Abstract
HER2-positive breast cancer correlates with more aggressive tumor growth, a poorer prognosis and reduced overall survival. Currently, trastuzumab (Herceptin), which is an anti-HER2 antibody, is one of the key drugs. There is evidence indicating that conjugation of trastuzumab with chemotherapy drugs, such as doxorubicin (DOX), for multiple targets could be more effective. However, incomplete penetration into tumors has been noted for those conjugates. Compared to an antibody, peptides may represent an attractive alternative. For HER2, a similar potency has been observed for a 12-amino-acid anti-HER2 peptide mimetic YCDGFYACYMDV-NH2 (AHNP, disulfide-bridged) and full-length trastuzumab. Thus, a peptide, GPLGLAGDDYCDGFYACYMDV-NH2, which consists of AHNP and an MMP-2 cleavable linker GPLGLAGDD, was first designed, followed by conjugation with DOX via a glycine residue at the N-terminus to form a novel DOX-peptide conjugate MAHNP-DOX. Using HER2-positive human breast cancer cells BT474 and SKBR3 as in vitro model systems and nude mice with BT474 xenografts as an in vivo model, this conjugate was comprehensively characterized, and its efficacy was evaluated and compared with that of free DOX. As a result, MAHNP-DOX demonstrated a much lower in vitro IC50, and its in vivo extent of inhibition in mice was more evident. During this process, enzymatic cleavage of MAHNP-DOX is critical for its activation and cellular uptake. In addition, a synergistic response was observed after the combination of DOX and AHNP. This effect was probably due to the involvement of AHNP in the PI3K–AKT signaling pathway, which can be largely activated by DOX and leads to anti-apoptotic signals.
Highlights
Overexpression of the human epidermal growth factor receptor family member HER2, which is known as erbB-2/neu, is found in approximately 20–30% of breast cancer cases (i.e. HER2-positive breast cancer) and correlates with more aggressive tumor growth, poorer prognosis and reduced overall survival (Tai et al, 2010; Dent et al, 2013; Rimawi et al, 2015)
The peptide component of the peptideDOX conjugate MAHNP-DOX is composed of the cleavable linker GPLGLAGDD and the anti-HER2 peptide AHNP, followed by conjugation with DOX (Figure 1)
The peptide was conjugated to N-Fmoc-DOX-14-Ohemiglutarate, and the Fmoc groups were removed with piperidine treatment to obtain MAHNP-DOX with 43.5% yield and 95.1% purity (Figure 2(A))
Summary
Overexpression of the human epidermal growth factor receptor family member HER2, which is known as erbB-2/neu, is found in approximately 20–30% of breast cancer cases (i.e. HER2-positive breast cancer) and correlates with more aggressive tumor growth, poorer prognosis and reduced overall survival (Tai et al, 2010; Dent et al, 2013; Rimawi et al, 2015). Despite its observed clinical efficacy, such a simple drug combination is generally not recommended due to low selectivity and severe cardiotoxicity coming from the cumulative effects of both trastuzumab and DOX (Wonders & Reigle, 2009, Rochette et al, 2015) In this context, a trastuzumab-DOX conjugate has been recently developed and provides improved selectivity in drug delivery and reduced cardiotoxicity by relying on antibody trastuzumab-mediated specific recognition of the tumor antigen HER2 (Tarcic & Yarden, 2013; Zhang et al, 2013). The trastuzumabDOX conjugate has had incomplete penetration of tumors due to the “binding site barrier” effect (Aina et al, 2002; Graff & Wittrup, 2003; Thurber et al, 2008), which is consistent with the results for most other antibody-drug conjugates (ADC)
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