Specifically Regulating Tumor Microenvironment by a Gemcitabine@Nanogel System via in vitro 3D Model for Synergistic Pancreatic Cancer Therapy

38 Pages Posted: 16 May 2019

See all articles by Di Chen

Di Chen

Second Military Medical University, International Joint Cancer Institute; Second Military Medical University, Changhai Hospital, Department of Radiation Oncology

Xiaofei Zhu

Second Military Medical University, Changhai Hospital, Department of Radiation Oncology

Ri Liu

Second Military Medical University, Changhai Hospital, Department of Radiology

Yajun Zhang

Second Military Medical University, International Joint Cancer Institute

Wanru Tao

Second Military Medical University, International Joint Cancer Institute

Tingying Zhang

Second Military Medical University, International Joint Cancer Institute

Yong Huag

Second Military Medical University, International Joint Cancer Institute

Lingong Jiang

Second Military Medical University, Changhai Hospital, Department of Radiation Oncology

Ying Tang

Second Military Medical University, Changhai Hospital, Department of Radiation Oncology

Haiyan Yu

Second Military Medical University, Changhai Hospital, Department of Radiation Oncology

Qiang Hao

Second Military Medical University, Changhai Hospital, Department of Radiology

Huojun Zhang

Second Military Medical University, Changhai Hospital, Department of Radiation Oncology

Wei Li

Second Military Medical University, International Joint Cancer Institute

Date Written: May 14, 2019

Abstract

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 nanogel system. This system consisting of a reduction-sensitive core, the payloads of gemcitabine, and the coronal of hyaluronidase was fabricated to improve intratumoral penetration andantitumor efficacy. The reduction-sensitive nanogel loaded gemcitabine with conjugated hyaluronidase (GEM@NGH). Physicochemical properties, reduction sensitivity, penetration ability, cellular biocompatibility and cytotoxicity, intracellular distribution and therapeutic effects were all evaluated. GEM@NGH had good enzymic activity for hyaluronan ablation and effectively penetrated in the extracellular matrix of 3D model. GEM@NGH could be disintegrated in the tumoral reductive cytoplasm after internalization and release gemcitabine to exhibit cytotoxicity. In the in vivo therapy, GEM@NGH displayed the highest tumor growth inhibition in PANC-1 tumor-bearing mice. The results obtained herein showed that the penetration ability could be remarkably increased by TME regulation through well design of GEM@NGH. The results indicate that specifically regulating TME by a Gemcitabine@Nanogel system via in vitro 3D Model is promising way for the pancreatic cancer therapy.

Keywords: Nanomedicine, Cancer therapy, Extracellular matrix, PDAC

Suggested Citation

Chen, Di and Zhu, Xiaofei and Liu, Ri and Zhang, Yajun and Tao, Wanru and Zhang, Tingying and Huag, Yong and Jiang, Lingong and Tang, Ying and Yu, Haiyan and Hao, Qiang and Zhang, Huojun and Li, Wei, Specifically Regulating Tumor Microenvironment by a Gemcitabine@Nanogel System via in vitro 3D Model for Synergistic Pancreatic Cancer Therapy (May 14, 2019). Available at SSRN: https://ssrn.com/abstract=3387640 or http://dx.doi.org/10.2139/ssrn.3387640

Di Chen

Second Military Medical University, International Joint Cancer Institute

Shanghai
China

Second Military Medical University, Changhai Hospital, Department of Radiation Oncology

Shanghai
China

Xiaofei Zhu

Second Military Medical University, Changhai Hospital, Department of Radiation Oncology ( email )

Shanghai
China

Ri Liu

Second Military Medical University, Changhai Hospital, Department of Radiology ( email )

Shanghai
China

Yajun Zhang

Second Military Medical University, International Joint Cancer Institute ( email )

Shanghai
China

Wanru Tao

Second Military Medical University, International Joint Cancer Institute

Shanghai
China

Tingying Zhang

Second Military Medical University, International Joint Cancer Institute

Shanghai
China

Yong Huag

Second Military Medical University, International Joint Cancer Institute

Shanghai
China

Lingong Jiang

Second Military Medical University, Changhai Hospital, Department of Radiation Oncology

Shanghai
China

Ying Tang

Second Military Medical University, Changhai Hospital, Department of Radiation Oncology

Shanghai
China

Haiyan Yu

Second Military Medical University, Changhai Hospital, Department of Radiation Oncology

Shanghai
China

Qiang Hao

Second Military Medical University, Changhai Hospital, Department of Radiology

Shanghai
China

Huojun Zhang

Second Military Medical University, Changhai Hospital, Department of Radiation Oncology

Shanghai
China

Wei Li (Contact Author)

Second Military Medical University, International Joint Cancer Institute

Shanghai
China

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