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Nano Lett. 2019 Jun 12;19(6):3527-3534. doi: 10.1021/acs.nanolett.9b00374. Epub 2019 May 14.

Codelivery Nanosystem Targeting the Deep Microenvironment of Pancreatic Cancer.

Author information

1
Key Laboratory of Smart Drug Delivery, Ministry of Education, State Key Laboratory of Medical Neurobiology, Research Center on Aging and Medicine, Department of Pharmaceutics, School of Pharmacy , Fudan University , Shanghai 201203 , China.
2
Department of Pancreatic and Hepatobiliary Surgery , Fudan University Shanghai Cancer Center , 270 Dongan Road , Shanghai 200032 , China.
3
Department of Oncology, Shanghai Medical College , Fudan University , Shanghai 200032 , China.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is considered as one of the most aggressive malignancies due to its unique microenvironment of which the cardinal histopathological feature is the remarkable desmoplasia of the stroma, taking up about 80% of the tumor mass. The desmoplastic stroma negatively affects drug diffusion and the infiltration of T cells, leading to an immunosuppressive microenvironment. However, this unique microenvironment can limit the physical spread of pancreatic cancer via a neighbor suppression effect. Here, a tumor central stroma targeting and microenvironment responsive strategy was applied to generate a nanoparticle coloading paclitaxel and phosphorylated gemcitabine. The designed nanoparticle disrupted the central stroma while preserving the external stroma, thereby promoting the antitumor effectiveness of chemotherapeutics. Additionally, the resulting nanoparticle can modulate the tumor immunosuppressive microenvironment by augmenting the number of cytotoxic T cells and restraining the percentage of T regulatory cells. The relatively intact external stroma can effectively maintain the neighbor suppression effect and prevent tumor metastasis. Combining stroma targeting with the delivery of stimuli-responsive polymeric nanoparticles embodies an effective tumor-tailored drug delivery system.

KEYWORDS:

Tumor microenvironment; codelivery; immune therapy; stroma disruption; tumor metastasis

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