Metallo‐Supramolecular Nanogels for Intracellular pH‐Responsive Drug Release

A simple process is developed to fabricate metallo‐supramolecular nanogels (MSNs) by the metallo‐supramolecular‐coordinated interaction between histidine and iron‐meso‐tetraphenylporphin. MSNs are composed of histidine‐modified dextran (DH) and iron‐meso‐tetraphenylporphin (Fe–Por) and exhibit excellent biocompatibility and stability. MSNs show pH responsiveness in the intracellular mildly acidic environment, which has great potential for acid‐triggered drug release delivery. In vitro drug release profiles demonstrate that the pH‐dependent disassembly of MSNs to histidine and Por results in a quicker release rate of loaded‐DOX at pH 5.3, while at pH 7.4 MSNs could hinder the release of loaded‐DOX due to the enhanced stability of MSNs.

     

Surfactant‐Free Emulsion‐Based Preparation of Redox‐Responsive Nanogels

A surfactant‐free emulsion‐based approach is developed for preparation of nanogels. A water‐in‐oil emulsion is generated feasibly from a mixture of water and a solution of disulfide‐containing hyperbranched PEGylated poly(amido amine)s, poly(BAC2‐AMPD1)‐PEG, in chloroform. The water droplets in the emulsion are stabilized and filled with poly(BAC2‐AMPD1)‐PEG, and the crosslinked poly(amido amine)s nanogels are formed via the intermolecular disulfide exchange reaction. FITC‐dextran is loaded within the nanogels by dissolving the compound in water before emulsification. Transmission electron microscopy and dynamic light scattering are applied to characterize the emulsion and the nanogels. The effects of the homogenization rate and the ratio of water/polymer are investigated. Redox‐induced degradation and FITC‐dextran release profile of the nanogels are monitored, and the results show efficient loading and redox‐responsive release of FITC‐dextran. This is a promising approach for the preparation of nanogels for drug delivery, especially for neutral charged carbohydrate‐based drugs.

     

A Comprehensive Outlook of Synthetic Strategies and Applications of Redox‐Responsive Nanogels in Drug Delivery

Increasing recognition of the role of oxidative stress in the pathogenesis of many clinical conditions and the existence of defined redox potential in healthy tissues has led to extensive research in the development of redox‐responsive materials for biomedical applications. Especially, considerable growth has been seen in the fabrication of polymeric nanogel–based drug delivery carriers utilizing redox‐responsive cross‐linkers bearing a variety of functional groups via various synthetic strategies. Redox‐responsive polymeric nanogels provide an advantage of facile chemical modification post synthesis and exhibit a remarkable response to biological redox stimuli. Due to the interdisciplinary nature of the subject, a more profound combined conceptual knowledge from a chemical and biological point of view is imperative for the rational design of redox‐responsive nanogels. The present review provides an insight into the design and fabrication of redox‐responsive nanogels with particular emphasis on synthetic strategies utilized for the development of redox‐responsive cross‐linkers, polymerization techniques being followed for nanogel development and biomedical applications. Cooperative effect of redox trigger with other stimuli such as pH and temperature in the evolution of dual and triple stimuli‐responsive nanogels is also discussed.     

Four‐fold Channel‐Nicked Human Ferritin Nanocages for Active Drug Loading and pH‐Responsive Drug Release

Human ferritins are emerging platforms for non‐toxic protein‐based drug delivery, owing to their intrinsic or acquirable targeting abilities to cancer cells and hollow cage structures for drug loading. However, reliable strategies for high‐level drug encapsulation within ferritin cavities and prompt cellular drug release are still lacking. Ferritin nanocages were developed with partially opened hydrophobic channels, which provide stable routes for spontaneous and highly accumulated loading of Fe^II‐conjugated drugs as well as pH‐responsive rapid drug release at endoplasmic pH. Multiple cancer‐related compounds, such as doxorubicin, curcumin, and quercetin, were actively and heavily loaded onto the prepared nicked ferritin. Drugs on these minimally modified ferritins were effectively delivered inside cancer cells with high toxicity.     

