Stimuli-responsive Polymeric Micelles Research Articles

Actively Targeting Redox-Responsive Multifunctional Micelles for Synergistic Chemotherapy of Cancer.

Stimuli-responsive polymeric micelles decorated with cancer biomarkers represent an optimal choice for drug delivery applications due to their ability to enhance therapeutic efficacy while mitigating adverse side effects. Accordingly, we synthesized a digoxin-modified novel multifunctional redox-responsive disulfide-linked poly(ethylene glycol-b-poly(lactic-co-glycolic acid) copolymer (Bi(Dig-PEG-PLGA)-S2) for the targeted and controlled release of doxorubicin (DOX) in cancer cells. Within the micellar aggregate, the disulfide bond confers redox responsiveness, while the presence of the digoxin moiety acts as a targeting agent and chemosensitizer for DOX. Upon self-assembly in aqueous solution, Bi(Dig-PEG-PLGA)-S2 formed uniformly distributed spherical micelles with a hydrodynamic diameter (D h ) of 58.36 ± 0.78 nm and a zeta potential of -24.71 ± 1.01 mV. The micelles exhibited desirable serum and colloidal stability with a substantial drug loading capacity (DLC) of 6.26% and an encapsulation efficiency (EE) of 83.23%. In addition, the release of DOX demonstrated the redox-responsive behavior of the micelles, with approximately 89.41 ± 6.09 and 79.64 ± 6.68% of DOX diffusing from DOX@Bi(Dig-PEG-PLGA)-S2 in the presence of 10 mM GSH and 0.1 mM H2O2, respectively, over 96 h. Therefore, in HeLa cell lines, DOX@Bi(Dig-PEG-PLGA)-S2 showed enhanced intracellular accumulation and subsequent apoptotic effects, attributed to the targeting ability and chemosensitization potential of digoxin. Hence, these findings underscore the promising characteristics of Bi(Dig-PEG-PLGA)-S2 as a multifunctional drug delivery vehicle for cancer treatment.

Stimuli-responsive polymeric micelles based on cellulose derivative containing imine groups with improved bioavailability and reduced aquatic toxicity of pyraclostrobin

Stimuli-responsive polymeric micelles based on cellulose derivative containing imine groups with improved bioavailability and reduced aquatic toxicity of pyraclostrobin

Application of Different Stimuli-Responsive Polymeric Micelles for Drug Release

Achieving controlled release of drugs in disease treatment can greatly improve the utilization rate and therapeutic effect of drugs. Therefore, the development of functional materials with controllable drug release has received more and more attention, such as stimuli-responsive polymeric micelles. The so-called stimuli-responsive polymeric micelles are a new type of polymer micelles that can be used to give responses to different stimulus conditions, such as endogenous stimuli (e.g. light, temperature, ultrasound intensity, magnetic field or electric field) and exogenous stimuli (e.g. redox potential, pH, or enzyme concentration). They can exhibit distinctive size and stability with the variations of the endogenous or exogenous environment. Stimuli-responsive polymeric micelles have several desirable biotechnology applications including their potential use as drug delivery vehicles because tumor tissue and normal tissue is different in physical and chemical properties, where they are very sensitive to endogenous or exogenous environmental changes. This research would mainly discuss different stimuli-responsive polymeric micelles for developing a diverse of drug delivery systems, including light and magnetism response, temperature and ultrasound response, redox response, pH response and enzyme response. Some recent advances and future directions would be briefly referred to as well.

Light- and Redox-Responsive Block Copolymers of mPEG-SS-ONBMA as a Smart Drug Delivery Carrier for Cancer Therapy.

