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已发表论文
以 αvβ3 整联蛋白为靶向的美登素 (mertansine) 前药胶束在体内有效地抑制三阴性乳腺癌
Authors Zhong P, Gu X, Cheng R, Deng C, Meng F, Zhong Z
Received 15 July 2017
Accepted for publication 25 September 2017
Published 27 October 2017 Volume 2017:12 Pages 7913—7921
DOI https://doi.org/10.2147/IJN.S146505
Checked for plagiarism Yes
Review by Single-blind
Peer reviewers approved by Dr Govarthanan Muthusamy
Peer reviewer comments 3
Editor who approved publication: Dr Linlin Sun
Abstract: Antibody-mertansine
(DM1) conjugates (AMCs) are among the very few active targeting therapeutics
that are approved or clinically investigated for treating various cancers
including metastatic breast cancer. However, none of the AMCs are effective for
the treatment of triple-negative breast cancers (TNBCs). Here, we show that
cRGD-decorated, redox-activatable micellar mertansine prodrug (cRGD-MMP) can
effectively target and deliver DM1 to αvβ3 integrin
overexpressing MDA-MB-231 TNBC xenografts in nude mice, resulting in potent
tumor growth inhibition. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
bromide (MTT) assays showed that cRGD-MMP had obvious targetability to
MDA-MB-231 cells with a low half-maximal inhibitory concentration (IC50) of 0.18 µM, which
was close to that of free DM1 and 2.2-fold lower than that of micellar
mertansine prodrug (MMP; nontargeting control). The confocal microscopy studies
demonstrated that cRGD-MMP mediated a clearly more efficient cellular uptake
and intracellular release of doxorubicin (used as a fluorescent anticancer drug
model) in MDA-MB-231 cells. Notably, cRGD-MMP loaded with
1,1'-dioctadecyltetramethyl indotricarbocyanine iodide (DiR; a hydrophobic
near-infrared dye) was shown to quickly accumulate in the MDA-MB-231 tumor with
strong DiR fluorescence from 2 to 24 h post injection. MMP loaded with DiR
could also accumulate in the tumor, although significantly less than cRGD-MMP.
The biodistribution studies revealed a high DM1 accumulation of 8.1%ID/g in the
tumor for cRGD-MMP at 12 h post injection. The therapeutic results
demonstrated that cRGD-MMP effectively suppressed MDA-MB-231 tumor growth at
1.6 mg DM1 equiv./kg without causing noticeable side effects, as shown by
little body weight loss and histological analysis. This MMP has appeared as a
promising platform for potent treatment of TNBCs.
Keywords: breast cancer, reduction-sensitive, drug conjugates, micelles, cRGD
Keywords: breast cancer, reduction-sensitive, drug conjugates, micelles, cRGD
