Efficient Anticancer Drug Delivery for Pancreatic Cancer Treatment Utilizing Supramolecular Polyethylene-Glycosylated Bromelain
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 h...
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Published in | ACS applied bio materials Vol. 3; no. 5; pp. 3005 - 3014 |
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Main Authors | , , , , , , , , , |
Format | Journal Article |
Language | English |
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United States
American Chemical Society
18.05.2020
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Abstract | 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 β-cyclodextrins (β-CyDs) containing 2 or 20 kDa PEG chains in water. SPRA-bromelain was formed by a host–guest interaction between adamantane and β-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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AbstractList | 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 β-cyclodextrins (β-CyDs) containing 2 or 20 kDa PEG chains in water. SPRA-bromelain was formed by a host–guest interaction between adamantane and β-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. 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 β-cyclodextrins (β-CyDs) containing 2 or 20 kDa PEG chains in water. SPRA-bromelain was formed by a host-guest interaction between adamantane and β-CyD ( > 10 M ). SPRA-bromelain showed high gelatin-degrading activity and enhanced not only the accumulation of fluorescein isothiocyanate (FITC)-dextran (2 MDa) in the tumor but also the 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. |
Author | Motoyama, Keiichi Arima, Hidetoshi Iohara, Daisuke Onodera, Risako Sato, Nana Misumi, Shogo Higashi, Taishi Kogo, Tetsuya Hirotsu, Tatsunori Nakamura, Hideaki |
AuthorAffiliation | Faculty of Pharmaceutical Sciences Graduate School of Pharmaceutical Sciences Laboratory of Evidence-Based Pharmacotherapy Priority Organization for Innovation and Excellence Kumamoto University |
AuthorAffiliation_xml | – name: Faculty of Pharmaceutical Sciences – name: Kumamoto University – name: Laboratory of Evidence-Based Pharmacotherapy – name: Priority Organization for Innovation and Excellence – name: Graduate School of Pharmaceutical Sciences |
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CitedBy_id | crossref_primary_10_3390_pharmaceutics16010043 crossref_primary_10_3389_fbioe_2023_1177151 crossref_primary_10_3390_life11040317 crossref_primary_10_5812_ijpr_134282 crossref_primary_10_3390_nu13124313 crossref_primary_10_1016_j_jconrel_2022_10_049 crossref_primary_10_1016_j_foodhyd_2023_109662 crossref_primary_10_1016_j_mtbio_2021_100160 crossref_primary_10_3390_pharmaceutics14010076 crossref_primary_10_1016_j_actbio_2023_05_043 crossref_primary_10_4164_sptj_58_368 crossref_primary_10_1021_acsabm_2c00486 crossref_primary_10_1016_j_jconrel_2023_07_039 crossref_primary_10_3390_nu16132060 crossref_primary_10_1016_j_jconrel_2022_03_043 crossref_primary_10_1016_j_jconrel_2022_11_007 |
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Title | Efficient Anticancer Drug Delivery for Pancreatic Cancer Treatment Utilizing Supramolecular Polyethylene-Glycosylated Bromelain |
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