The development of stimuli-responsive polymeric micelles for targeted drug delivery has attracted much research interest in improving therapeutic outcomes. This study designs copolymers responsive to ultraviolet (UV) light and glutathione (GSH). A disulfide linkage is positioned between a hydrophilic poly(ethylene glycol) monomethyl ether (mPEG) and a hydrophobic o-nitrobenzyl methacrylate (ONBMA) to yield amphiphilic copolymers termed mPEG-SS-pONBMA. Three copolymers with different ONBMA lengths are synthesized and formulated into micelles. An increase in particle size and a decrease in critical micelle concentration go together with increasing ONBMA lengths. The ONB cleavage from mPEG-SS-pONBMA-formed micelles results in the transformation of hydrophobic cores into hydrophilic ones, accelerating drug release from the micelles. Obvious changes in morphology and molecular weight of micelles upon combinational treatments account for the dual-stimuli responsive property. Enhancement of a cell-killing effect is clearly observed in doxorubicin (DOX)-loaded micelles containing disulfide bonds compared with those containing dicarbon bonds upon UV light irradiation. Collectedly, the dual-stimuli-responsive mPEG-SS-pONBMA micelle is a better drug delivery carrier than the single-stimuli-responsive mPEG-CC-pONBMA micelle. After HT1080 cells were treated with the DOX-loaded micelles, the high expression levels of RIP-1 and MLKL indicate that the mechanism involved in cell death is mainly via the DOX-induced necroptosis pathway.

Enhanced delivery of artesunate by stimuli-responsive polymeric micelles for lung tumor therapy

Artesunate (ART) as a traditional chinese medicine has been reported to have a good antitumor effect on some cancers. However, the poor hydrophilicity and instability in the intestine limit its bioavailability and further application. Herein, this work reported a redox-sensitive micelle system encapsulating ART to enhance the therapeutic effect on lung tumor. Specifically, K5 capsular polysaccharide-SS-d-α-tocopheryl succinate (K5-SS-TOS, KSST) copolymers can self-assemble to form micelles and effectively load ART into the hydrophobic core. Simultaneously, redox-insensitive K5 capsular polysaccharide-d-α-tocopheryl succinate (K5-TOS, KT) copolymers were synthesized as control. ART-loaded micelles (ART/KSST) with a spherical particle size had good polydispersity. The drug loading content and entrapment efficiency of the ART/KSST were (13.5 ± 0.92) % and (81.09 ± 2.61) %, respectively. Moreover, ART/KSST can release ART quickly in the presence of glutathione, showing a good redox release behavior. In addition, the ART loaded micelles had negligible toxicity to normal cells. However, ART/KSST which can be uptaken through energy-dependent pathways by A549 cells showed higher cytotoxicity than ART/KT. The results suggested that disulfide bond can be ruptured in the tumor cells, resulting in disintegration of the micelle structure and fast release of ART to achieve better therapeutic effect. Therefore, the redox-sensitive KSST copolymers as potential nanocarriers can deliver ART effectively to improve the therapeutic effect of lung tumors.

Polymeric micelles for anticancer drug delivery.

Polymeric micelles have gained interest as novel drug delivery systems for the treatment and diagnosis of cancer, as they offer several advantages over conventional drug therapies. This includes drug targeting to tumor tissue, in vivo biocompatibility and biodegradability, prolonged circulation time, enhanced accumulation, retention of the drug loaded micelle in the tumor and decreased side effects. This article provides an overview on the current state of micellar formulations as nanocarriers for anticancer drugs and their effectiveness in cancer therapeutics, including their clinical status. The type of copolymers used, their physicochemical properties and characterization as well as recent developments in the design of functional polymeric micelles are highlighted. The article also presents the design and outcomes of various types of stimuli-responsive polymeric micelles.

Tumor Microenvironment Stimuli-Responsive Polymeric Prodrug Micelles for Improved Cancer Therapy.

