Dual-responsive Polymeric Micelles Research Articles

Phenylboronic Acid-Modified pH/Glucose Dual-Responsive Polymeric Micelles for Targeted Anticancer Drug Delivery

Phenylboronic Acid-Modified pH/Glucose Dual-Responsive Polymeric Micelles for Targeted Anticancer Drug Delivery

Electric and reactive oxygen species dual-responsive polymeric micelles improve the therapeutic efficacy of lamotrigine in pentylenetetrazole kindling rats

Although nanocarriers hold great promise for treating epilepsy by improving target drug delivery, on-demand drug release remains a significant challenge. We previously developed electro-responsive brain-targeting Pluronic F127/ferrocene (Fc) modified D-α-tocopherol polyethylene glycol succinate mixed micelles (FTC) micelles to optimize the delivery of antiseizure drug lamotrigine (LTG). However, the responsive characteristics are still not fully understood and the therapeutic effect of this responsive drug delivery system in epilepsy model is yet to be confirmed. Except for electricity, we discovered that such Fc functionalized mixed micelles delivered LTG in a triggered manner precisely controlled by H2O2. Furthermore, a study on pentylenetetrazole kindling rats revealed that the as-prepared LTG-loaded FTC micelles not only improved the antiseizure effects of LTG, but also exerted antiepileptogenesis function at a much lower dose than the free formulation. Hippocampal neuron loss was also reversed after treatment with responsive micelles. Our findings show that FTC micelles are responsive to both electric and reactive oxygen species, suggesting their use as a novel vehicle for on-demand treatment of epilepsy.

NIR Activated Upper Critical Solution Temperature Polymeric Micelles for Trimodal Combinational Cancer Therapy.

The balance between drug efficiency and its side effects on normal tissues is still a challenging problem to be solved in current cancer therapies. Among different strategies, cancer therapeutic methods based on nanomedicine delivery systems have received extensive attention due to their unique advantages such as improved circulation and reduced toxicity of drugs in the body. Herein, we constructed dual-responsive polymeric micelles DOX&ALS@MFM based on an upper critical solution temperature (UCST) polymer to simultaneously combine chemotherapy, photothermal therapy (PTT), and photodynamic therapy (PDT). Amphiphilic block copolymer P(AAm-co-AN)-b-PEI-ss-PEG-FA with a critical point of 42 °C was able to self-assemble into polymeric micelles under physiological conditions, which further encapsulated anticancer drug doxorubicin (DOX) and photosensitizer ALS to obtain drug-loaded micelles DOX&ALS@MFM. Micelles aggregated at tumor sites due to folate targeting and an enhanced permeability retention (EPR) effect. After that, the high intracellular concentration of glutathione (GSH) and near-infrared (NIR) light prompted disassembly of the polymer to release DOX and ALS. ALS not only plays a role in PTT but also produces singlet oxygen, therefore killing tumor cells by PDT. Both in vitro and in vivo studies demonstrated the photothermal conversion and reactive oxygen species generation ability of DOX&ALS@MFM micelles, at the same time as the excellent inhibitory effect on tumor growth with NIR light irradiation. Thus, our research substantiated a new strategy for the biomedical application of UCST polymers in the cited triple modal tumor therapy.

Glucose-responsive oral insulin delivery platform for one treatment a day in diabetes

Glucose-responsive oral insulin delivery platform for one treatment a day in diabetes

PH and redox dual-responsive polymeric micelles with charge conversion for paclitaxel delivery

Here we demonstrate a type of pH and redox dual-responsive micelles, which were self-assembled in aqueous solution by an amphiphilic polymer, methoxypoly(ethylene glycol)-cystamine-poly(L-glutamic acid)-imidazole (mPEG-SS-PGA-IM). Considering tumor cells or tissues exhibiting low pH values and high glutathione (GSH) concentration, mPEG-SS-PGA-IM micelles possessed the charge conversion at pH of tumor tissues, which can facilitate cellular uptake of tumor cells. Furthermore, mPEG-SS-PGA-IM micelles can escape from endo/lysosomes based on the proton sponge effect, following degraded by higher concentration of GSH in cytoplasm. CLSM images of HCT116 cells indicated that mPEG-SS-PGA-IM micelles can escape from endo/lysosomes and enter cytoplasm. MTT assay showed that (paclitaxel) PTX-loaded mPEG-SS-PGA-IM micelles had higher cytotoxicity against HCT116 cells compared with PTX-loaded mPEG-PBLG and mPEG-SS-PBLG micelles. These results indicated that these mPEG-SS-PGA-IM micelles, as novel and effective pH- and redox-responsive nanocarriers, have great potential to both improve drug targeting efficiency while also enhancing the antitumor efficacy of PTX.

Glucose and H2O2 Dual-Responsive Polymeric Micelles for the Self-Regulated Release of Insulin.

