MOE Key Laboratory of High Performance Polymer Materials and Technology and Department of Polymer Science & Engineering, College of Chemistry & Chemical Engineering, Nanjing University, Nanjing, 210023, P. R. China.
Department of Radiation Oncology, School of Medicine, Stanford University, Stanford, CA, 94305, USA.
Adv Mater. 2023 Jun;35(24):e2210920. doi: 10.1002/adma.202210920. Epub 2023 Apr 27.
Tumor vascular disrupting therapy has offered promising opportunities to treat cancer in clinical practice, whereas the overall therapeutic efficacy is notably limited due to the off-target effects and repeated dose toxicity of vascular disrupting agents (VDAs). To tackle this problem, a VDA-free biomimetic semiconducting polymer nanoparticle (SPN ) is herein reported for precise tumor vascular disruption through two-stage light manipulation. SPN consists of a semiconducting polymer nanoparticle as the photothermal agent camouflaged with platelet membranes that specifically target disrupted vasculature. Upon the first photoirradiation, SPN administered in vivo generates mild hyperthermia to trigger tumor vascular hemorrhage, which activates the coagulation cascade and recruits more SPN to injured blood vessels. Such enhanced tumor vascular targeting of photothermal agents enables intense hyperthermia to destroy the tumor vasculature during the second photoirradiation, leading to complete tumor eradication and efficient metastasis inhibition. Intriguingly, the mechanism study reveals that this vascular disruption strategy alleviates splenomegaly and reverses the immunosuppressive tumor microenvironment by reducing myeloid-derived suppressor cells. Therefore, this study not only illustrates a light-driven self-recruitment strategy to enhance tumor vascular disruption via a single dose of biomimetic therapeutics but also deciphers the immunotherapeutic role of vascular disruption therapy that is conducive to clinical studies.
肿瘤血管破坏疗法为癌症的临床治疗提供了很有前景的机会，然而由于血管破坏剂（VDA）的脱靶效应和重复剂量毒性，其整体治疗效果显著受限。为了解决这个问题，本文报道了一种无 VDA 的仿生半导体聚合物纳米粒子（SPN），通过两阶段光操纵实现精确的肿瘤血管破坏。SPN 由作为光热剂的半导体聚合物纳米粒子和专门针对破坏血管的血小板膜组成。首次光辐照后，体内给予的 SPN 会产生温和的热疗以引发肿瘤血管出血，从而激活凝血级联反应并募集更多的 SPN 到受损的血管。这种增强的光热剂对肿瘤血管的靶向作用使第二次光辐照时能够产生强烈的热疗来破坏肿瘤血管，从而实现完全的肿瘤根除和有效的转移抑制。有趣的是，机制研究表明，这种血管破坏策略通过单次给予仿生治疗剂来减轻脾肿大并逆转免疫抑制性肿瘤微环境，从而减少髓源抑制细胞。因此，本研究不仅说明了一种通过单次给予仿生治疗剂来增强肿瘤血管破坏的光驱动自招募策略，还揭示了血管破坏疗法的免疫治疗作用，这有利于临床研究。
