Self‐Assembly of Amphiphilic Janus Dendrimers into Mechanically Robust Supramolecular Hydrogels for Sustained Drug Release

Compounds that can gelate aqueous solutions offer an intriguing toolbox to create functional hydrogel materials for biomedical applications. Amphiphilic Janus dendrimers with low molecular weights can readily form self‐assembled fibers at very low mass proportion (0.2 wt %) to create supramolecular hydrogels (G′?G′′) with outstanding mechanical properties and storage modulus of G′>1000 Pa. The G′ value and gel melting temperature can be tuned by modulating the position or number of hydrophobic alkyl chains in the dendrimer structure; thus enabling exquisite control over the mesoscale material properties in these molecular assemblies. The gels are formed within seconds by simple injection of ethanol‐solvated dendrimers into an aqueous solution. Cryogenic TEM, small‐angle X‐ray scattering, and SEM were used to confirm the fibrous structure morphology of the gels. Furthermore, the gels can be efficiently loaded with different bioactive cargo, such as active enzymes, peptides, or small‐molecule drugs, to be used for sustained release in drug delivery.     

Molecular Imprinting of Cyclodextrin Supramolecular Hydrogels Improves Drug Loading and Delivery

Cyclodextrin‐based controlled delivery materials have previously been developed for controlled release of different therapeutic drugs. In this study, a supramolecular hydrogel made from cyclodextrin‐based macromonomers is subjected to molecular imprinting to investigate the impact on release kinetics and drug loading, when compared with non‐imprinted, or alternately imprinted hydrogels. Mild synthesis conditions are used to molecularly imprint three antibiotics—novobiocin, rifampicin, and vancomycin—and to test two different hydrogel chemistries. The release profile and drug loading of the molecularly imprinted hydrogels are characterized using ultraviolet spectroscopy over a period of 35 days and compared to non‐imprinted, and alternately imprinted hydrogels. While only modest differences are observed in the release rate of the antibiotics tested, a substantial difference is observed in the total drug‐loading amount possible for hydrogels releasing drugs which has been templated by those drugs. Hydrogels releasing drugs which are templated by other drugs do not show improved release or loading. Analysis by FTIR does not show substantial incorporation of drug into the polymer. Lastly, bioactivity assays confirmed long‐term stability and release of incorporated antibiotics.     

Self‐Adhesive Microneedles with Interlocking Features for Sustained Ocular Drug Delivery

The interests in sustained ocular drug delivery have grown rapidly in recent years, with hope to replace repeated intravitreal injections. Microneedles (MNs), which are minimally invasive, have been shown to be a feasible vehicle for sustained drug delivery. However, securing an MN patch in the eye remains challenging. In this study, a new design of hydrogel MNs with interlocking features to achieve self‐adhesion is proposed. Upon swelling, the swollen interlocking features help secure the MNs in place. A new molding process is developed to fabricate MNs with interlocking features that can cause issues when demolding using the regular micromolding process. MNs with two different interlocking feature designs are used in this study and are made with polyvinyl alcohol. MNs with the interlocking features show an 80% increase in adhesion strength and a small amount of increase in penetration force, in comparison to MNs without any feature. The experiments are performed using both a sclera‐mimicking phantom and ex vivo eyes harvested from rabbits and are shown to have comparable results. This study demonstrates the feasibility of incorporating interlocking features to MNs to achieve self‐adhesion that can enable sustained drug delivery via MNs.     

Supramolecular Proteoglycan Aggregate Mimics: Cyclodextrin‐Assisted Biodegradable Polymer Assemblies for Electrostatic‐Driven Drug Delivery

Self‐assembled, noncovalent polymeric biodegradable materials mimicking proteoglycan aggregates were synthesized from inclusion complexes of cationic surfactants with γ‐cyclodextrin and the natural anionic polymer hyaluronan. The amorphous structure of this ternary system was proven by X‐ray diffraction and thermal analysis. Light‐scattering measurements showed that there was a competition between hyaluronic acid and the surfactant for the cyclodextrin cavity. These self‐assembled supramolecular matrices were loaded with both hydrophilic and lipophilic drug substances for dissolution studies. The release of the entrapped drugs was found to be controlled by cations in the surrounding media and by biodegradation. Slow drug release in an ion‐free medium became faster in physiological salt solution in which the macroscopic polymer matrix was disassembled. In contrast, the enzymatic degradation of hyaluronan was hindered in the polymeric matrix. The supramolecular systems consisting of γ‐cyclodextrin as a macrocyclic host, a cationic surfactant guest, and hyaluronic acid as the anionic polymer electrostatically cross‐linked by the inclusion complex of the first two was found to be a novel drug‐delivery system for the controlled release of traditional drugs such as curcumin and ketotifen and proteins such as bovine serum albumin.     

