing multi-drug chemoimmunotherapy. To improve tumor targeting ability and bioavailability of hydrophobic drugs, an amphiphilic prodrug conjugate (HA-PTX) was chemically modified with paclitaxel (PTX) and hyaluronic acid (HA) as a backbone. Based on this concept, CD44-targeted nanodrugs (A@HAP NPs) were developed for co-delivery of A and P in colorectal cancer treatment, aiming to achieve synergistic toxicity-based chemo-immunotherapy. The uniform size and high drug loading capacity of A@HAP NPs facilitated their accumulation within tumors through enhanced permeability and retention effect as well as HA-mediated targeting, providing a solid foundation for subsequent synergistic therapy and immunoregulation. In vitro and in vivo studies demonstrated that A@HAP NPs exhibited potent cytotoxicity against tumor cells while also remodeling the immune-suppressive tumor microenvironment by promoting antigen presentation and inducing dendritic cell maturation, thus offering a novel approach for colorectal cancer chemoimmunotherapy.