Abstract
Significant efforts on the design and development of advanced drug delivery systems for targeted cancer chemotherapy continue to be a major challenge. Here, we reported a kind of reduction-responsive PEGylated doxorubicin (DOX) prodrug via the simple esterification and amidation reactions, which self-assembled into the biodegradable micelles in solutions. Since there was an obvious difference in the reduction potentials between the oxidizing extracellular milieu and the reducing intracellular fluids, these PEG–disulfide–DOX micelles were localized intracellularly and degraded rapidly by the stimulus to release the drugs once reaching the targeted tumors, which obviously enhanced the therapeutic efficacy with low side effects. Moreover, these reduction-sensitive micelles could also physically encapsulate the free DOX drug into the polymeric cargo, exhibiting a two-phase programmed drug release behavior. Consequently, it showed a potential to develop an intelligent and multifunctional chemotherapeutic payload transporter for the effective tumor therapy.
Highlights
Biodegradable nanoparticles with low side effects are intensively employed as potential candidates for the targeted tumor chemotherapy because they can promote the drug solubility in solutions, prolong the circulation time with high stability, enhance the pharmacokinetic property, keep the bioavailability, and improve the tumor accumulation and therapeutic effects by the enhanced permeability and retention (EPR) effect (Lyass et al, 2000; Lukyanov and Torchilin, 2004; Torchilin, 2006; Chao et al, 2012; Huang et al, 2018; Sun et al, 2019)
DOX-loaded carriers have been applied for many applications, they possess many inherent shortcomings like low drug loading, premature burst release, and insensitive manipulation, which are mainly attributed to the high hydrophilicity of DOX drugs
Based on the simple esterification reaction of 3,3′-dithiodipropionic acid and sequential amidation reaction of DOX, the PEG–disulfide–DOX was feasibly synthesized by the 1H Nuclear magnetic resonance (NMR) spectra
Summary
Biodegradable nanoparticles with low side effects are intensively employed as potential candidates for the targeted tumor chemotherapy because they can promote the drug solubility in solutions, prolong the circulation time with high stability, enhance the pharmacokinetic property, keep the bioavailability, and improve the tumor accumulation and therapeutic effects by the enhanced permeability and retention (EPR) effect (Lyass et al, 2000; Lukyanov and Torchilin, 2004; Torchilin, 2006; Chao et al, 2012; Huang et al, 2018; Sun et al, 2019). Low drug loading capacity and incomplete drug release greatly limited the tumor therapy because of the unpredictable drug release by physical encapsulation from the nanoparticles to the cytoplasm. Stability, drug loading, and stimuli-triggered drug release should be considered for the fabrication of intelligent carriers to improve the tumor chemotherapy. Doxorubicin (DOX) is an FDA-approved and a typical anticancer drug for the tumor treatment, but it possesses obvious disadvantages in truly clinical application, such as severe toxicity, low bioavailability, and high dose requirement. Among the various drug carriers, physical encapsulation and chemical conjugates are two main strategies for the fabrication of drug delivery. DOX-loaded carriers have been applied for many applications, they possess many inherent shortcomings like low drug loading, premature burst release, and insensitive manipulation, which are mainly attributed to the high hydrophilicity of DOX drugs. Polymer conjugates have made great progress on account of their simple architectural design, feasible preparation method, and smart functional fabrication, which provides an alternative for the cancer chemotherapy (Hu and Jing, 2009; Chytil et al, 2012; Hu et al, 2012; Li et al, 2020; Song et al, 2021)
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