Dynamic Hydrogels from Host–Guest Supramolecular Interactions

Hydrogel biomaterials are pervasive in biomedical use. Applications of these soft materials range from contact lenses to drug depots to scaffolds for transplanted cells. A subset of hydrogels is prepared from physical cross‐linking mediated by host–guest interactions. Host macrocycles, the most recognizable supramolecular motif, facilitate complex formation with an array of guests by inclusion in their portal. Commonly, an appended macrocycle forms a complex with appended guests on another polymer chain. The formation of poly(pseudo)rotaxanes is also demonstrated, wherein macrocycles are threaded by a polymer chain to give rise to physical cross‐linking by secondary non‐covalent interactions or polymer jamming. Host–guest supramolecular hydrogels lend themselves to a variety of applications resulting from their dynamic properties that arise from non‐covalent supramolecular interactions, as well as engineered responsiveness to external stimuli. These are thus an exciting new class of materials.     

Carbon Nanotube Reinforced Supramolecular Hydrogels for Bioapplications

Nanocomposite hydrogels based on carbon nanotubes (CNTs) are known to possess remarkable stiffness, electrical, and thermal conductivity. However, they often make use of CNTs as fillers in covalently cross‐linked hydrogel networks or involve direct cross‐linking between CNTs and polymer chains, limiting processability properties. Herein, nanocomposite hydrogels are developed, in which CNTs are fillers in a physically cross‐linked hydrogel. Supramolecular nanocomposites are prepared at various CNT concentrations, ranging from 0.5 to 6 wt%. Incorporation of 3 wt% of CNTs leads to an increase of the material's toughness by over 80%, and it enhances electrical conductivity by 358%, compared to CNT‐free hydrogel. Meanwhile, the nanocomposite hydrogels maintain thixotropy and processability, typical of the parent hydrogel. The study also demonstrates that these materials display remarkable cytocompatibility and support cell growth and proliferation, while preserving their functional activities. These supramolecular nanocomposite hydrogels are therefore promising candidates for biomedical applications, in which both toughness and electrical conductivity are important parameters.     

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.

     

Dual‐Responsive Supramolecular Hydrogels from Water‐Soluble PEG‐Grafted Copolymers and Cyclodextrin

Novel temperature and pH dual‐responsive hydrogels were constructed by inclusion of poly(PEGMA)‐co‐poly(DMA) with α‐cyclodextrin in aqueous solution. The temperature‐ or pH‐induced sol/gel transition in the hydrogels was completely reversible. Studies on structure/property relationships show that chain uniformity, graft density and copolymer concentration affect the hydrogel behavior. A dual‐responsive mechanism is proposed. The in vitro release of a model drug from this hydrogel was studied. It was found that the release kinetics were greatly accelerated at higher temperature and at acidic pH conditions, indicating potential applications in controlled drug delivery.

     

Nucleobase‐Functionalized Supramolecular Micelles with Tunable Physical Properties for Efficient Controlled Drug Release

Complementary nucleobase‐functionalized polymeric micelles, a combination of adenine‐thymine (A‐U) base pairs and a blend of hydrophilic–hydrophobic polymer pairs, can be used to construct 3D supramolecular polymer networks; these micelles exhibit excellent self‐assembly ability in aqueous solution, rapid pH‐responsiveness, high drug loading capacity, and triggerable drug release. In this study, a multi‐uracil functionalized poly(ε‐caprolactone) (U‐PCL) and adenine end‐capped difunctional oligomeric poly(ethylene glycol) (BA‐PEG) are successfully developed and show high affinity and specific recognition in solution owing to dynamically reversible A‐U‐induced formation of physical cross‐links. The U‐PCL/BA‐PEG blend system produces supramolecular micelles that can be readily adjusted to provide the desired critical micellization concentration, particle size, and stability. Importantly, in vitro release studies show that doxorubicin (DOX)‐loaded micelles exhibit excellent DOX‐encapsulated stability under physiological conditions. When the pH value of the solution is reduced from 7.4 to 5.0, DOX‐loaded micelles can be rapidly triggered to release encapsulated DOX, suggesting these polymeric micelles represent promising candidate pH‐responsive nanocarriers for controlled‐release drug delivery and pharmaceutical applications.

