期刊
ACS APPLIED BIO MATERIALS
卷 3, 期 5, 页码 3005-3014出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsabm.0c00070
关键词
cyclodextrin; adamantane; poly(ethylene glycol); bromelain; pancreatic cancer
资金
- Leading Initiative for Excellent Young Researchers (LEADER), Ministry of Education, Culture, Sports, Science and Technology
- Program for Leading Graduate Schools HIGO (Health life science: Interdisciplinary and Glocal Oriented) Program, Kumamoto University
- Center for Clinical and Translational Research of Kyushu University
- Uehara Memorial Foundation
- Research Center for Biomedical Engineering
- The Research Foundation for Pharmaceutical Sciences
- The Mochida Memorial Foundation for Medical and Pharmaceutical Research
Pancreatic cancer is one of the most difficult cancers to treat largely because of the inability of anticancer drugs to penetrate into the cancer tissue as the result of the dense extracellular matrix (ECM). On the other hand, bromelain is known to degrade the ECM in cancerous tissue. However, the half-life of bromelain in blood is short, leading to its low accumulation in tissues. Recently, we developed a reversible poly(ethylene glycol) (PEG) modification technology that is able to improve blood retention of proteins without loss of activity and termed it Self-assembly PEGylation Retaining Activity (SPRA) technology. Here, we prepared reversible PEGylated bromelain using SPRA technology (SPRA-bromelain) possessing high activity, long blood retention, and high tumor accumulation and evaluated its potential as a drug delivery system for pancreatic cancer. SPRA-bromelain was prepared by mixing adamantane-modified bromelain and multisubstituted-PEGylated beta-cyclodextrins (beta-CyDs) containing 2 or 20 kDa PEG chains in water. SPRA-bromelain was formed by a host-guest interaction between adamantane and beta-CyD (K-c > 104 M-1). SPRA-bromelain showed high in vitro gelatin-degrading activity and enhanced not only the accumulation of fluorescein isothiocyanate (FITC)-dextran (2 MDa) in the tumor but also the in vivo antitumor activities of doxorubicin and doxorubicin encapsulated in PEGylated liposomes (DOXIL) after intravenous administration in tumor-bearing mice. These findings suggest that SPRA-bromelain could be a powerful tool for drug delivery in pancreatic cancer.
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