pH-triggered surface charge-switchable polymer micelles for the co-delivery of paclitaxel/disulfiram and overcoming multidrug resistance in cancer

Abstract

Multidrug resistance (MDR) remains a major challenge for providing effective chemotherapy for many cancer patients. To address this issue, we report an intelligent polymer-based drug co-delivery system which could enhance and accelerate cellular uptake and reverse MDR. The nanodrug delivery systems were constructed by encapsulating disulfiram (DSF), a P-glyco-protein (P-gp) inhibitor, into the hydrophobic core of poly(ethylene glycol)- block -poly( l -lysine) (PEG- b -PLL) block copolymer micelles, as well as 2,3-dimethylmaleic anhydride (DMA) and paclitaxel (PTX) were grafted on the side chain of l -lysine simultaneously. The surface charge of the drug-loaded micelles represents as negative in plasma (pH 7.4), which is helpful to prolong the circulation time, and in a weak acid environment of tumor tissue (pH 6.5–6.8) it can be reversed to positive, which is in favor of their entering into the cancer cells. In addition, the carrier could release DSF and PTX successively inside cells. The results of in vitro studies show that, compared to the control group, the DSF and PTX co-loaded micelles with charge reversal exhibits more effective cellular uptake and significantly increased cytotoxicity of PTX to MCF-7/ADR cells which may be due to the inhibitory effect of DSF on the efflux function of P-gp. Accordingly, such a smart pH-sensitive nanosystem, in our opinion, possesses significant potential to achieve combinational drug delivery and overcome drug resistance in cancer therapy.

pH-triggered charge-reversal and redox-sensitive drug release polymer micelles co-deliver doxorubicin and triptolide for prostate tumor therapy

“…21,39 In the spectrum of PEG-b-PLL and PEG-b-PLLZ ( Figure S2), all the peaks were consistent with the previous studies. 17,21 The degree of polymerization (DP) of lysine (Z) was calculated by comparing the signal intensities of lysine methylene protons with methylene protons of PEG, and the value was 18. 17 After deprotection, the typical peaks of carbobenzoxy groups at δ 5.0 ppm and 7.1-7.4 ppm disappeared in PEG-b-PLL, which indicated that the deprotection was complete, and the DP of lysine in PEG-b-PLL was also calculated using the same method as for PEG-b-PLLZ, and the value also was 18.…”

“…The degree of substitution of DMA on PLL is 72% by calculating through the peak area of MDA and PEG. The DOX content in PEG-b-P((LLg-ss-DOX)-(LL-g-DMA)) was calculated as 11.8% (weight ratio) by comparing the peak integration of the phenyl proton of DOX with that of the PEG methylene proton signal, 17,21 and the content of DOX was measured as 9.5% by the UV spectrophotometer. 39 Because of the relative accuracy of UV spectrophotometer, we finally chose 9.5% as the content of DOX.…”

“…PEG-b-PLL was synthesized by ring opening polymerization of Lys-NCA using mPEG-NH 2 as a macroinitiator according to the previous studies. 17,21,31 Briefly, Lys-NCA (3.93 g, 1.2 mM) was dissolved in 60 mL of dry DMF. Then, mPEG-NH 2 (2.0 g, 0.4 mM) was dissolved in 50 mL of dry DMF as the macroinitiator and added to Lys-NCA solution via a syringe under dry argon.…”

“…Reduced nonspecific protein adsorption of the charged nanoparticles is an important indicator for the prolonged blood circulation. 17,33 Moreover, serum protein in the blood mostly possess negative charges and readily bind onto positively charged nanoparticles through electrostatic interaction, which leads to their aggregation. 45,46 Therefore, keeping drug delivery nanoparticles negatively charged is beneficial for their stabilization in blood circulation.…”

“…15 Recently, since the nanoparticles can increase the solubility of soluble drugs, prolong circulation time in the blood, enrich the drug at tumor tissue through the enhanced permeability and retention (EPR) effect, and release drug on-demand, they have been widely used in drug delivery. [16][17][18] Moreover, the tumor microenvironment stimuli-responsive drug delivery systems have attracted great attention in cancer therapy. It is well known that the pH value varies in normal tissues and tumor tissues; the pH value in the blood and normal tissues is about pH 7.4, but the pH value in tumor tissues is slightly acidic (pH=6.5-7.2 in tumor tissues; pH=4.5-6.5 in endosomes and lysosomes).…”