期刊
BIOMATERIALS SCIENCE
卷 7, 期 8, 页码 3404-3417出版社
ROYAL SOC CHEMISTRY
DOI: 10.1039/c9bm00323a
关键词
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资金
- Ministry of Science and Technology, Taiwan [MOST 107-2320-B-037-024-MY3, MOST107-2320-B-037-028-MY2]
- National Health Research Institutes, Taiwan [NHRI-EX108-10729EI]
- Academia Sinica, Taiwan [AS-TP-107-L11]
- Program for Translational Innovation of Biopharmaceutical Development-Technology Supporting Platform Axis, Academia Sinica, Taiwan
- KMU-KMUH Co-Project of Key Research from Kaohsiung Medical University, Taiwan [KMU-DK108002]
- Research Foundation from Kaohsiung Medical University, Taiwan [KMU-Q108001]
- Kaohsiung Medical University Research Center Grant (Drug Development and Value Creation Research Center) [KMU-TC108A03]
For those patients with HER2-overexpressing breast cancer, treatment with PEGylated liposomal doxorubicin (PLD) is inefficacious due to the intrinsic low sensitivity to doxorubicin. A very large increase in drug accumulation by active targeting may enhance the therapeutic efficacy of PLD. We established a humanized bispecific antibody (BsAb; mPEG x HER2) which has dual specificity for methoxy-polyethylene glycol (mPEG) and human epidermal growth factor receptor 2 (HER2) to enhance the specificity, internalization and anticancer activity of PLD for cancer cells that overexpress HER2. One-step formulation of PLD with mPEG x HER2 converted the PLD into HER2 targeted liposomes that were stable at 4 degrees C in PBS as well as at 37 degrees C in the presence of serum. alpha HER2/PLD induced receptor-mediated endocytosis and enhanced doxorubicin accumulation in MCF7/HER2 (HER2-amplified) breast cancer cells. alpha HER2/PLD also displayed more than 200-fold increased cytotoxicity to MCF7/HER2 cells and 28-fold increased cytotoxicity to drug-resistant MDA-MB-361 cells with a physical deletion of the TOP2A gene. alpha HER2/PLD specifically accumulated doxorubicin in the nucleus of cancer cells in tumor-bearing mice and produced significantly greater antitumor activity against MCF7/HER2 (P < 0.0001) and MDA-MB-361 (P < 0.05) tumors as compared to untargeted PLD. Furthermore, the cardiotoxicity of alpha HER2/PLD was similar to that of PLD in human cardiomyocytes and in mice. Our results indicate that the one-step formulation of PLD by mPEG x HER2 is a simple method to confer tumor specificity, increase drug internalization and enhance the anticancer activity of PLD against HER2-overexpressing and doxorubicin-resistant breast cancer.
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