Redox‐ and pH‐Responsive Cysteamine‐Modified Poly(aspartic acid) Showing a Reversible Sol–Gel Transition

Synthesis and characterization of a pH‐ and redox‐sensitive hydrogel of poly(aspartic acid) are reported. Reversible gelation and dissolution are achieved both in dimethylformamide and in aqueous medium via a thiol‐disulphide interconversion in the side chain of the polymers. Structural changes are confirmed by Raman microscopy and rheological measurements. Injectable aqueous solutions of thiolated poly(aspartic acid) can be converted into mechanically stable gels by oxidation, which can be useful for drug encapsulation and targeted delivery. Reduction‐facilitated release of an entrapped drug from disulphide cross‐linked hydrogels is studied.

     

Mild Oxidation of Thiofunctional Polymers to Cytocompatible and Stimuli‐Sensitive Hydrogels and Nanogels

Nanogels consist of three dimensionally cross‐linked hydrophilic polymer chains and can thus be easily modified through functionalization of the polymeric building blocks, for example to yield stimuli‐sensitive materials. For drug transport and intracellular release, redox‐sensitive systems are especially of interest, as the intracellular space is reductive. In this study, parameters that allow preparation of nanogels with tunable size between 150 and 350 nm are systematically evaluated and identified. Most importantly, a new and mild oxidation catalyst, alloxan, is introduced for the preparation of the nanogels. This broadens the range of possible payloads to more‐sensitive molecules. Particle stability, degradation in cytosolic conditions, and cytocompatibility in concentrations up to 10 mg · mL^?1 are demonstrated.

     

In Situ Probing Intracellular Drug Release from Redox‐Responsive Micelles by United FRET and AIE

Redox‐responsive micelles are versatile nanoplatforms for on‐demand drug delivery, but the in situ evaluation of drug release is challenging. Fluorescence resonance energy transfer (FRET) technique shows potential for addressing this, while the aggregation‐caused quenching effect limits the assay sensitivity. The aim of the current work is to combine aggregation‐induced emission (AIE) probe with FRET to realize drug release assessment from micelles. Tetraphenylethene (TPE) is selected as AIE dye and curcumin (Cur) is chosen as the model drug as well as FRET receptor. The drug is covalently linked to a block copolymer via the disulfide bond linker and TPE is also chemically linked to the polymer via an amide bond; the obtained amphiphilic polymer conjugate self‐assembles into micelles with a hydrodynamic size of ≈125 nm. Upon the supplement of glutathione or tris(2‐carboxyethyl)phosphine) trigger (10 × 10⁻³m ), the drug release induces the fluorescence increase of both TPE and Cur. Accompanied with the FRET decay, absorption enhancement and particle size increase are observed. The same phenomenon is observed in MCF‐7 cells. The FRET–AIE approach can be a useful addition to the spectrum of available methods for monitoring drug release from stimuli‐responsive nanomedicine.     

Degradable Cationic Nanohydrogel Particles for Stimuli‐Responsive Release of siRNA

Well‐defined nanogels have become quite attractive as safe and stable carriers for siRNA delivery. However, to avoid nanoparticle accumulation, they need to provide a stimuli‐responsive degradation mechanism that can be activated at the payload's site of action. In this work, the synthetic concept for generating well‐defined nanohydrogel particles is extended to incorporate disulfide cross‐linkers into a cationic nanonetwork for redox‐triggered release of oligonucleotide payload as well as nanoparticle degradation under reductive conditions of the cytoplasm. Therefore, a novel disulfide‐modified spermine cross‐linker is designed that both allows disassembly of the nanogel as well as removal of cationic charge from residual polymer fragments. The degradation process is monitored by scanning electron microscopy (SEM) and fluorescence correlation spectroscopy (FCS). Moreover, siRNA release is analyzed by agarose gel electrophoresis and a fluorescent RNA detection assay. The results exemplify the versatility of the applied nanogel manufacturing process, which allows alternative stimuli‐responsive core cross‐linkers to be integrated for triggered oligonucleotide release as well as effective biodegradation for reduced nanotoxicity.

