Abstract
Although doxorubicin (dox), an anthracycline antibiotic, is widely used and effective in treating cancer, its treatment efficiency is limited by low blood plasma solubility, poor pharmacokinetics, and adverse side effects, including irreversible cardiotoxicity. Moreover, cancer cells often develop drug resistance over time, which decreases the efficacy of anti-cancer drugs, including dox. In this study, we examine a macromolecular drug delivery system for its ability to specifically deliver doxorubicin to cancer cells with and without drug resistance. This drug delivery system consists of a multi-part macromolecule, which includes the following: elastin-like polypeptide (ELP), cell penetrating peptide (CPP), a cleavable linker (releasing at low pH), and a derivative of doxorubicin. ELP is thermally responsive and improves drug solubility, while the CPP mediates cellular uptake of macromolecules. We compared cytotoxicity of two doxorubicin derivatives, where one is cleavable (DOXO) and contains a pH-sensitive linker and releases dox in an acidic environment, and the other is non-cleavable (ncDox) doxorubicin. Cytotoxicity, apoptosis, cell cycle distribution and mechanism of action of these constructs were tested and compared between dox-responsive MCF-7 and dox-resistant NCI/ADR cell lines. Dox delivered by the ELP construct is comparably toxic to both sensitive and drug resistant cell lines, compared to unconjugated doxorubicin, and given the pharmacokinetic and targeting benefits conveyed by conjugation to ELP, these biopolymers have potential to overcome dox resistance in vivo.
Highlights
The current treatment for patients with solid malignant tumors consists of multimodal therapy, including surgery, followed by radiotherapy and chemotherapy
Multidrug resistance (MDR) can be induced by the initial administration of a single drug, and it expands resistance to cover a wide array of other unrelated chemo drugs [4,5], which are diverse both structurally and mechanistically, such as cisplatin, daunorubicin, docetaxel, doxorubicin, and epirubicin
We reported earlier that thermal targeting of an acid-sensitive doxorubicin conjugate of elastin-like polypeptide enhances the therapeutic efficacy compared with the parent compound in vivo, confirming that dox delivered by the macromolecular carrier ELP has potential as a thermally targeted carrier for doxorubicin delivery [22,23]
Summary
The current treatment for patients with solid malignant tumors consists of multimodal therapy, including surgery, followed by radiotherapy and chemotherapy. The systemic chemotherapy approach has limited utility due to off-target damage to healthy tissues, resulting in increased mortality. In addition to systemic toxicity, one of the common causes for the failure of the standard cancer chemotherapies is development of multidrug resistance (MDR) [1,2]. MDR can be induced by the initial administration of a single drug, and it expands resistance to cover a wide array of other unrelated chemo drugs [4,5], which are diverse both structurally and mechanistically, such as cisplatin, daunorubicin, docetaxel, doxorubicin, and epirubicin. Many studies have attempted to target and attenuate MDR via introducing different agents such as bexarotene, biricodar (VX710), dexrazoxane, ethacrynic acid, verapamil, valspodar (PSC833), and tariquidar (XR9576) [6].
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