Smart pH-Sensitive and Temporal-Controlled Polymeric Micelles for Effective Combination Therapy of Doxorubicin and Disulfiram

Abstract

The combination of a chemotherapeutic drug with a multidrug resistance (MDR) modulator has emerged as a promising strategy for treating MDR cancer. To ensure two drugs could be simultaneously delivered to tumor region at the optimum ratio, and the MDR modulator could be released earlier and faster than the chemotherapeutic drug to inactivate P-glycoprotein (P-gp) and subsequently inhibit the pumping out of the chemotherapeutic drug, a smart pH-sensitive polymeric micelles system with high drug loading and precise drug ratio was designed and prepared by conjugating doxorubicin (DOX) to poly(styrene-co-maleic anhydride) (SMA) derivative with adipic dihydrazide (ADH) through a acid-cleavable hydrazone bond, and then encapsulating disulfiram (DSF), a P-gp inhibitor as well as an apoptosis inducer, into the micelles formed by the self-assembly of SMA-ADH-DOX (SAD) conjugate. The pH-sensitive polymeric micelles system enabled a temporal release of two drugs: encapsulated DSF was released fast to inhibit the activity of P-gp and restore cell apoptotic signaling pathways, while conjugated DOX was released in a sustained and pH-dependent manner and highly accumulated in drug resistant cells to exert therapeutic effect, due to the inactivation of P-gp by DSF. The smart co-delivery system was very effective in enhancing the cytotoxicity by increasing the intracellular accumulation of DOX and promoting the apoptotic response, and showed the most effective inhibitory effect on the growth of drug-resistant breast cancer xenografts as compared to other combinations of both drugs. In a word, this smart co-delivery system has significant promise for the clinical therapy of MDR cancer.

pH-Responsive therapeutic solid lipid nanoparticles for reducing P-glycoprotein-mediated drug efflux of multidrug resistant cancer cells

“…11,18 The 50% cellular growth inhibition (IC 50 ) values of C-PEG2k/5k-SLNs against MCF-7/MDR were 9.2 and 8.1 μM of the DOX concentrations, respectively. These values are slightly higher than that reported in the literature, ~1-3 μM for TPGS and disulfiram, 8,18 due to the short co-incubation time, 6 hours instead of 48 hours, used in this study.…”

“…Enhanced active transport of chemotherapeutic agents, such as doxorubicin (DOX), cisplatin, topotecan, and paclitaxel, out of cancer cells by P-gp prevents cellular drug accumulation, and thus reduces the efficacy of chemotherapy. 5,6 To this end, several P-gp inhibitors, such as verapamil and disulfiram, 7,8 have been co-encapsulated in nanocarriers to reduce the MDR of cancer cells. However, the inherent toxicity of these P-gp inhibitors, partly resulting from the inhibition of Ca 2+ channels in smooth muscle that line blood vessels and heart, often leads to hypotension and bradycardia in cancer patients.…”

Nanomedicine-Mediated Combination Drug Therapy in Tumor

“…Cisplatin and paclitaxel PEG-PGlu90-PPhe25 hybrid micelles Ovarian cancer [56] Linear-dendritic telodendrimer micelles Ovarian cancer [57] Doxorubicin and disulfiram Polymeric micelles Breast cancer [58] Doxorubicin and curcumin Polymeric micelles Breast cancer [59] Doxorubicin and paclitaxel Pluronic mixed micelles Breast cancer [60] Docetaxel and chloroquine PEO-PPO-PCL/TPGS micelles Breast cancer [61] Paclitaxel and curcumin PEG-PE and vitamin E micelles Ovarian cancer [62] In order to eradicate ovarian cancer, Desale et al [56] synthesized biodegradable triblock copolymers containing ethylene glycol, glutamic acid, and phenylalanine (PEG-PGlu-PPhe). These copolymers self-assembled to form micelles for the co-delivery of CDDP and PTX, and the resulting nanomedicine mounted strong tumor suppression effects both in vitro and in vivo.…”

“…Finally, Duan et al [58] developed a pH-sensitive polymeric micelle system to achieve the temporal release of two drugs. The researchers conjugated DOX to a poly (styrene-co-maleic anhydride) (SMA) derivative with adipic dihydrazide (ADH) through an acid-cleavable hydrazone bond.…”

“…The researchers conjugated DOX to a poly (styrene-co-maleic anhydride) (SMA) derivative with adipic dihydrazide (ADH) through an acid-cleavable hydrazone bond. They then loaded disulfiram (DSF) into the polymer micelles through the self-assembly of a SMA-ADH-DOX (SAD) conjugate [58]. This nanomedicine rapidly released DSF to inhibit the activity of P-glycoprotein and then slowly released DOX to increase its accumulation within tumor cells and enhance the antitumor response.…”