The discovery of nano drug delivery system has rendered a great hope for improving cancer therapy. However, there are some inevitable obstacles that constrain its development, such as the physical and biological barriers, the toxicity of carrier materials and the physiological toxicity of drugs. Here, we report a polymeric prodrug micelle (PPM) with pH/redox dual-sensitivity, which was prepared using methoxy poly (ethylene glycol) (mPEG) with favorable biosafety to improve cancer therapy. The tumor microenvironment stimuli-responsive PPMs were prepared and characterized in vitro and in vivo. Our data displayed that the PPMs with excellent biocompatibility exhibited the stimuli-responsive drug release behavior under the microenvironment of cancer cells, superior cellular internalization and lower cytotoxicity. A new method to control drug release behavior was proposed by comparing the release behavior of PPMs formed by PEG of different molecular weight. Furthermore, the fabricated PPMs exhibited the "oral-like" blood concentration curve, improved biodistribution, reduced tissue toxicity and excellent antitumor efficiency in vivo. Consistently, these results indicated that PPMs improved chemotherapeutic efficiency and reduced side effects of the model drug doxorubicin (DOX). The prepared pH/redox dual-sensitive PPM enhanced the chemotherapy effect on the tumor site while reducing the physiological toxicity of DOX. Graphical Abstract.

Dual pH/Redox-Responsive Mixed Polymeric Micelles for Anticancer Drug Delivery and Controlled Release.

Stimuli-responsive polymeric micelles (PMs) have shown great potential in drug delivery and controlled release in cancer chemotherapy. Herein, inspired by the features of the tumor microenvironment, we developed dual pH/redox-responsive mixed PMs which are self-assembled from two kinds of amphiphilic diblock copolymers (poly(ethylene glycol) methyl ether-b-poly(β-amino esters) (mPEG-b-PAE) and poly(ethylene glycol) methyl ether-grafted disulfide-poly(β-amino esters) (PAE-ss-mPEG)) for anticancer drug delivery and controlled release. The co-micellization of two copolymers is evaluated by measurement of critical micelle concentration (CMC) values at different ratios of the two copolymers. The pH/redox-responsiveness of PMs is thoroughly investigated by measurement of base dissociation constant (pKb) value, particle size, and zeta-potential in different conditions. The PMs can encapsulate doxorubicin (DOX) efficiently, with high drug-loading efficacy. The DOX was released due to the swelling and disassembly of nanoparticles triggered by low pH and high glutathione (GSH) concentrations in tumor cells. The in vitro results demonstrated that drug release rate and cumulative release are obviously dependent on pH values and reducing agents. Furthermore, the cytotoxicity test showed that the mixed PMs have negligible toxicity, whereas the DOX-loaded mixed PMs exhibit high cytotoxicity for HepG2 cells. Therefore, the results demonstrate that the dual pH/redox-responsive PMs self-assembled from PAE-based diblock copolymers could be potential anticancer drug delivery carriers with pH/redox-triggered drug release, and the fabrication of stimuli-responsive mixed PMs could be an efficient strategy for preparation of intelligent drug delivery platform for disease therapy.

Recent advances in stimuli-responsive polymeric micelles via click chemistry

Stimuli-responsive polymeric micelles via click chemistry are divided into six major sections (temperature, light, ultrasound, pH, enzymes, and redox).

PH-responsive polymeric micelles with tunable aggregation-induced emission and controllable drug release

Stimuli-responsive polymeric micelles as a drug delivery vehicle have made important contributions to the development of controllable drug release. Here we develop pH-responsive polymeric micelles with tunable aggregation-induced emission and controllable drug release. Polymeric micelles in nano-sized spherical shape (about 140 nm) were mediated via hydrogen-bonding interaction between phenol groups of 4,4′-(1,2-diphenylethene-1,2-diyl)diphenol (TPE-2OH) and amine groups of poly(ethylene glycol)-block-linear polyethylenimine-block-poly(e-caprolactone) (PEG-PEI-PCL). The results show that polymeric micelles are pH-responsive with turn-on fluorescence and sustained drug release inside cells, which has hope in simultaneously achieving cell imaging and cancer therapy.

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.

Stimuli-responsive polymeric micelles for drug delivery and cancer therapy.

