Regulating Glucose Metabolism with Prodrug Nanoparticles for Promoting Photoimmunotherapy of Pancreatic Cancer

Abstract

The low immunogenicity, insufficient infiltration of T lymphocytes, and dismal response to immune checkpoint blockade therapy pose major difficulties in immunotherapy of pancreatic cancer. Photoimmunotherapy by photodynamic therapy (PDT) can induce an antitumor immune response by triggering immunogenic cell death in the tumor cells. Notwithstanding, PDT‐driven oxygen consumption and microvascular damage can further aggravate hypoxia to exaggerates glycolysis, leading to lactate accumulation and immunosuppressive tumor microenvironment. Herein, a supramolecular prodrug nanoplatform codelivering a photosensitizer and a prodrug of bromodomain‐containing protein 4 inhibitor (BRD4i) JQ1 for combinatory photoimmunotherapy of pancreatic cancer are demonstrated. The nanoparticles are fabricated by host–guest complexation between cyclodextrin‐grafted hyaluronic acid (HA‐CD) and adamantine‐conjugated heterodimers of pyropheophorbide a (PPa) and JQ1, respectively. HA can achieve active tumor targeting by recognizing highly expressed CD44 on the surface of pancreatic tumors. PPa‐mediated PDT can enhance the immunogenicity of the tumor cells and promote intratumoral infiltration of the cytotoxic T lymphocytes. Meanwhile, JQ1 combats PDT‐mediated immune evasion through inhibiting expression of c‐Myc and PD‐L1, which are key regulators of tumor glycolysis and immune evasion. Collectively, this study presents a novel strategy to enhance photoimmunotherapy of the pancreatic cancer by provoking T cells activation and overcoming adaptive immune resistance.

Biomarkers in Pancreatic Cancer as Analytic Targets for Nanomediated Imaging and Therapy

“…Research combined imaging with therapy methods [ 96 , 103 ], further demonstrating the multitude of benefits in using nanotechnology in PC treatment. The use of photodynamic therapy also holds promise for better outcomes in PC [ 104 ], but obstacles regarding its side effects and potential toxicity are still an impediment for clinical use [ 71 ]. Other potential benefits for improving imaging methods in PC is rapid detection as already mentioned, as it takes years for PanIN lesions to develop into PC, and unfortunately there also no approved biomarkers for early detection.…”

“…A: nanoparticle internalization leading to endosome development; B: High osmotic pressure and swelling of the endosome; C: release of the conjugated nanoparticles. Reprinted with permission from [ 104 ].…”

Nanomaterials-Based Photodynamic Therapy with Combined Treatment Improves Antitumor Efficacy Through Boosting Immunogenic Cell Death

“… [ 94 ] Pyropheoph-orbide Cyclodextrin‐grafted hyaluronic acid (HA-CD) PD-L1 JQ1 671 nm Panc02-pancreatic tumor model This study consistently verified that it could elicit a potent antitumor immune response in pancreatic cancer while relieving immunosuppression. [ 96 ] IR775 Liposome PD-L1 Metformin 785 nm MB49 and CT26 tumor murine models The weights of collected tumors in the PBS group were 8-fold heavier than that in the NPs + Laser group, indicating this therapy possessed excellent antitumor efficacy for various types of cancers. [ 97 ] …”

“…Therefore, to solve this problem, Sun and colleagues developed supramolecular NPs co-delivering a PS and a prodrug named JQ1 for PDT combining immunotherapy of pancreatic cancer. 96 In addition, JQ1 acted as a bromodomain-containing protein 4 inhibitor (BRD4i), which inhibited glycolysis and prevented the transcription of c-Myc under tumor hypoxia microenvironment. More importantly, JQ1 could reverse PDT-triggered immune tolerance by significantly down-regulated tumor cells’ expression of PD-L1.…”

“…2021;8(4):2002746. doi:10.1002/advs.202002746. 96 ( C ) Schematic illustration of the preparation of IR775@Met@Lip and the mechanism of enhanced photodynamic immunotherapy mediated by reversing hypoxia and decreasing PD-L1 expression in vivo. Reprinted with permission from Xiong W, Qi L, Jiang N, et al Metformin Liposome-Mediated PD-L1 Downregulation for Amplifying the Photodynamic Immunotherapy Efficacy.…”