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Matrix metalloproteinase 2/9-triggered-release micelles for inhaled drug delivery to treat lung cancer: preparation and in vitro/in vivo studies

Authors Wang X, Chen Q, Zhang X, Ren X, Zhang X, Meng L, Liang H, Sha X, Fang X

Received 26 February 2018

Accepted for publication 30 April 2018

Published 13 August 2018 Volume 2018:13 Pages 4641—4659

DOI https://doi.org/10.2147/IJN.S166584

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Alexander Kharlamov

Peer reviewer comments 2

Editor who approved publication: Dr Lei Yang


Xiaofei Wang,1,2 Qinyue Chen,1 Xiaoyan Zhang,1 Xiaoqing Ren,1 Xiulei Zhang,1 Lin Meng,1 Huihui Liang,1 Xianyi Sha,1 Xiaoling Fang1

1Key Laboratory of Smart Drug Delivery, Ministry of Education of China, School of Pharmacy, Fudan University, Shanghai, People’s Republic of China; 2Shanghai Omni Pharmaceuticall Co., Ltd., Shanghai, People’s Republic of China

Background: Improvement in drug accumulation in the lungs through inhalation administration and high expression of MMP2 and MMP9 in lung tumors have both been widely reported.
Methods: MMP2/9-triggered-release micelles were constructed and in vitro and in vivo studies of inhalation administration against lung tumor carried out. Pluronic P123 (P123) was modified with GPLGIAGQ-NH2 (GQ8) peptide to obtain P123-GQ8 (PG). MMP2/9-triggered-release micelles were constructed using PG and succinylated gelatin (SG) and loading paclitaxel (Ptx). To study biodistribution of micelles, DiR encapsulated in micelles was dosed to rats via intravenous injection or inhalation before ex vivo imaging for detecting DiR quantity in lungs. And B16F10 lung cancer-bearing nude mice were chosen as animal models to evaluate in vivo efficacy of MMP2/9-triggered-release micelles.
Results: Ptx-release efficiency from PG-SG-Ptx micelles was MMP2/9-concentration-dependent. For A549 cells, PG-SG-Ptx cytotoxicity was significantly greater (P<0.001) compared to P123-Ptx. Aerosol inhalation was chosen as the method of administration. In biodistribution experiment, DiR quantity in lungs was 5.8%±0.4% of that in major organs, while the ratio was 38.8%±0.5% for inhalation. For B16F10 lung cancer-bearing nude mice, the efficacy of inhalation of PG-SG-Ptx was significantly higher (P<0.001) than Taxol inhalation and injected PG-SG-Ptx. Inhaled PG-SG-Ptx also significantly inhibited the expression of Pgp in lung cancer.
Conclusion: Inhalation of MMP2/9-triggered-release micelles increased tumor sensitivity to chemotherapeutics and reduced the toxicity of chemotherapy to healthy lung cells, which has great potential in lung cancer therapy.

Keywords:
matrix metalloproteinases, inhalation, Pluronic, paclitaxel, P-glycoprotein

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