Polymeric micelles (PMs) have been widely investigated as nanocarriers for drug delivery and cancer treatments due to their excellent physicochemical properties, drug loading and release capacities, facile preparation methods, biocompatibility, and tumor targetability. They can be easily engineered with various functional moieties to further improve their performance in terms of bioavailability, circulation time, tumor specificity, and anticancer activity. The stimuli-sensitive PMs capable of responding to various extra- and intracellular biological stimuli (eg, acidic pH, altered redox potential, and upregulated enzyme), as well as external artificial stimuli (eg, magnetic field, light, temperature, and ultrasound), are considered as “smart” nanocarriers for delivery of anticancer drugs and/or imaging agents for various therapeutic and diagnostic applications. In this article, the recent advances in the development of stimuli-responsive PMs for drug delivery, imaging, and cancer therapy are reviewed. The article covers the generalities of stimuli-responsive PMs with a focus on their major delivery strategies and newly emerging technologies/nanomaterials, discusses their drawbacks and limitations, and provides their future perspectives.

Dual-stimuli responsive polymeric micelles: preparation, characterization, and controlled drug release

The preparation of stimuli-responsive polymeric micelles sensitive to both temperature and UV irradiation is achieved through the self-assembly from a series of amphiphilic block copolymers, poly(triethylene glycol methacrylate)-b-poly(2-nitrobenzyl methacrylate) (PTEGMA-b-PNBMA). The block ratios of the hydrophilic and thermo-responsive PTEGMA block to the hydrophobic and photoclevable PNBMA block are manipulated in the range of 4:1 to 1:1. The nanostructure and stimuli-responsive properties of the micelles are well-correlated with the chemical structures of the copolymers. The thermal transition temperature of micelles is reduced to 38–41 °C and close to body temperature as compared to that of PTEGMA homopolymer around 52 °C. After UV irradiation, the enhanced hydrophilicity of micelle core causes swelling and increased size of micelles. The capabilities of these micelles for drug encapsulation are demonstrated by using doxorubicin as the model drug and the subsequent drug release could be triggered by elevated temperature and/or UV irradiation. Furthermore, the potential application of these micelles in controlled drug release is explored by studying the in vitro cytotoxicity of drug-loaded micelles as triggered by external stimuli.

Synthesis of amphiphilic polyethylene-b-poly(l-glutamate) block copolymers with vastly different solubilities and their stimuli-responsive polymeric micelles in aqueous solution

This paper describes the synthesis, characterization, and self-assembly behavior of amphiphilic polyethylene-block-poly(l-glutamate) (PE-b-PGA) diblock copolymers. PE-b-PGA diblock copolymers were obtained by ring-opening polymerization (ROP) of γ-benzyl-l-glutamate-N-carboxyanhydride (BLG-NCA) using PE–COOCH(iPr)NH2 as a macroinitiator and subsequent deprotection of the benzylester groups. The self-assembly behaviors of the PE-b-PGA copolymers in water were studied as a function of pH and ionic strength by means of fluorescence spectroscopy, laser light scattering, UV-circular dichroism, and transmission electron microscopy. The size of the polymeric micelles decreases with a decreasing pH value even at high salt concentrations because the solvating PGA units can perform a coil-to-helix transition.

Multiple stimuli-responsive polymeric micelles for controlled release

Multiple stimuli-responsive polymeric micelles that can respond to light, temperature and pH have been prepared by a novel polymer, pyrene-functionalized poly (dimethylaminoethyl methacrylate), where the pyrene-quaternized segments form a light-responsive shell and the unquaternized segments form a temperature/pH-responsive core. Under UV irradiation, the micelles could be dissociated; when the temperature increased above the lower critical solution temperature, the micelles shrunk. At pH 3, the micelles could be swelled/dissociated and at pH 10, the micelles could be collapsed to complex micelles. The controlled release of Nile Red from the micelle under stimuli was demonstrated. This novel multiple stimuli-responsive micelle shows potential as a new nanocarrier and delivery system.

