An iron-containing nanomedicine for inducing deep tumor penetration and synergistic ferroptosis in enhanced pancreatic cancer therapy
Aiping Huang, Qingnian Li, Xinyi Shi, Junyi Gao, Yiran Ma, Jinsong Ding, Surong Hua, Wenhu Zhou
Abstract
Pancreatic cancer is an aggressive and challenging malignancy with limited treatment options, largely attributed to the dense tumor stroma and intrinsic drug resistance. Here, we introduce a novel iron-containing nanoparticle formulation termed PTFE, loaded with the ferroptosis inducer Erastin, to overcome these obstacles and enhance pancreatic cancer therapy. The PTFE nanoparticles were prepared through a one-step assembly process, consisting of an Erastin-loaded PLGA core stabilized by a MOF shell formed by coordination between Fe 3+ and tannic acid. PTFE demonstrated a unique capability to repolarize tumor-associated macrophages (TAMs) into the M1 phenotype, leading to the regulation of dense tumor stroma by modulating the activation of tumor-associated fibroblasts (TAFs) and reducing collagen deposition. This resulted in enhanced nanoparticle accumulation and deep penetration, as confirmed by in vitro multicellular tumor spheroids and in vivo mesenchymal-rich subcutaneous pancreatic tumor models. Moreover, PTFE effectively combated tumor resistance by synergistically employing the Fe 3+ -induced Fenton reaction and Erastin-induced ferroptosis, thereby disrupting the redox balance. As a result, significant tumor growth inhibition was achieved in mice-bearing tumor model. Comprehensive safety evaluations demonstrated PTFE's favorable biocompatibility, highlighting its potential as a promising therapeutic platform to effectively address the formidable challenges in pancreatic cancer treatment. This study presents a deep tumour penetration and synergistic iron metabolic response drug delivery system. Through the synergistic effect of iron ions and Erastin, PTFE regulated TAFs and tumor dense stroma by inducing M2-to-M1 polarization of macrophages, thereby improving nanoparticle permeability and overcoming drug delivery barriers. Meanwhile, the formulation disrupts the redox balance at the tumor site, inducing ferroptosis in cancer cells, and presents a promising therapeutic strategy for pancreatic cancer.