Targeted delivery of doxorubicin through conjugation with EGF receptor–binding peptide overcomes drug resistance in human colon cancer cells. (12th March 2013)

• Record Type: Journal Article
• Authors: Ai, Shibin; Jia, Tao; Ai, Weilun; Duan, Jianli; Liu, Yongmei; Chen, Jing; Liu, Xin; Yang, Fan; Tian, Yuan; Huang, Zebo
• Is Part Of: British journal of pharmacology. Volume 168:Number 7(2013:Apr.)
• Page Start: 1719
• Page End: 1735
• Publication Date: 2013-03-12
• Subjects: doxorubicin -- doxorubicin–peptide conjugate -- drug delivery -- drug resistance -- EGF receptor; Pharmacology -- Periodicals; Chemotherapy -- Periodicals; Drug Therapy -- Periodicals; Pharmacology -- Periodicals; 615.1
• DOI: 10.1111/bph.12055
• Languages: English
• ISSNs: 0007-1188

Abstract

Abstract : Background and Purpose: Induction of multidrug resistance by doxorubicin (DOX), together with non‐specific toxicities, has restricted DOX‐based chemotherapy. Recently, we demonstrated that DOX conjugated with an EGF receptor‐binding peptide (DOX‐EBP) had enhanced anticancer efficacy and reduced systemic toxicity when targeting EGF receptor‐overexpressing tumours. Here we investigated whether DOX‐EBP is able to overcome drug resistance and the underlying molecular mechanisms. Experimental Approach: DOX‐resistant SW480/DOX cells were derived from non‐resistant SW480 cells by stepwise exposure to increasing concentrations of DOX, and P‐glycoprotein overexpression induced by DOX was confirmed by Western blotting. Cytotoxicity and intracellular distribution of drugs were evaluated by MTT assay and fluorescence microscopy respectively. EGF receptor‐mediated endocytosis was determined in EGF receptor and endocytosis inhibition assays. Drug accumulation in tumour cells and murine xenografts was determined by HPLC. Key Results: The cytotoxicity and accumulation of DOX‐EBP in SW480/DOX cells were almost the same as in SW480 cells, but those of free DOX were reduced. DOX‐EBP accumulation was prevented by inhibitors of both EGF receptors and endocytosis, suggesting EGF receptors mediate endocytotic uptake. Tumour accumulation of DOX‐EBP was significantly higher than free DOX in mice, and the levels of DOX‐EBP were similar in DOX‐resistant and non‐resistant tumour tissues. Importantly, DOX‐EBP, but not free DOX, was effective at inhibiting solid tumour growth and increased survival rate in both sensitive and resistant models. Conclusion and Implications: DOX‐EBP can overcome DOX resistance of tumour cells and increase in vivo antitumour efficacy. Therefore, it has the potential to be a potent therapeutic agent for treating drug‐resistant cancers.