Dataset Information

Co-encapsulation of docetaxel and cyclosporin A into SNEDDS to promote oral cancer chemotherapy.

ABSTRACT: Self-nanoemulsifying drug delivery system (SNEDDS) have been considered as a promising platform for oral delivery of many BCS (biopharmaceutics classification system) class IV drugs, such as docetaxel (DTX). However, oral chemotherapy with DTX is also restricted by its active P-glycoprotein (P-gp) efflux and hepatic first-pass metabolism. To address these challenges, we developed a novel SNEDDS co-loaded with DTX and cyclosporine A (CsA) to achieve effective inhibition of P-gp efflux and P450 enzyme metabolization, improving oral bioavailability of DTX. The SNEDDS showed uniform droplet size of about 30?nm. Additionally, the prepared SNEDDS exhibited a sequential drug release trend of CsA prior to DTX. The intestinal experiments confirmed that the membrane permeability of DTX was significantly increased in the whole intestinal tract, especially in the jejunum segment. Furthermore, the oral bioavailability of co-loaded SNEDDS was 9.2-fold and 3.4-fold higher than DTX solution and DTX SNEDDS, respectively. More importantly, it exhibited a remarkable antitumor efficacy with a reduced toxicity compared with intravenously administered DTX solution. In summary, DTX-CsA co-loaded SNEDDS is a promising platform to facilitate oral docetaxel-based chemotherapy.

SUBMITTER: Cui W

PROVIDER: S-EPMC6534241 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Co-encapsulation of docetaxel and cyclosporin A into SNEDDS to promote oral cancer chemotherapy.

Cui Weiping W Zhao Hanqing H Wang Chen C Chen Yao Y Luo Cong C Zhang Shenwu S Sun Bingjun B He Zhonggui Z

Drug delivery 20191201 1

Self-nanoemulsifying drug delivery system (SNEDDS) have been considered as a promising platform for oral delivery of many BCS (biopharmaceutics classification system) class IV drugs, such as docetaxel (DTX). However, oral chemotherapy with DTX is also restricted by its active P-glycoprotein (P-gp) efflux and hepatic first-pass metabolism. To address these challenges, we developed a novel SNEDDS co-loaded with DTX and cyclosporine A (CsA) to achieve effective inhibition of P-gp efflux and P450 en ...[more]

PMID: 31090467

Similar Datasets

Project description:BACKGROUND:Infiltration into lymphatic vessels is a critical step in breast cancer metastasis. Lymphatics undergo changes that facilitate metastasis as a result of activation of the cells lining lymphatic vessels, lymphatic endothelial cells (LECs). Inhibition of activation by targeting VEGFR3 can reduce invasion toward lymphatics. To best benefit patients, this approach should be coupled with standard of care that slows tumor growth, such as chemotherapy. Little is known about how chemotherapies, like docetaxel, may influence lymphatics and conversely, how lymphatics can alter responses to therapy. METHODS:A novel 3D in vitro co-culture model of the human breast tumor microenvironment was employed to examine the contribution of LECs to tumor invasion and viability with docetaxel and anti-VEGFR3, using three cell lines, MDA-MB-231, HCC38, and HCC1806. In vivo, the 4T1 mouse model of breast carcinoma was used to examine the efficacy of combinatorial therapy with docetaxel and anti-VEGFR3 on lymph node metastasis and tumor growth. Lymphangiogenesis in these mice was analyzed by immunohistochemistry and flow cytometry. Luminex analysis was used to measure expression of lymphangiogenic cytokines. RESULTS:In vitro, tumor cell invasion significantly increased with docetaxel when LECs were present; this effect was attenuated by inhibition of VEGFR3. LECs reduced docetaxel-induced cell death independent of VEGFR3. In vivo, docetaxel significantly increased breast cancer metastasis to the lymph node. Docetaxel and anti-VEGFR3 combination therapy reduced lymph node and lung metastasis in 4T1 and synergized to reduce tumor growth. Docetaxel induced VEGFR3-dependent vessel enlargement, lymphangiogenesis, and expansion of the LEC population in the peritumoral microenvironment, but not tumor-free stroma. Docetaxel caused an upregulation in pro-lymphangiogenic factors including VEGFC and TNF-? in the tumor microenvironment in vivo. CONCLUSIONS:Here we present a counter-therapeutic effect of docetaxel chemotherapy that triggers cancer cells to elicit lymphangiogenesis. In turn, lymphatics reduce cancer response to docetaxel by altering the cytokine milieu in breast cancer. These changes lead to an increase in tumor cell invasion and survival under docetaxel treatment, ultimately reducing docetaxel efficacy. These docetaxel-induced effects can be mitigated by anti-VEGFR3 therapy, resulting in a synergism between these treatments that reduces tumor growth and metastasis.

Dataset Information

Co-encapsulation of docetaxel and cyclosporin A into SNEDDS to promote oral cancer chemotherapy.

Publications

Co-encapsulation of docetaxel and cyclosporin A into SNEDDS to promote oral cancer chemotherapy.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure