Dataset Information

Selective Activation of Anticancer Chemotherapy by Cancer-Associated Fibroblasts in the Tumor Microenvironment.

ABSTRACT:

Background

The tumor microenvironment has recently emerged as a new target of anticancer chemotherapy. Selective activation of anticancer chemotherapy in the tumor microenvironment would further reduce the toxicity of anticancer drugs toward normal tissues. Fibroblast activation protein (FAP) is known to be selectively overexpressed on cancer-associated fibroblasts (CAFs) in the tumor microenvironment. Here, we designed an anticancer chemotherapeutic system based on promelittin, a peptide toxin that is selectively converted from an inactive form to the pore-forming melittin upon cleavage by FAP in the tumor microenvironment.

Methods

We conjugated promelittin-containing FAP-cleavable sequences to pegylated phospholipids and anchored them to reduced graphene oxide (rGO) nanosheets. The resulting nanosheets, PL-rGO, were tested for hemolysis and used for doxorubicin delivery. In vitro cocultures and in vivo tumor growth (n?=?5 mice per group) with tissue immunostaining were used to test the selective activation of anticancer chemotherapy by FAP expressed on CAFs.

Results

FAP-specific hemolytic activity of PL-rGO was observed in cocultures of CAFs and HT29 cells but not in HT29 cells alone. Doxorubicin-loaded PL-rGO (Dox/PL-rGO) showed 3.4-fold greater cell-killing efficacy (compared with free Dox in the CAF/HT29 coculture system, effects that were not observed in HT29 cells alone). Intravenously administered Dox/PL-rGO reduced the growth of HT29 tumors more effectively than other treatments (Dox/PL-rGO: mean = 200.6?mm(3), 95% confidence interval [CI] = 148.7 to 252.5?mm(3); free Dox: mean = 697.0?mm(3), 95% CI?=?646.9 to 747.1?mm(3), PL: mean = 565.0?mm(3), 95% CI?=?550.5 to 579.6?mm(3); Dox/rGO: mean = 637.6?mm(3), 95% CI?=?619.5 to 655.7?mm(3); PL-rGO: mean = 464.4?mm(3), 95% CI?=?433.0 to 495.8?mm(3)). Immunostaining of tumor tissues revealed that survival of CAFs and HT29 cells was lowest in the group treated with Dox/PL-rGO.

Conclusions

The demonstration of selective activation of PL-rGO by FAP on CAFs suggests that PL-rGO may serve as a tumor microenvironment-responsive anticancer chemotherapy system.

SUBMITTER: Kim MG

PROVIDER: S-EPMC6284259 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Publications

Selective Activation of Anticancer Chemotherapy by Cancer-Associated Fibroblasts in the Tumor Microenvironment.

Kim Mi-Gyeong MG Shon Yuna Y Kim Jinyoung J Oh Yu-Kyoung YK

Journal of the National Cancer Institute 20160911 1

<h4>Background</h4>The tumor microenvironment has recently emerged as a new target of anticancer chemotherapy. Selective activation of anticancer chemotherapy in the tumor microenvironment would further reduce the toxicity of anticancer drugs toward normal tissues. Fibroblast activation protein (FAP) is known to be selectively overexpressed on cancer-associated fibroblasts (CAFs) in the tumor microenvironment. Here, we designed an anticancer chemotherapeutic system based on promelittin, a peptid ...[more]

PMID: 27615014

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Dataset Information

Selective Activation of Anticancer Chemotherapy by Cancer-Associated Fibroblasts in the Tumor Microenvironment.

Background

Methods

Results

Conclusions

Publications

Selective Activation of Anticancer Chemotherapy by Cancer-Associated Fibroblasts in the Tumor Microenvironment.

Similar Datasets

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