State Key Laboratory of Silkworm Genome Biology, College of Sericulture, Textile, and Biomass Sciences, Southwest University, Chongqing, 400715, China.
Department of Biomedical Engineering, University Medical Center Groningen, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, Netherlands; W.J. Kolff Institute for Biomedical Engineering and Materials Science, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, Netherlands.
Biomaterials. 2023 Nov;302:122332. doi: 10.1016/j.biomaterials.2023.122332. Epub 2023 Sep 15.
The treatment efficacies of conventional medications against colorectal cancer (CRC) are restricted by a low penetrative, hypoxic, and immunosuppressive tumor microenvironment. To address these restrictions, we developed an innovative antitumor platform that employs calcium overload-phototherapy using mitochondrial N770-conjugated mesoporous silica nanoparticles loaded with CaO (CaO-N770@MSNs). A loading level of 14.0 wt% for CaO-N770@MSNs was measured, constituting an adequate therapeutic dosage. With the combination of oxygen generated from CaO and hyperthermia under near-infrared irradiation, CaO-N770@MSNs penetrated through the dense mucus, accumulated in the colorectal tumor tissues, and inhibited tumor cell growth through endoplasmic reticulum stress and mitochondrial damage. The combination of calcium overload and phototherapy revealed high therapeutic efficacy against orthotopic colorectal tumors, alleviated the immunosuppressive microenvironment, elevated the abundance of beneficial microorganisms (e.g., Lactobacillaceae and Lachnospiraceae), and decreased harmful microorganisms (e.g., Bacteroidaceae and Muribaculaceae). Moreover, together with immune checkpoint blocker (αPD-L1), these nanoparticles showed an ability to eradicate both orthotopic and distant tumors, while potentiating systemic antitumor immunity. This treatment platform (CaO-N770@MSNs plus αPD-L1) open a new horizon of synergistic treatment against hypoxic CRC with high killing power and safety.
常规药物治疗结直肠癌（CRC）的疗效受到低渗透性、缺氧和免疫抑制肿瘤微环境的限制。为了解决这些限制，我们开发了一种创新的抗肿瘤平台，该平台使用线粒体 N770 共轭介孔硅纳米粒子负载 CaO（CaO-N770@MSNs）进行钙超载-光疗。测量了 CaO-N770@MSNs 的装载水平为 14.0wt%，构成了足够的治疗剂量。CaO-N770@MSNs 与 CaO 产生的氧气和近红外辐射下的热疗相结合，穿透致密的粘液，在结直肠肿瘤组织中积累，并通过内质网应激和线粒体损伤抑制肿瘤细胞生长。钙超载和光疗的联合使用对原位结直肠肿瘤具有很高的治疗效果，减轻了免疫抑制微环境，增加了有益微生物（如乳杆菌科和lachnospiraceae）的丰度，并减少了有害微生物（如拟杆菌科和muribaculaceae）。此外，这些纳米颗粒与免疫检查点抑制剂（αPD-L1）联合使用，具有根除原位和远处肿瘤的能力，同时增强了全身抗肿瘤免疫。这种治疗平台（CaO-N770@MSNs 加αPD-L1）为具有高杀伤力和安全性的缺氧 CRC 的协同治疗开辟了新的前景。
