Cancer Metastasis Alert and Prevention Center, College of Chemistry, and Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, Fuzhou University, Fuzhou 350108, China.
College of Chemistry, Key Laboratory of Molecule Synthesis and Function Discovery (Fujian Province University), Fuzhou University, Fuzhou, Fujian 350116, China.
J Colloid Interface Sci. 2025 Jan 15;678(Pt C):897-912. doi: 10.1016/j.jcis.2024.09.133. Epub 2024 Sep 19.
Modulating the immunosuppressive tumor immune microenvironment (TIME) is considered a promising strategy for cancer treatment. However, effectively modulating the immunosuppressive TIME within hypoxic zones remains a significant challenge. In this work, we developed a hypoxia-responsive amphiphilic drug carrier using boron-dipyrromethene (BODIPY) dye-modified chitosan (CsB), and then fabricated a hypoxia-targeted nanotheranostic system, named CsBPNs, through self-assembly of CsB and pexidartinib (5-((5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)-N-((6-(trifluoromethyl)pyridin-3-yl)methyl), PLX3397), an immunotherapeutic drug targeting tumor-associated macrophages (TAMs), for synergistic photothermal/immunotherapy and hypoxia imaging. CsBPNs demonstrated uniform size, good stability, and hypoxia-switchable fluorescence and photothermal effects, enabling deep penetration and hypoxia imaging capacities in three-dimensional tumor cell spheres and tumor tissues. In vitro and in vivo experiments showed that CsBPNs under laser irradiation promoted TAMs repolarization, reversed the immunosuppressive TIME, and enhanced the therapeutic outcome of PLX3397 in solid tumors by facilitating deep delivery into hypoxic regions and synergistic photothermal therapy. This work provides a new strategy for detecting and modulating the immunosuppressive TIME in hypoxic zones, potentially enabling more precise and effective photo-immunotherapy in the future.
调控免疫抑制性肿瘤免疫微环境（TIME）被认为是癌症治疗的一种有前途的策略。然而，有效地调节缺氧区域内的免疫抑制性 TIME 仍然是一个重大挑战。在这项工作中，我们使用硼二吡咯亚甲基（BODIPY）染料修饰壳聚糖（CsB）开发了一种缺氧响应性两亲药物载体，然后通过 CsB 和培昔替尼（5-（（5-氯-1H-吡咯并[2,3-b]吡啶-3-基）甲基）-N-（（6-（三氟甲基）吡啶-3-基）甲基），PLX3397）的自组装制备了一种缺氧靶向纳米治疗系统，命名为 CsBPNs，培昔替尼是一种针对肿瘤相关巨噬细胞（TAMs）的免疫治疗药物，用于协同光热/免疫治疗和缺氧成像。CsBPNs 表现出均匀的尺寸、良好的稳定性以及缺氧开关荧光和光热效应，使其能够在三维肿瘤细胞球体和肿瘤组织中进行深层渗透和缺氧成像。体外和体内实验表明，激光照射下的 CsBPNs 促进 TAMs 重极化，通过促进向缺氧区域的深层递送和协同光热治疗，逆转了免疫抑制性 TIME，并增强了 PLX3397 在实体瘤中的治疗效果。这项工作为检测和调节缺氧区域内的免疫抑制性 TIME 提供了一种新策略，有望在未来实现更精确和有效的光免疫治疗。