     

Redox‐Responsive Micelles with Cores Crosslinked via Click Chemistry

Redox‐responsive micelles with cores crosslinked via click chemistry are developed to improve the stability of polymer micelles. Amphiphilic block copolymer mPEG‐b‐P(DTC‐ADTC) with pendant azido groups on the hydrophobic chains is synthesized by the ring‐opening polymerization of 2,2‐bis(azidomethyl)trimethylene carbonate (ADTC) and 2,2‐dimethyltrimethylene carbonate (DTC) with monomethoxy poly(ethylene glycol) (mPEG) as an initiator. mPEG‐b‐P(DTC‐ADTC) self‐assemble to form the micelles in aqueous solution and the cores of the micelles are crosslinked via click chemistry to afford redox‐responsive core‐crosslinked micelles. Core‐crosslinking enhances the stability of the micelles in aqueous solution and improve the drug‐loading property. The redox‐responsive core‐crosslinked micelles can be reduced by the addition of reducing agents such as dithiothreitol (DTT), and thus release the loaded drug quickly in the presence of DTT.

     

Glucose and pH Dual‐Responsive Nanogels for Efficient Protein Delivery

Direct delivery of protein suffers from their in vitro and in vivo instability, immunogenicity, and a relatively short half‐life within the body. To overcome these challenges, pH and glucose dual‐responsive biodegradable nanogels comprised of dextran and poly(L‐glutamic acid)‐g‐methoxy poly‐(ethylene glycol)/phenyl boronic acid (PLG‐g‐mPEG/PBA) are designed. The cross‐linked network imparted drug‐loading efficacy of α‐amylase up to 55.6% and hyaluronidase up to 29.1%. In vitro protein release profiles reveal that the release of protein is highly dependent on the pH or glucose concentrations, that is, less amount of protein is released at pH 7.4 or healthy blood glucose level (1 mg mL^?1 glucose), while quicker release of protein occurs at pH 5.5 or diabetic blood glucose level (above 3 mg mL^?1 glucose). Circular dichroism spectra show that the secondary structure of released protein is maintained compared to naive protein. Overall, the nanogels have provided a simple and effective strategy to deliver protein.     

One‐Pot Synthesis of Redox‐Responsive Polymers‐Coated Mesoporous Silica Nanoparticles and Their Controlled Drug Release

A versatile one‐pot strategy for the preparation of reversibly cross‐linked polymer‐coated mesoporous silica nanoparticles (MSNs) via surface reversible addition–fragmentation chain transfer (RAFT) polymerization is presented for the first time in this paper. The less reactive monomer oligo(ethylene glycol) acrylate (OEGA) and the more reactive cross‐linker N,N′‐cystaminebismethacrylamide (CBMA) are chosen to be copolymerized on the external surfaces of RAFT agent‐functionalized MSNs to form the cross‐linked polymer shells. Owing to the reversible cleavage and restoration of disulfide bonds via reduction/oxidation reactions, the polymer shells can control the on/off switching of the nanopores and regulate the drug loading and release. The redox‐responsive release of doxorubicin (DOX) from this drug carrier is realized. The protein adsorption, in vitro cytotoxicity assays, and endocytosis studies demonstrate that this biocompatible vehicle is a potential candidate for delivering drugs. It is expected that this versatile grafting strategy may help fabricate satisfying MSN‐based drug delivery systems for clinical application.