In the past decades, insulin delivery systems have been widely developed for diabetes treatment. Though a few works have investigated polymeric micelles with glucose and H2O2 dual-responsiveness for the delivery of insulin, great efforts should still be devoted to enhancing the therapeutic efficacy. Herein, glucose/H2O2 dual-responsive polymeric micelles were fabricated for the self-regulated insulin delivery. The polymeric micelles were self-assembled by poly(ethylene glycol)-block-poly(amino phenylboronic ester) (PEG-b-PAPBE), where the hydrophilic PEG offered the shell and the hydrophobic PAPBE endowed the polymeric micelles with the dual-sensibility to glucose and H2O2. The built-in phenylboronic ester (PBE) could be not only broken by glucose but also hydrolyzed by H2O2, thus resulting in the disintegration of the polymeric micelles. The glucose-responsive release of insulin was achieved and could be further facilitated by the coencapsulation of glucose oxidase (GOx) in the micelles, which would produce H2O2 by catalytic oxidation of glucose and thus lead to the hydrolysis of the phenylboronic ester by H2O2. Compared with free insulin or micelles that carried insulin alone, a subcutaneous injection of the insulin/GOx-coloaded polymeric micelles to the diabetic mice presented a superior hypoglycemic effect in vivo. This kind of polymeric micelle with glucose and H2O2 dual-responsiveness provides a promising approach for diabetes therapy.

Preparation and controlled drug release ability of the poly[N-isopropylacryamide-co-allyl poly(ethylene glycol)]-b-poly(γ-benzyl-l-glutamate) polymeric micelles

The polymeric micelles were prepared through a copolymerization of allyl polyethylene glycol (APEG) and N-isopropylacrylamide in the presence of 2-aminoethanethiol (AET), followed by a ring opening polymerization of γ-benzyl-l-glutamate N-carboxyanhydride (BLG-NCA). Doxorubicin (DOX) as a model drug was covalently conjugated into the core of micelles via hydrazone bonds. The drug loading capacity could reach up to 15% with drug encapsulation efficiency of 80%. The pH/thermo sensitivities were observed in the process of in vitro drug release. The DOX-loaded micelles exhibited accelerated drug release behaviors in an acidic condition, and enhanced therapeutic efficacy was observed. Furthermore, the cytotoxicity of micelles against Hela and 3T3 cells was evaluated before and after drug loading. The DOX-loaded micelles showed strong cytotoxic activity to the cancer cells. But the blank micelles showed non-cytotoxicity. Therefore, the thermo/pH dual-responsive polymeric micelles have a promising future applied as a controlled drug delivery system for anticancer drugs.

Synthesis of high drug loading, reactive oxygen species and esterase dual-responsive polymeric micelles for drug delivery

Stimulus-responsive, controlled-release systems are of great importance in medical science and have drawn significant research attention, leading to the development of many stimulus-responsive materials over the past few decades. However, these materials are mainly designed to respond to external stimuli and ignore the key problem of the amount of drug loading. In this study, exploiting the synergistic effect of boronic esters and N-isopropylacrylamide (NIPAM) pendant, we present a copolymer as an ROS and esterase dual-stimulus responsive drug delivery system that has a drug loading of up to 6.99 wt% and an entrapment efficiency of 76.9%. This copolymer can successfully self-assemble into polymer micelles in water with a narrow distribution. Additionally, the measured CMC hinted at the good stability of the polymeric micelles in water solution, ensuing long circulation time in the body. This strategy for increasing the drug loading on the basis of stimulus response opens up a new avenue for the development of drug delivery systems.

Preparation of pH/redox dual responsive polymeric micelles with enhanced stability and drug controlled release

Stimuli-responsive polymeric micelles were prepared through self-assembly of amphiphilic copolymers poly(ethylene glycol)-poly(γ-benzyl l-glutamate), followed by a core-crosslinking reaction using cystamine as the crosslinking agent. The crosslinked micelles with spherical morphologies in nanometer size showed enhanced stability against dilution and concentrated salt solutions compared to the micelles before crosslinking. Doxorubicin (DOX) as a model drug was encapsulated into the core of micelles through electrostatic interactions between carboxylic acid and DOX. In vitro drug release under pH and redox conditions was investigated. Furthermore, the cytotoxicity of micelles was evaluated before and after drug loading. The endocytosis of DOX-loaded micelles and the intracellular drug release were studied. DOX-loaded micelles exhibited accelerated drug release behaviors in an acidic and reductive environment, and showed an inhibited premature release behavior as compared to the noncrosslinked micelles. Considering their enhanced stability, pH and redox dual triggered responsive characteristics, the polymeric micelles can serve as potential systems for controlled drug delivery.

Redox and pH Dual-Responsive Polymeric Micelles with Aggregation-Induced Emission Feature for Cellular Imaging and Chemotherapy.

Intelligent polymeric micelles for antitumor drug delivery and tumor bioimaging have drawn a broad attention because of their reduced systemic toxicity, enhanced efficacy of drugs, and potential application of tumor diagnosis. Herein, we developed a multifunctional polymeric micelle system based on a pH and redox dual-responsive mPEG-P(TPE- co-AEMA) copolymer for stimuli-triggered drug release and aggregation-induced emission (AIE) active imaging. These mPEG-P(TPE- co-AEMA)-based micelles showed excellent biocompatibility and emission property, exhibiting great potential application for cellular imaging. Furthermore, the antitumor drug doxorubicin (DOX) could be encapsulated during self-assembly process with high loading efficiency, and a DOX-loaded micelle system with a size of 68.2 nm and narrow size distribution could be obtained. DOX-loaded micelles demonstrated great tumor suppression ability in vitro, and the dual-responsive triggered intracellular drug release could be further traced. Moreover, DOX-loaded micelles could efficiently accumulate at the tumor site because of enhanced permeability and retention effect and long circulation of micelles. Compared with free DOX, DOX-loaded micelles exhibited better antitumor effect and significantly reduced adverse effects. Given the efficient accumulation targeting to tumor tissue, dual-responsive drug release, and excellent AIE property, this polymeric micelle would be a potential candidate for cancer therapy and diagnosis.