Tumor-specific delivery of doxorubicin through conjugation of pH-responsive peptide for overcoming drug resistance in cancer

• Published in: International journal of pharmaceutics Vol. 528; no. 1-2; pp. 322 - 333
• Main Authors: Feng, Chunlai, Rui, Mengjie, Shen, Haijun, Xin, Yuanrong, Zhang, Jie, Li, Jun, Yue, Lixiang, Lai, Wenlong, Xu, Ximing
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 07-08-2017
• Subjects: Animals; Antitumor therapy; ATP Binding Cassette Transporter, Sub-Family B - metabolism; Cell Line, Tumor; Doxorubicin - administration & dosage; Drug Delivery Systems; Drug resistance; Drug Resistance, Neoplasm; Female; Humans; Hydrogen-Ion Concentration; MCF-7 Cells; Mice, Inbred BALB C; Neoplasms - drug therapy; Peptides - chemistry; Prodrug; Targeted drug delivery; Tumor microenvironment-sensitivity; Xenograft Model Antitumor Assays; Targeted drug delivery; Tumor microenvironment-sensitivity; Prodrug; Drug resistance; Antitumor therapy
• ISSN: 0378-5173; 1873-3476
• DOI: 10.1016/j.ijpharm.2017.06.022

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The major obstacles opposed to doxorubicin (Dox) based chemotherapy are the induction of drug resistance, together with non-specific toxicities for healthy cells. In this study, we prepared a peptide-Dox conjugate aimed at offering Dox molecules a tumor-specific functionality and improving the therapeutic effects of Dox against resistant tumor cells. A slightly acidic pH-sensitive peptide (SAPSP) with high selectivity for cancer cells was attached to Dox to obtain SAPSP-Dox prodrug. The structures and properties of this prodrug were characterized, confirming several merits, including desirable pH-sensitive property, good serum stability and favorable release behavior. Cellular uptake studies demonstrated that SAPSP-Dox was preferably accumulated in cancer cells (Dox-sensitive MCF-7 and Dox-resistant MCF-7/ADR), followed by displaying 26-fold less toxic toward noncancerous MCF-10A cells than free Dox do. The conjugated peptides enabled Dox to escape the efflux effect of P-glycoprotein mediated pump via endocytotic pathway, giving rise to remarkable cytotoxicity and apoptotic effect on MCF-7/ADR cells. Moreover, the superior inhibition efficacy of SAPSP-Dox in vivo was more evident in the both drug-sensitive and drug-resistant xenograft tumor animal models, which enabled Dox to primarily accumulated in tumor. The conjugates also demonstrated a longer half-life in plasma and a lower side effect, for example, reduced cardiac toxicity. Evidence of this study suggests that SAPSP-Dox has the potential to be a potent prodrug for treating drug resistant cancers.