Journal
CARBOHYDRATE POLYMERS
Volume 220, Issue -, Pages 30-42Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.carbpol.2019.05.051
Keywords
Low molecular weight heparin; Supramolecular assembly; Anti-angiogenesis; Mitochondrial damage; (KLAKLAK)(2) peptide
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Funding
- National Natural Science Foundation of China [81773655]
- 333 Project Talent Training Fund of Jiangsu Province [BRA2017432]
- 12th of Six Talent Peak Foundation of Jiangsu Province [YY-001]
- Open Project of Jiangsu Key Laboratory of Druggability of Biopharmaceuticals [JKLDBKF201702]
- Project Program of State Key Laboratory of Natural Medicines, China Pharmaceutical University [JKGQ201107, SKLNMZZJQ201605]
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Low molecular weight heparin (LMWH) is a natural sulfated glycosaminoglycan with the affinity to proangiogenic factors, rendering it a promising agent for tumor therapy. Inspired by DOX binding to the helix of DNA, mitochondrial damage KLA peptide derivative (mKLA) and anti-angiogenic LMWH-chrysin conjugate (LC) are constructed to simulate the double strands for doxorubicin (DOX) binding (LKD nanocomplex). Initiated and locked by DOX, mKLA and LC temporarily aggregate by pi-pi stacks, electrostatic and hydrophobic interactions in aqueous condition with self-amplified DOX loading (19.07 +/- 1.08 wt%). During endosome-lysosome trafficking, DOX protonated by H+ could unlock the LKD nanocomplex to disassemble, which enables mKLA and DOX to damage mitochondria and nucleus DNA respectively, and LMWH could also inhibit angiogenesis. Based on the strong inhibition of tumors at all stages in vivo, we hold that LKD nanocomplex provides a new opportunity based on smart construction of carbohydrate materials for clinically advanced cancer patients.
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