Abstract
In this work, we prepared pH/redox dual-responsive mixed polyprodrug micelles (MPPMs), which were co-assembled from two polyprodrugs, namely, poly(ethylene glycol) methyl ether-b-poly (β-amino esters) conjugated with doxorubicin (DOX) via redox-sensitive disulfide bonds (mPEG-b-PAE-ss-DOX) and poly(ethylene glycol) methyl ether-b-poly (β-amino esters) conjugated with DOX via pH-sensitive cis-aconityl bonds (mPEG-b-PAE-cis-DOX) for effective anticancer drug delivery with enhanced therapeutic efficacy. The particle size of MPPMs was about 125 nm with low polydispersity index, indicating the reasonable size and uniform dispersion. The particle size, zeta-potential, and critical micelle concentration (CMC) of MPPMs at different mass ratios of the two kinds of polyprodrugs were dependent on pH value and glutathione (GSH) level, suggesting the pH and redox responsiveness. The drug release profiles in vitro of MPPMs at different conditions were further studied, showing the pH—and redox-triggered drug release mechanism. Confocal microscopy study demonstrated that MPPMs can effectively deliver doxorubicin molecules into MDA-MB-231 cells. Cytotoxicity assay in vitro proved that MPPMs possessed high toxic effect against tumor cells including A549 and MDA-MB-231. The results of in vivo experiments demonstrated that MPPMs were able to effectively inhibit the tumor growth with reduced side effect, leading to enhanced survival rate of tumor-bearing mice. Taken together, these findings revealed that this pH/redox dual-responsive MPPMs could be a potential nanomedicine for cancer chemotherapy. Furthermore, it could be a straightforward way to fabricate the multifunctional system basing on single stimuli-responsive polyprodrugs.
Highlights
In clinical practice, chemotherapy is still one of the most common strategies for cancer treatment (Galluzzi et al, 2015; Srinivasan et al, 2018; Men et al, 2019), some emerging therapies like immunotherapy have been recently raised (Chen et al, 2016; Nam et al, 2019; Wang et al, 2019; Yan et al, 2019)
In this work, inspired by the specific acidic pH and high GSH level in tumor microenvironment (TME), we developed a multifunctional system for drug delivery with pH/redox dual-triggered drug release property based on two polyprodrugs: methyl ether poly(ethylene glycol)-b-poly(β-amino esters) conjugated with DOX via pHsensitive acid-labile cis-aconityl moiety and methyl ether poly(ethylene glycol)-b-poly(βamino esters) conjugated with DOX via GSH-sensitive disulfide bond
A pH/redox dual-responsive mixed polyprodrug micelles (MPPMs) system self-assembled from pH-sensitive polyprodrug mPEG-b-PAEcis-DOX and redox-responsive polyprodrug mPEG-b-PAE-ssDOX at different mass ratios were prepared and used for drug delivery with improved therapeutic efficacy and reduced side effect
Summary
Chemotherapy is still one of the most common strategies for cancer treatment (Galluzzi et al, 2015; Srinivasan et al, 2018; Men et al, 2019), some emerging therapies like immunotherapy have been recently raised (Chen et al, 2016; Nam et al, 2019; Wang et al, 2019; Yan et al, 2019). Polyprodrug Micelles for Cancer Chemotherapy cardiotoxicity, leading to severe reverse effects and poor therapeutic efficiency due to the low bioavailability (Shabalala et al, 2017; Mao et al, 2019). To overcome these obstacles, drug delivery systems (DDSs), which could be a promising approach to address these issues, have attracted more and more attention in these decades (Bauri et al, 2018; Talebian et al, 2018). Xiao et al reported a polyprodrug based on poly(disulfide) conjugated with DOX on the polymer side chains that exhibited glutathione depletion and cascade DOX activation for drug resistance reversal to improve cancer therapy (Xiao et al, 2021)
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