     

Pillararene-Based Supramolecular Vesicles for Stimuli-Responsive Drug Delivery

Supramolecular vesicles (SMVs) self-assembled from the supra-amphiphiles, consisting of two scaffolds linked together through noncovalent interactions, can realize stimuli-responsive controlled release of encapsulated drugs for enhanced therapeutic efficacy and minimized side effect of drugs. Pillararenes (PAs), an emerging kind of macrocyclic hosts in 2008, are easy to modify with a variety of functionalities. SMVs from PAs and specific guests mainly based on the host–guest interactions have attracted increasing attention because of their drug delivery and controlled drug release. A great progress in the construction and stimuli-responsive drug delivery of the PA-based SMVs has been made since the first work was reported in 2012. This review summarizes the major achievements of the PA-based SMVs for stimuli-responsive drug delivery over the past 5 years, including the microstructures of SMVs, multiple stimuli-responsive SMVs, prodrug SMVs from prodrug PAs and guests, bola-type SMVs, multifunctional SMVs, glucose-responsive SMVs for insulin delivery, novel SMVs from responsive PAs, thermo-responsive SMVs, and ternary SMVs, for chemotherapy, photothermal therapy, photodynamic therapy, and other biological applications. The future challenges and research directions of PA-based SMVs are also outlined from the points of views of the fundamental research, biological applications, and clinical applications of PA-based SMVs.     

Supramolecular Hydrogel from Nanoparticles and Cyclodextrins for Local and Sustained Nanoparticle Delivery

Injectable and biodegradable supramolecular hydrogel mPECT NP/α‐CD^gel composed of high‐concentration nanoparticle dispersion (≤20% W/V) and α‐cyclodextrins (α‐CD) are prepared by a two‐level physical cross‐linking using amphiphilic block polymer methoxy poly(ethylene glycol)‐b‐poly(ε‐caprolactone‐co‐1,4,8‐trioxa[4.6]spiro‐9‐undecanone) (mPECT) and α‐CD. The gelation behavior depends on the concentration of nanoparticles and α‐CD. The viscoelasticity and shear thinning of mPECT NP/α‐CD^gel are confirmed. In vitro hydrogel erosion is demonstrated to be mainly a concentration‐dependent dissociation process with general release of discrete mPECT nanoparticles about 50 nm that can be easily taken up by cells. The in vitro release behavior can be modulated by changing the concentration of nanoparticles or α‐CD. In vitro and in vivo cytotoxicity study demonstrates its biocompatibility and biosafety. Gel formation after subcutaneous injection is also confirmed and mPECT NP/α‐CD^gel shows about 2 weeks retention time. This work validates the potential application for this supramolecular hydrogel in local and sustained delivery of nanoparticles.

     

Self‐Assembly of Hierarchical Nanostructures from Dopamine and Polyoxometalate for Oral Drug Delivery

The preparation of 3D hierarchical nanostructures by a simple and versatile strategy of self‐assembly of dopamine (DA) and phosphotungstic acid (PTA) is described. The size and morphology of the hierarchical nanostructures could be simply controlled by varying the ratio of the two components, their concentrations, and the pH of the initial Tris‐HCl solution. The self‐assembly of the flowerlike microspheres has been found to involve a two‐stage growth process. Moreover, use of the hierarchical nanostructures as a possible carrier for an anticancer drug in chemotherapy has been explored. The nanostructures showed an intriguing pH‐dependent release behavior, making them promising for applications in biomedical science.     

