Tumor Microenvironment Remodeling‐Mediated Sequential Drug Delivery Potentiates Treatment Efficacy
Yajun Xu, Jianlin Lv, Fuyao Liu, Jinqiang Wang, Ya Liu, Chaoying Kong, Yanran Li, Na Shen, Zhen Gu, Zhaohui Tang, Xuesi Chen
Abstract
Abstract Toll‐like receptor 7/8 agonists, such as imidazoquinolines (IMDQs), are promising for the de novo priming of antitumor immunity. However, their systemic administration is severely limited due to the off‐target toxicity. Here, this work describes a sequential drug delivery strategy. The formulation is composed of two sequential modules: a tumor microenvironment remodeling nanocarrier (poly( l ‐glutamic acid)‐ graft‐ methoxy poly(ethylene glycol)/combretastatin A4, termed CA4‐NPs) and an immunotherapy nanocarrier (apcitide peptide‐decorated poly( l ‐glutamic acid)‐ graft ‐IMDQ‐N 3 conjugate, termed apcitide‐PLG‐IMDQ‐N 3 ). CA4‐NPs, as a vascular disrupting agent, are utilized to remodel the tumor microenvironment for enhancing tumor coagulation and hypoxia. Subsequently, the apcitide‐PLG‐IMDQ‐N 3 could identify and target tumor coagulation through the binding of surface apcitide peptide to the GPIIb‐IIIa on activated platelets. Afterward, IMDQ is activated selectively through the conversion of “‐N 3 ” to “‐NH 2 ” in the presence of hypoxia. The biodistribution results confirm their high tumor uptake of activated IMDQ (22.66%ID/g). By augmenting the priming and immunologic memory of tumor‐specific CD8 + T cells, 4T1 and CT26 tumors with a size of ≈500 mm 3 are eradicated without recurrence in mouse models.