In situ formed reactive oxygen species-responsive scaffold with gemcitabine and checkpoint inhibitor for combination therapy

Chao Wang; Jinqiang Wang; Xudong Zhang; Shuangjiang Yu; Di Wen; Quanyin Hu; Yanqi Ye; Hunter Bomba; Xiuli Hu; Zhuang Liu; Gianpietro Dotti; Zhen Gu

doi:10.1126/scitranslmed.aan3682

In situ formed reactive oxygen species-responsive scaffold with gemcitabine and checkpoint inhibitor for combination therapy

Sci Transl Med. 2018 Feb 21;10(429):eaan3682. doi: 10.1126/scitranslmed.aan3682.

Authors

Chao Wang^{1

2}, Jinqiang Wang^{1

2}, Xudong Zhang^{1

2}, Shuangjiang Yu^{1

2}, Di Wen^{1

2}, Quanyin Hu^{1

2}, Yanqi Ye^{1

2}, Hunter Bomba^{1

2}, Xiuli Hu¹, Zhuang Liu³, Gianpietro Dotti⁴, Zhen Gu^{5

2

6}

Affiliations

¹ Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Raleigh, NC 27695, USA.
² 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.
³ Institute of Functional Nano and Soft Materials, Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou 215123, China.
⁴ Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁵ Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Raleigh, NC 27695, USA. zgu@email.unc.edu.
⁶ Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

PMID: 29467299
DOI: 10.1126/scitranslmed.aan3682

Abstract

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Cell Line, Tumor
Combined Modality Therapy
Deoxycytidine / analogs & derivatives*
Deoxycytidine / therapeutic use
Female
Gemcitabine
Hydrogel, Polyethylene Glycol Dimethacrylate / chemistry
Immunotherapy / methods
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Programmed Cell Death 1 Receptor / metabolism

Substances

Programmed Cell Death 1 Receptor
Deoxycytidine
Hydrogel, Polyethylene Glycol Dimethacrylate
Gemcitabine