原位形成的活性氧响应支架，联合吉西他滨和检查点抑制剂的用于联合治疗。
In situ formed reactive oxygen species-responsive scaffold with gemcitabine and checkpoint inhibitor for combination therapy.
机构信息
Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Raleigh, NC 27695, USA.
Division of Pharmacoengineering and Molecular Pharmaceutics and Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
出版信息
Sci Transl Med. 2018 Feb 21;10(429). doi: 10.1126/scitranslmed.aan3682.
Patients with low-immunogenic tumors respond poorly to immune checkpoint blockade (ICB) targeting the programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway. Conversely, patients responding to ICB can experience various side effects. We have thus engineered a therapeutic scaffold that, when formed in situ, allows the local release of gemcitabine (GEM) and an anti-PD-L1 blocking antibody (aPDL1) with distinct release kinetics. The scaffold consists of reactive oxygen species (ROS)-degradable hydrogel that releases therapeutics in a programmed manner within the tumor microenvironment (TME), which contains abundant ROS. We found that the aPDL1-GEM scaffold elicits an immunogenic tumor phenotype and promotes an immune-mediated tumor regression in the tumor-bearing mice, with prevention of tumor recurrence after primary resection.
低免疫原性肿瘤患者对针对程序性死亡-1（PD-1）/程序性死亡配体 1（PD-L1）通路的免疫检查点阻断（ICB）反应不佳。相反，对 ICB 有反应的患者可能会出现各种副作用。因此，我们设计了一种治疗性支架，当在原位形成时，允许局部释放具有不同释放动力学的吉西他滨（GEM）和抗 PD-L1 阻断抗体（aPDL1）。该支架由活性氧（ROS）可降解水凝胶组成，可在富含 ROS 的肿瘤微环境（TME）中以程序化的方式释放治疗药物。我们发现，aPDL1-GEM 支架引发免疫原性肿瘤表型，并促进荷瘤小鼠的免疫介导的肿瘤消退，在原发性切除后预防肿瘤复发。
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