State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, College of Biological Science and Medical Engineering, Donghua University, Shanghai, 201620, China.
School of Chemistry, Chemical Engineering and Biotechnology, Lee Kong Chian School of Medicine, Nanyang Technological University, 70 Nanyang Drive, Singapore, 637457, Singapore.
Angew Chem Int Ed Engl. 2023 Jul 24;62(30):e202305200. doi: 10.1002/anie.202305200. Epub 2023 Jun 6.
Immunotherapy has provided a promising modality for cancer treatment, while it often has the issues of limited response rates and potential off-target side effects in clinical practice. We herein report the construction of semiconducting polymer pro-nanomodulators (SPpMs) with ultrasound (US)-mediated activatable pharmacological actions for deep-tissue sono-immunotherapy of orthotopic pancreatic cancer. Such SPpMs consist of a sonodynamic semiconducting polymer backbone grafted with poly(ethylene glycol) chains linked with two immunomodulators (a programmed death-ligand 1 blocker and an indoleamine 2,3-dioxygenase inhibitor) via a singlet oxygen ( O )-cleavable segment. In view of the excellent sonodynamic property of the semiconducting polymer core, SPpMs enable effective generation of O under US treatment, even in a deep-tissue depth up to 12 cm. The generated O not only ablates tumors via a sonodynamic effect and induces immunogenic cell death, but also destroys the O -cleavable segments to allow in situ release of immunomodulators in tumors. This synergetic action results in boosted antitumor immune response via reversing two tumor immunosuppressive pathways. As such, SPpMs mediate deep-tissue sono-immunotherapy to completely eradicate orthotopic pancreatic cancer and effectively prevent tumor metastasis. Moreover, such an immune activation reduces the possibility of immune-related adverse events. This study thus provides a smart activatable nanoplatform for precise immunotherapy of deep-seated tumors.
免疫疗法为癌症治疗提供了一种有前景的方式，但在临床实践中，它常常存在应答率有限和潜在的脱靶副作用等问题。我们在此报告了具有超声（US）介导的激活型药理作用的半导体聚合物前纳米调节剂（SPpM）的构建，用于原位胰腺癌的深组织声免疫治疗。这种 SPpM 由接枝有聚乙二醇链的声动力学半导体聚合物主链组成，通过单线态氧（ O ）可裂解片段与两种免疫调节剂（程序性死亡配体 1 阻断剂和吲哚胺 2,3-双加氧酶抑制剂）相连。鉴于半导体聚合物核的优异声动力学特性，SPpM 能够在 US 治疗下有效产生 O ，即使在深达 12cm 的深部组织中也是如此。产生的 O 不仅通过声动力学效应消融肿瘤并诱导免疫原性细胞死亡，还破坏 O 可裂解片段，使免疫调节剂在肿瘤中原位释放。这种协同作用通过逆转两种肿瘤免疫抑制途径来增强抗肿瘤免疫反应。因此，SPpM 介导深组织声免疫治疗以完全根除原位胰腺癌，并有效防止肿瘤转移。此外，这种免疫激活降低了免疫相关不良事件的可能性。因此，本研究为深部肿瘤的精确免疫治疗提供了一种智能可激活的纳米平台。