Amino Acid Based Hydrogels with Dual Responsiveness for Oral Drug Delivery

This study reports a series of novel amino acid based dual‐responsive hydrogels. Prepared by a facile one‐pot 1‐ethyl‐3‐(3‐dimethylaminopropyl)carbodiimide (EDC) coupling reaction, the solid content, structure, and mechanical behavior of hydrogels could be easily adjusted by changing the concentrations of the polymers and the crosslinkers. With pH‐responsive anionic pseudo‐peptides as backbones and disulfide‐containing l ‐cystine dimethyl ester as crosslinkers, these hydrogels are able to collapse and form relatively compact structure at an acidic pH, while swelled and partly dissociated at a neutral pH. Further addition of dithiothreitol (DTT) facilitated complete degradation of hydrogels. The high loading efficiency, rapid but complete triggered‐release, and good biocompatibility make these hydrogels promising candidates for oral delivery.

     

Dual Photo‐ and pH‐Responsive Supramolecular Nanocarriers Based on Water‐Soluble Pillar[6]arene and Different Azobenzene Derivatives for Intracellular Anticancer Drug Delivery

Two novel types of supramolecular nanocarriers fabricated by the amphiphilic host–guest inclusion complex formed from water‐soluble pillar[6]arene ( WP6 ) and azobenzene derivatives G1 or G2 have been developed, in which G1 is structurally similar to G2 but has an extra phenoxy group in its hydrophobic region. Supramolecular micelles can be initially formed by WP6 with G1 , which gradually transform into layered structures with liquid‐crystalline properties, whereas stable supramolecular vesicles are obtained from WP6 and G2 , which exhibit dual photo‐ and pH‐responsiveness. Notably, the resulting WP6 ? G2 vesicles can efficiently encapsulate anticancer drug mitoxantrone (MTZ) to achieve MTZ‐loaded vesicles, which maintain good stability in a simulated normal physiological environment, whereas in an acid environment similar to that of tumor cells or with external UV irradiation, the encapsulated drug is promptly released. More importantly, cytotoxicity assay indicates that such vesicles have good biocompatibility and the MTZ‐loaded vesicles exhibit comparable anticancer activity to free MTZ, especially with additional UV stimulus, whereas its cytotoxicity for normal cells was remarkably reduced. Flow cytometric analysis further confirms that the cancer cell death caused by MTZ‐loaded vesicles is associated with apoptosis. Therefore, the dual pH‐ and UV‐responsive supramolecular vesicles are a potential platform for controlled release and targeted anticancer drug delivery.     

Highly Efficient Drug Delivery Nanosystem via L‐Phenylalanine Triggering Based on Supramolecular Polymer Micelles

An intelligent drug delivery nanosystem has been developed based on biodegradable supramolecular polymer micelles (SMPMs). The drug release can be triggered from SMPMs responsively by a bioactive agent, L ‐phenylalanine in a controlled fashion. The SMPMs are constructed from ethylcellulose‐graft‐poly(ε‐caprolactone) (EC‐g‐PCL) and α‐cyclodextrin (α‐CD) derivate via host–guest and hydrophobic interactions. It has been found that these SMPMs have disassembled rapidly in response to an additional L ‐phenylalanine, due to great affinity discrepancy to α‐CD between L ‐phenylalanine and PCL. Experiments have been carried out on trigger‐controlled in vitro drug release of the SMPMs loaded with a model porphyrin based photosensitizer THPP. The result shows that the SMPMs released over 85% THPP in 6 h, which is two orders magnitudes faster than that of control. Also investigated is the photodynamic therapy (PDT) of THPP‐loaded SMPMs with and without L ‐phenylalanine on MCF‐7 carcinoma cell line. An effective trigger‐concentration dependent lethal effect has been found showing promise in clinical photodynamic therapy.

