Zwitterionic Polymer Micelles with Dual Conjugation of Doxorubicin and Curcumin: Synergistically Enhanced Efficacy against Multidrug-Resistant Tumor Cells

Abstract

This paper reports a novel redox-sensitive micellar system for the co-delivery of doxorubicin (Dox) and a chemosensitizer (curcumin, Cur) to overcome the multidrug resistance (MDR) in cancer cells. Dox and Cur were co-conjugated onto a zwitterionic polymer, poly(carboxybetaine) (pCB), to form Cur-pCB-Dox that self-assembled into stable micelles (164.2 ± 4.8 nm). Single-drug conjugates (pCB-Dox and pCB-Cur) were prepared for comparisons. Compared to the high half-maximal inhibitory concentration (IC 50 ) of Dox (437.2 μg/mL), the IC 50 value of pCB-Dox (14.1 μg/mL) was only 1/33 that of Dox. Confocal laser scanning microscopy and flow cytometry revealed the greatly enhanced cell uptake of the conjugate due to the enhanced permeability and retention effect of tumor cells on the micellar conjugate. Co-delivery of pCB-Dox with pCB-Cur further reduced the IC 50 value by 37% (8.9 μg/mL). More importantly, Cur-pCB-Dox exhibited the strongest cytotoxicity against MCF-7/Adr cells (IC 50 , 5.87 μg/mL) because the codelivered Dox and Cur on one carrier specifically transported into the same cells, which inhibited the efflux of Dox by Cur, led to a higher intracellular Dox concentration and made the drugs exert synergistic effects at the targeting regions. The results proved the zwitterionic micelles as promising drug co-delivery vehicles for fighting against MDR.

Polychemotherapy with Curcumin and Doxorubicin via Biological Nanoplatforms: Enhancing Antitumor Activity

“…These studies demonstrate that drug transporters participate in DOX resistance and they are potential targets of curcumin in providing chemosensitivity. As an example, it was shown that colocal delivery of DOX and curcumin can synergistically increase the effectiveness toward multidrug-resistant cancer cells, e.g., further reducing the IC 50 value by 37% (8.9 µg/mL; Figure 2) [139]. The nanosized feature of the zwitterionic antifouling micelles and endocytic pathway to bypass P-gp-mediated drug efflux led to high cellular uptake of the conjugated drugs that were released in the tumor cells of high GSH concentration.…”

“…Cur: curcumin; Dox: doxorubicin; MDR: multidrug resistance; pCB: poly(carboxybetaine). Addapted with permission from [139].…”

“…Using nanoparticles such as micelles remarkably promotes intracellular uptake of curcumin and DOX, leading to more efficiency in suppressing chemoresistance compared to DOX or curcumin alone [139]. The ideology of coadministration of curcumin and DOX during cancer chemotherapy was better advocated, when it was found that DOX is also capable of promoting cellular uptake of curcumin in enhancing its antitumor activity against prostate cancer cells [146].…”

Curcumin encapsulation in nanostructures for cancer therapy: A 10-year overview

“…Polymeric micelles (PMs) have gathered significant interest as DDS because of their low toxicity, good biocompatibility, modified release pattern, increased blood circulation time, and ability to solubilize hydrophobic drugs such as CUR in the micelles' core (Akbar et al, 2018). The hydrophobic segments in the polymers/copolymers form the micelle core that acts as a reservoir for hydrophobic drugs, while the hydrophilic headgroups form the micellar shell that can improve the colloidal stability and prevent protein adsorption, thus prolonging the circulation time (Gou et al, 2011;Zhao et al, 2020). In particular, one type of material that is used as a biocompatible complexing agent to improve the water solubility, stability, and bioavailability of poor aqueous soluble drugs is Pluronic ® copolymers, which contain hydrophobic poly(propylene oxide) (PPO) blocks and hydrophilic poly(ethylene oxide) (PEO) blocks arranged in a triblock structure, PEO-PPO-PEO.…”

A pH-Responsive Zwitterionic Polyurethane Prodrug as Drug Delivery System for Enhanced Cancer Therapy

“…Jiang's group [23][24][25] has prepared several polymers (such as PCBMA, PSBMA and PMPC), which exhibited excellent stability and antifouling properties in vivo. Meanwhile, it has been reported that the cellular uptake efficiency of Molecules 2021, 26, 5274 2 of 8 micelles would be increased by the modification of a zwitterionic segment in tumor tissues [26,27]. The main reason is the difference in pH between normal tissue cells (pH = 7.4) and tumor tissue (acidic).…”