     

Controlled Release of a Sparingly Water‐Soluble Anticancer Drug through pH‐Responsive Functionalized Gold‐Nanoparticle‐Decorated Liposomes

The binding and detachment of carboxyl‐modified gold nanoparticles from liposomes is used for controlled drug delivery. This study reveals that the binding and detachment of nanoparticles from liposomes depends on the degree of hydration of the liposomes. Liposomes with a lower hydration level undergo stronger electrostatic interactions with negatively charged gold nanoparticles, thus leading to a slower detachment of the carboxyl‐modified gold nanoparticles under gastric conditions. Therefore, under gastric conditions, gold‐nanoparticle‐decorated dipalmitoylphosphatidylcholine (DPPC) liposomes exhibit an at least ten‐times‐slower drug release compared to gold‐nanoparticle‐decorated 1,2‐dimyristoyl‐sn‐glycero‐3‐phosphocholine (DMPC) liposomes, although both liposomes in the bare state fail to pursue controlled release. Our study also reveals that one can modulate the drug‐release rate by simply varying the concentration of nanoparticles. This study highlights a novel strategy for the controlled release of drug molecules from liposomes.     

Self‐Assembled Supramolecular Nanogels as a Safe and Effective Drug Delivery Vector for Cancer Therapy

Simple construction and manipulation of low‐molecular‐weight supramolecular nanogels, based on the introduction of multiple hydrogen bonding interactions, with the desired physical properties to achieve effective and safe delivery of drugs for cancer therapy remain highly challenging. Herein, a novel supramolecular oligomer cytosine (Cy)‐polypropylene glycol containing self‐complementary multiple hydrogen‐bonded Cy moieties is developed, which undergoes spontaneous self‐assembly to form nanosized particles in an aqueous environment. Phase transitions and scattering studies confirm that the supramolecular nanogels can be readily tailored to obtain the desired phase‐transition temperature and temperature‐induced release of the anticancer drug doxorubicin (DOX). The resulting nanogels exhibit an extremely high load carrying capacity (up to 24.8%) and drug‐entrapment stability, making the loading processes highly efficient. Importantly, in vitro cytotoxicity assays indicate that DOX‐loaded nanogels possess excellent biosafety for drug delivery applications under physiological conditions. When the environmental temperature is increased to 40 °C, DOX‐loaded nanogels trigger rapid DOX release and exert cytotoxic effects, significantly reducing the dose required compared to free DOX. Given its simplicity, low cost, high reliability, and efficiency, this newly developed temperature‐responsive nanocarrier has highly promising potential for controlled release drug delivery systems.

     

Cationic Vesicles Based on Amphiphilic Pillar[5]arene Capped with Ferrocenium: A Redox‐Responsive System for Drug/siRNA Co‐Delivery

A novel ferrocenium capped amphiphilic pillar[5]arene (FCAP) was synthesized and self‐assembled to cationic vesicles in aqueous solution. The cationic vesicles, displaying low cytotoxicity and significant redox‐responsive behavior due to the redox equilibrium between ferrocenium cations and ferrocenyl groups, allow building an ideal glutathione (GSH)‐responsive drug/siRNA co‐delivery system for rapid drug release and gene transfection in cancer cells in which higher GSH concentration exists. This is the first report of redox‐responsive vesicles assembled from pillararenes for drug/siRNA co‐delivery; besides enhancing the bioavailability of drugs for cancer cells and reducing the adverse side effects for normal cells, these systems can also overcome the drug resistance of cancer cells. This work presents a good example of rational design for an effective stimuli‐responsive drug/siRNA co‐delivery system.     

Redox‐ and Glucose‐Induced Shape‐Memory Polymers

A novel redox‐induced shape‐memory polymer (SMP) is prepared by crosslinking β‐cyclodextrin modified chitosan (β‐CD‐CS) and ferrocene modified branched ethylene imine polymer (Fc‐PEI). The resulting β‐CD‐CS/Fc‐PEI contains two crosslinks: reversible redox‐sensitive β‐CD‐Fc inclusion complexes serving as reversible phases, and covalent crosslinks serving as fixing phases. It is shown that this material can be processed into temporary shapes as needed in the reduced state and recovers its initial shape after oxidation. The recovery ratio and the fixity ratio are both above 70%. Furthermore, after entrapping glucose oxidase (GOD) in the system, the material shows a shape memory effect in response to glucose. The recovery ratio and the fixity ratio are also above 70%.