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Regulation of pancreatic cancer microenvironment by an intelligent gemcitabine@nanogel system via in vitro 3D model for promoting therapeutic efficienc

Journal of Controlled Release 324 (2020) 545–559


Bin Liu,a Hao Zhang,a Tengning Ma,a Lubing Bai,b Jinyi Lin,b and Dan Lu,a*

Di Chen a,b,1, Xiaofei Zhu b,1, Wanru Tao a,1, Yan Kong d, Yong Huag a, Yajun Zhang a, Ri Liu c, Lingong Jiang b, Ying Tang b, Haiyan Yu b, Qiang Hao c,⁎, Xiangqun Yang d, Hao Zou e, Jianming Chen e, Ying Lu e, Huojun Zhang b,⁎, Wei Li a,⁎

a Laboratory of Nano Biomedicine & International Joint Cancer Institute, Naval Medical University, Shanghai 200433, China 

b Department of Radiation Oncology, Changhai Hospital, Naval Medical University, Shanghai 200433, China 

c Department of Radiology, Shanghai Changhai Hospital, Naval Medical University, Shanghai 200433, China 

d Department of Anatomy, Institute of Biomedical Engineering, Naval Medical University, Shanghai 200433, China 

e Department of Pharmacy, Naval Medical University, Shanghai 200433, China




The passive targeting via nanomedicine to pancreatic tumor microenvironment (TME) is identified as an optimized therapeutic strategy for pancreatic ductal adenocarcinoma (PDAC) because lacking specific biomarkers and the intractable anatomical position. Herein, an in vitro 3D PDAC model was set up to evaluate the regulation of extracellular matrix (ECM) by an intelligent gemcitabine@nanogel system (GEM@NGH). This GEM@NGH system consisting of a reduction-sensitive core, the payloads of gemcitabine, and the coronal of hyaluronidase arrayed on the cationic surface was fabricated to improve intratumoral penetration and antitumor efficacy. The physicochemical properties, reduction sensitivity, cellular biocompatibility and cytotoxicity, intracellular distribution and therapeutic effects were all evaluated. Particularly, the GEM@NGH system showed excellent ECM eradication and in vitro/vivo solid tumor penetration ability as evaluated by home-built equipment and in vitro 3D PDAC model, which confirmed that GEM@NGH could be disintegrated in the tumoral reductive cytoplasm afterinternalizationandreleasegemcitabinetoexhibitpromotedcytotoxicity.Intheinvivotherapy,GEM@NGH displayed the highest tumor growth inhibition in PANC-1 tumor-bearing mice with the remarkably increased tumor penetration ability by TME regulation. The results obtained in this study indicate that specifically regulating TME by a well-designed intelligent gemcitabine@nanogel is promising way for the pancreatic cancer therapy.


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