Lin Lizhou, Du Yichao, Hao Jialing, Wu Rong, Du Lianfang
Department of Ultrasound, Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200080, China.
Department of Neurosurgery, Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200080, China.
Biomed Pharmacother. 2023 Apr;160:114322. doi: 10.1016/j.biopha.2023.114322. Epub 2023 Feb 3.
Pancreatic cancer (PaCa) is a hypovascular type of tumor and is not very responsive to conventional chemotherapy due to the problem of low drug accumulation. Recent advancements in ultrasound targeted microbubble destruction (UTMD) have improved drug delivery into target tissues. UTMD operates via microbubble interaction with vascular endothelial cells; however, the molecular mechanism and interrelationship in the PaCa microenvironment remain enigmatic. Tumor-associated macrophages (TAMs) have different phenotypes and regulate tumorigenesis. Using a PaCa orthotopic model, we established that UTMD improved chemotherapy by redirecting TAM polarization from M2 macrophages to tumor-inhibiting M1 macrophages, remodeling vessel normalization, and inducing anti-tumor immune responses. Tumor vascular maturity and function were also improved, and an insignificant change in vascular density resulting in enhanced blood perfusion and inhibited tumor growth and metastasis were observed. Therefore, this research unveils the crucial role of TAM polarization on UTMD-induced tumor vessel normalization and inhibition of tumor progression. These findings offer a novel insight into UTMD-mediated drug delivery for anti-tumor and anti-angiogenic treatment.
胰腺癌（PaCa）是一种低血供型肿瘤，由于药物蓄积量低的问题，对传统化疗反应不佳。超声靶向微泡破坏（UTMD）技术的最新进展改善了药物向靶组织的递送。UTMD通过微泡与血管内皮细胞相互作用发挥作用；然而，胰腺癌微环境中的分子机制和相互关系仍不清楚。肿瘤相关巨噬细胞（TAM）具有不同的表型并调节肿瘤发生。利用胰腺癌原位模型，我们证实UTMD通过将TAM极化从M2巨噬细胞重定向为具有肿瘤抑制作用的M1巨噬细胞、重塑血管正常化以及诱导抗肿瘤免疫反应来改善化疗效果。肿瘤血管的成熟度和功能也得到改善，观察到血管密度无显著变化，但血液灌注增强，肿瘤生长和转移受到抑制。因此，本研究揭示了TAM极化在UTMD诱导的肿瘤血管正常化和抑制肿瘤进展中的关键作用。这些发现为UTMD介导的抗肿瘤和抗血管生成治疗药物递送提供了新的见解。
