期刊
PHARMACEUTICAL RESEARCH
卷 35, 期 5, 页码 -出版社
SPRINGER/PLENUM PUBLISHERS
DOI: 10.1007/s11095-018-2365-x
关键词
anti-CD3; HER2-positive breast cancer; immunoliposomes; trastuzumab; doxorubicin
资金
- Research Starter Grant Award in Translational Medicine and Therapeutics from the PhRMA Foundation
Purpose Trastuzumab combined with Doxorubicin (DOX) demonstrates significant clinical activity in human epidermal growth factor receptor-2 (HER2)-positive breast cancer (BC). However, emergence of treatment resistance and trastuzumab associated cardiotoxicity remain clinical challenges. In an effort to improve patient outcome, we have developed and evaluated novel tri-functional immunoliposomes (TFIL) that target HER2-receptors on BC cells and CD3-receptors on Tlymphocytes, and deliver DOX. Methods Trastuzumab (anti-HER2) and OKT-3 (anti-CD3) antibodies were conjugated to liposomes using a micelletransfer method. Cytotoxicity of targeted immunoliposomes loaded withDOXwas examined in vitro onHER2-positive BC cells (BT474), with peripheral blood monocytic cells (PBMC) as immune effector cells. Results TFIL demonstrated high antibody-liposome conjugation ratios (100-130 mu g protein/mu mol phospholipid) and cargo capacity (0.21 mol: mol drug: lipid), highly efficient DOX loading (> 90%), a particle size favorable for extended circulation (similar to 150 nm), and good stability (up to 3 months at 4 degrees C). In the presence of PBMCs, TFIL showed complete killing of BT474 cells, and were superior to mono-targeted trastuzumab-bearing liposomes, non-targeted liposomes, and free Trastuzumab and DOX. Conclusions Novel anti-HER2xCD3 + DOX TFIL show promise as a means to both engage immune cells against HER2 positive breast cancer cells and deliver chemotherapy, and have the potential to improve clinical outcomes.
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