Aqueous polymeric micelles of poly[N-isopropylacrylamide-b-sodium 2-(acrylamido)-2-methylpropanesulfonate] with a spiropyran dimer pendant: quadruple stimuli-responsiveness

Poly[N-isopropylacrylamide-b-sodium 2-(acrylamido)-2-methylpropane sulfonate] tagged with a spiropyran dimer at the poly(N-isopropylacrylamide) end (SP2-b-NIPAM154-b-AMPS148) was synthesized by reversible addition–fragmentation chain transfer (RAFT) polymerization to investigate multiple stimuli-responsive micelles. The micelles formed in aqueous solutions were stimulated by various chemical and physical stimuli and characterized by dynamic light scattering, scanning electron microscopy, transmission electron microscopy, UV-Vis spectroscopy and ζ-potential measurements. It was found that the block copolymer is responsive to four different types of stimulus viz. light, temperature, metal ion and pH. The NIPAM154 block gives thermo-responsiveness to the block copolymer and the AMPS148 block shows metal ion responsiveness. Due to the presence of the photochromic spiropyran moiety, the block copolymer also shows light and thermo-responsiveness. To the best of our knowledge this is the first report that deals with quadruple stimuli-responsive polymeric micelles. Such quadruple stimuli-responsive block copolymer micelles are expected to open up new applications in a variety of fields.

New approaches to stimuli-responsive polymeric micelles and hollow spheres

This article briefly describes some new approaches to stimuli-sensitive polymeric micelles and hollow spheres, which were developed in the authors’ laboratory in recent years. (1) Self-assembly of component polymers to non-covalently connected micelles (NCCM) driven by specific interactions. For example, in water, PCL and PAA formed core-shell nanospheres due to interpolymer hydrogen bonding. After crosslinking the PAA shell and removing the PCL core, “nanocages” made of PAA network were obtained. This hollow structure shows perfect reversible size-pH dependence. (2) Simultaneous in-situ polymerization of monomers and self-assembly of the polymers. In this approach, PNIPAM network was formed by radical polymerization covering PCL particles. Hollow spheres of PNIPAM network were then obtained by biodegradation of the PCL core. Both the core-shell spheres and hollow spheres show reversible size dependence on temperature change because of the phase transition of PNIPAM around 32°C. (3) Complexation-induced micellization and transition between the micelles and hollow spheres. Graft copolymers of hydroxylethyl cellulose (HEC) and PAA were prepared by free radical polymerization. The copolymers showed pH dependent micellization, i.e., micelles formed when pH of the graft copolymer solution decreased to around 3. The micellar structure could be locked by crosslinking the PAA grafts. The resultant cross-linked micelles undergo pH-dependent transition between the micelles and hollow spheres, which accompanies a remarkable particle size change. Both the micellization and the structure transition were found to be reversible and associated with H-bonding complexation between the main chain and grafts.

Intelligent thermoresponsive polymeric micelles for targeted drug delivery

Nano-order sized supramolecular assemblies called polymeric micelles possess two-separated phase structure; a hydrated hydrophilic outer shell provides their highly structural stabilities in aqueous media and a hydrophobic inner core acts as a drug loading container. First anticancer polymeric micelle carrier systems showed a selective accumulation at solid tumor tissues and a subsequent in vivo anticancer activity. Recently, stimuli-responsive polymeric micelles have been designed as the next generation of micelle systems for application in selective drug release at target sites by physical and/or chemical signals. We suggested a concept using thermoresponsive polymeric micelle drug carriers in conjunction with local heating systems for multi-targeting therapeutic systems to achieve effective cancer chemotherapy with fewer side effects. The present review article mainly focuses on strategy and molecular design of thermoresponsive polymeric micelles and discusses their potential for an intelligent targeted drug carrier system with some examples containing anti-cancer drugs.