State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing 211198, China.
School of Flexible Electronics (Future Technologies) and Institute of Advanced Materials (IAM), Nanjing Tech University (Nanjing Tech), Nanjing 211816, China.
ACS Nano. 2024 Oct 1;18(39):26784-26798. doi: 10.1021/acsnano.4c07403. Epub 2024 Sep 20.
Accurate imaging and precise treatment are critical to controlling the progression of pancreatic cancer. However, current approaches for pancreatic cancer theranostics suffer from limitations in tumor specificity and invasive surgery. Herein, a pancreatic cancer-specific phototheranostic modulator (AuHQ) dominated by aggregation-induced emission (AIE) luminogens-tethered gold nanoparticles is meticulously designed to facilitate prominent fluorescence-photoacoustic bimodal imaging-guided photothermal immunotherapy. Once reaching the pancreatic tumor microenvironment (TME), the peptide Ala-Gly-Phe-Ser-Leu-Pro-Ala-Gly-Cys (AGFSLPAGC) linkage within AuHQ can be specifically cleaved by the overexpressed enzyme Cathepsin E (CTSE), triggering the dual self-assembly of AuNPs and AIE luminogens. The aggregation of AuNPs mediated by enzymatic cleavage results in potentiated photothermal therapy (PTT) under near-infrared (NIR) laser irradiation, induced immunogenic cell death (ICD), and enhanced photoacoustic imaging. Simultaneously, AIE luminogen aggregates formed by hydrophobic interaction can generate AIE fluorescence, enabling real-time and specific fluorescence imaging of pancreatic cancer. Furthermore, coadministration of an indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor with AuHQ can address the limitations of PTT efficacy imposed by the immunosuppressive TME and leverage the synergistic potential to activate systemic antitumor immunity. Thus, this well-designed phototheranostic modulator AuHQ facilitates the intelligent enzymatic dual self-assembly of imaging and therapeutic agents, providing an efficient and precise approach for pancreatic cancer theranostics.
准确的成像和精确的治疗对于控制胰腺癌的进展至关重要。然而，目前用于胰腺癌治疗诊断的方法在肿瘤特异性和侵入性手术方面存在局限性。在此，我们精心设计了一种由聚集诱导发射（AIE）发光体连接的金纳米粒子主导的胰腺癌特异性光热治疗调节剂（AuHQ），以促进显著的荧光-光声双模式成像引导光热免疫治疗。一旦到达胰腺肿瘤微环境（TME），AuHQ 中的肽 Ala-Gly-Phe-Ser-Leu-Pro-Ala-Gly-Cys（AGFSLPAGC）连接可以被过表达的酶组织蛋白酶 E（CTSE）特异性切割，触发 AuNPs 和 AIE 发光体的双重自组装。酶切介导的 AuNPs 聚集导致在近红外（NIR）激光照射下增强光热治疗（PTT）、诱导免疫原性细胞死亡（ICD）和增强光声成像。同时，由疏水相互作用形成的 AIE 发光体聚集物可以产生 AIE 荧光，实现胰腺癌的实时特异性荧光成像。此外，AuHQ 与吲哚胺 2,3-双加氧酶 1（IDO1）抑制剂的联合给药可以解决由免疫抑制 TME 对 PTT 疗效的限制，并利用协同潜力激活系统性抗肿瘤免疫。因此，这种精心设计的光热治疗调节剂 AuHQ 促进了成像和治疗剂的智能酶促双重自组装，为胰腺癌治疗诊断提供了一种高效、精确的方法。
