An Integrated Tumor Microenvironment Responsive Polymeric Micelle for Smart Drug Delivery and Effective Drug Release

Abstract

Tumor microenvironment (TME) responsive polymeric micelles are promising carriers for drug delivery. In order to meet the needs of various applications, multifarious TME-responsive switches are used to construct smart polymeric micelles, which causes the complexity and corpulence of the polymeric micelle system and increases the difficulty of preparation. In this study, we designed and synthesized an ingenious TME-responsive switch through grafting disulfide bond-modified piperidinepropionic acid (CPA) on copolymer poly(ethylene glycol)-b-poly(aspartate)(PEG-b-PAsp) and built a novel pH/reduction-responsive PEG-b-PAsp-g-CPA polymeric micelle delivery system. The CPA-pendants can reverse the surface charge of the polymeric micelle from negative to positive at pH 6.5 because of the protonation of piperidine groups, thereby enhancing the internalization of cell. Subsequently, more piperidine groups are protonated at pH 5.0 which will increase the hydrophilicity of polymeric micelles and cause the hydrophobic core to swell, thus making the disulfide bonds packed in the core to be more easily broken by GSH. With the synergistic effect of the pH-triggered protonation of piperidine groups and reduction triggered break of disulfide bonds, the polymeric micelles will disintegrate and achieve efficient intracellular drug release. The TME-responsive polymeric micelles exhibited good biological safety, enhanced internalization, and rapid intracellular doxorubicin (DOX) release in vitro. Moreover, the PEG-b-PAsp-g-CPA/DOX polymeric micelles showed excellent antitumor efficacy and low systemic toxicity in lung tumor-bearing BALB/C mice. These results indicated that the novel integrated TME-responsive switch CPA helps the PEG-b-PAsp-g-CPA polymeric micelles to obtain excellent TME-responsiveness and antitumor drug delivery capabilities, while it also makes the preparation of TME-responsive polymeric micelles simpler and more convenient. This work provides a new idea for the architecture of TMEresponsive polymeric micelles.

Synthesis and Characterization of Linear Polyglycidol Derivatives: Surface Activity and Potential for Advanced Doxorubicin Delivery Application

“…Confocal laser scanning microscopy (CLSM, TCS-SP5, Leica) was used to examine the intracellular transportation of the drug following endocytosis . Briefly, HepG2 cells were planted in confocal dishes (BS-15-GJM, Biosharp).…”

“…Confocal laser scanning microscopy (CLSM, TCS-SP5, Leica) was used to examine the intracellular transportation of the drug following endocytosis. 28 Briefly, HepG2 cells were planted in confocal dishes (BS-15-GJM, Biosharp). After incubation (24 h), the free DOX and DOX@LPGE-SS-n micelles (DOX-equivalent dose: 10 μg/mL) were added.…”

“…In cancer-related drug carrier development, the disulfide bond has been of particular interest as it cleaves to thiols under a high glutathione (GSH) concentration in cancer cells. Therefore, these moieties are commonly embedded into the hydrophobic part of anticancer drug-carrying polymers. − Herein, we present the synthesis and evaluation of GSH-responsive amphiphilic comb-like copolymers derived from an LPG backbone (as shown in Scheme ). A thorough investigation of their surface-active properties and solubilization capacity on selected insoluble drugs was conducted, resulting in the successful establishment of a comprehensive structure–surfactant property profile.…”

Cell membrane biomimetic nanomedicines for cancer phototherapy

“…After the cell membrane biomimetic nanomaterials are loaded with drugs, the properties of TME (e.g., acidity, high concentration of H 2 O 2 , and reduced glutathione) and light-triggered methods can be used to control drug release. 105 In 2017, Peng et al 97 constructed a biomimetic nanoparticle (PBMn-DOX@RBC) based on H 2 O 2 and acidic environment response to relieve tumor hypoxia and control drug release. Among them, Prussian blue/manganese dioxide (PBMn) nanoparticles could not only serve as a H 2 O 2 catalyst and DOX carrier, but also have strong absorption in the NIR region, which could be used for PTT.…”

Self-Immolative and Amphiphilic Poly(benzyl ether)-Based Copolymers: Synthesis and Triggered Demicellization via Head-to-Tail Depolymerization

“…Hence, copolymer surfactants have been typically designed to comprise labile groups in the backbone, which are then selectively cleaved when exposed to specific stimuli. The cleavable linkers of recent interest include disulfide, − o -nitrobenzyl, , acetal, ester, , carbonate, N -nitrosoamine, and benzoquinone moieties. However, these polymers randomly degrade to generate numerous uncontrolled reaction products, and inevitably, additional stimuli are consistently required during multiplicative cleavage reactions.…”