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

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.