Tumour cells secrete various proangiogenic factors like VEGF, PDGF, and EGF that result in the formation of highly vascularized tumours with an immunosuppressive tumour microenvironment. As tumour growth and metastasis are highly dependent on angiogenesis, targeting tumour vasculature along with rapidly dividing tumour cells is a potential approach for cancer treatment. Here, we specifically engineered sub-100 sized nanomicelles (DTX-CA4 NMs) targeting proliferation and angiogenesis using an esterase-sensitive phosphocholine-tethered docetaxel conjugate of lithocholic acid (LCA) (PC-LCA-DTX) and a poly(ethylene glycol) (PEG) derivative of an LCA–combretastatin A4 conjugate (PEG-LCA-CA4). DTX-CA4 NMs effectively inhibit the tumour growth in syngeneic (CT26) and xenograft (HCT116) colorectal cancer models, inhibit tumour recurrence, and enhance the percentage survival in comparison with individual drug-loaded NMs. DTX-CA4 NMs enhance the T cell-mediated anti-tumour immune response and DTX-CA4 NMs in combination with an immune checkpoint inhibitor, anti-PDL1 antibody, enhance the anti-tumour response. We additionally showed that DTX-CA4 NMs effectively attenuate the production of ceramide-1-phosphate, a key metabolite of the sphingolipid pathway, by downregulating the expression of ceramide kinase at both transcriptional and translational levels. Therefore, this study presents the engineering of effective DTX-CA4 NMs for targeting the tumour microenvironment that can be explored further for clinical applications.

中文翻译：

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针对增殖和血管生成的工程纳米胶束通过损害神经酰胺-1-磷酸的合成来抑制肿瘤进展

肿瘤细胞分泌各种促血管生成因子，如 VEGF、PDGF 和 EGF，导致形成具有免疫抑制肿瘤微环境的高度血管化肿瘤。由于肿瘤生长和转移高度依赖于血管生成，因此靶向肿瘤血管系统以及快速分裂的肿瘤细胞是癌症治疗的潜在方法。在这里，我们使用石胆酸 (LCA) (PC-LCA-DTX) 和聚乙二醇的酯酶敏感磷酸胆碱束缚的多西紫杉醇缀合物专门设计了亚 100 尺寸的纳米胶束 (DTX-CA4 NM)，靶向增殖和血管生成LCA-combretastatin A4 缀合物的 (PEG) 衍生物 (PEG-LCA-CA4)。与单个载药NMs相比，DTX-CA4 NMs可有效抑制同基因（CT26）和异种移植（HCT116）结直肠癌模型中的肿瘤生长，抑制肿瘤复发，并提高生存率。 DTX-CA4 NM 增强 T 细胞介导的抗肿瘤免疫反应，DTX-CA4 NM 与免疫检查点抑制剂抗 PDL1 抗体联合使用，增强抗肿瘤反应。我们还发现，DTX-CA4 NM 通过在转录和翻译水平下调神经酰胺激酶的表达，有效减弱神经酰胺-1-磷酸（鞘脂途径的关键代谢物）的产生。因此，本研究提出了针对肿瘤微环境的有效 DTX-CA4 NM 的工程设计，可以进一步探索其临床应用。