     

Synthesis and Evaluation of Biocompatible pH‐Sensitive Hydrogels as Colon‐Specific Drug Delivery Systems

Because of the growing importance of pH‐sensitive hydrogels as drug delivery systems, biocompatible copolymeric hydrogels based N‐vinyl‐2‐pyrrolidinone (NVP) and methacrylic acid (MAA) were designed and synthesized. These hydrogels were investigated for oral drug delivery. Radical copolymerizations of N‐vinyl‐2‐pyrrolidinone (NVP) and methacrylic acid (MAA) with the various ratios of cross‐linking agent were carried out at 70 °C. Azabisisobutyronitrile (AIBN) was the free‐radical initiator employed and Cubane‐1,4‐dicarboxylic acid (CDA) linked to two 2‐hydroxyethyl methacrylate (HEMA) group was the crosslinking agent (CA) used for hydrogel preparations. The hydrogels were characterized by differential scanning calorimetry and FT‐IR. Equilibrium swelling studies were carried out in enzyme‐free simulated gastric and intestinal fluids (SGF and SIF, respectively). A model drug, olsalazine [3,3′‐azobis (6‐hydroxy benzoic acid)] (OSZ) as an azo derivative of 5‐aminosalicylic acid (5‐ASA), was entrapped in these gels and the in‐vitro release profiles were established separately in both enzyme‐free SGF and SIF. The drug‐release profiles indicated that the amount of drug released depended on the degree of swelling. The swelling was modulated by the amount of crosslinking of the polymer bonded drug (PBDs) prepared. Based on the great difference in hydrolysis rates at pH 1 and 7.4, these pH‐sensitive hydrogels appear to be good candidates for colon‐specific drug delivery.     

Affinity‐Based Drug Delivery

Affinity‐based drug delivery systems utilize interactions between the therapeutic drug and the delivery system to manipulate drug loading and to control drug release. In this paper, affinity‐based drug delivery system syntheses, types of therapeutic factors delivered, and delivery system loading and release are discussed in detail. The paper is divided into three subsections, based on the type of delivery system: molecular imprinting systems, growth‐factor delivery, and cyclodextrin‐based delivery. The objective of this paper is to examine the current state of research, highlight the breakthroughs and challenges, point out potential impacts of this relatively new technology, and explore future developmental areas.

     

Controllable Synthesis of Multiarm Star‐Shaped Copolymers Composed of Phosphoester Chains and Their Application on Drug Delivery

Novel biodegradable polymers with specific properties, structures, and tailorable designs or modifications are in great demand. Poly(phosphoester)s with good biocompatibility and degradability, as well as other adjustable properties have been studied widely because of their potential in biomedical applications. To meet more versatile and diverse biomedical applications, a novel multiarm star‐shaped phosphorester triblock copolymer poly(amido amine)‐block‐poly(2‐butynyl phospholane)‐block‐poly(2‐methoxy phospholane) (PAMAM‐PBYP‐PMP) is synthesized via organo‐catalyzed sequential ring‐opening polymerization. Supramolecular micelles with good architectural stability are self‐assembled into uniform spherical morphology in aqueous solution. Doxorubicin (DOX) can be encapsulated into the micelles with efficient loading capacity. A slow and sustained release in the environment of simulated intracellular lysosome (pH 5.0 with phosphodiesterase I) is observed. In addition, the copolymers and DOX‐loaded supramolecular micelles exhibit low cell‐toxicity and excellent anticancer activity toward HeLa cells. As a consequence, this multiarm star‐shaped PAMAM‐PBYP‐PMP has great potential in drug delivery system for tumor treatment.

     

Supramolecular Drug Delivery Systems Based on Water‐Soluble Pillar[n]arenes

Supramolecular drug delivery systems (SDDSs), including various kinds of nanostructures that are assembled by reversible noncovalent interactions, have attracted considerable attention as ideal drug carriers owing to their fascinating ability to undergo dynamic switching of structure, morphology, and function in response to various external stimuli, which provides a flexible and robust platform for designing and developing functional and smart supramolecular nano‐drug carriers. Pillar[n]arenes represent a new generation of macrocyclic hosts, which have unique structures and excellent properties in host–guest chemistry. This account describes recent progress in our group to develop pillararene‐based stimuli‐responsive supramolecular nanostructures constructed by reversible host–guest interactions for controllable anticancer drug delivery. The potential applications of these supramolecular drug carriers in cancer treatment and the fundamental questions facing SDDSs are also discussed.

     

Cyclodextrin Complexation for Affinity‐Based Antibiotic Delivery

Novel β‐cyclodextrin polymer (CD)‐based drug delivery hydrogels were prepared by varying type and concentration of crosslinkers and optimizing the gel synthesis conditions. For comparison, dextrose gels were prepared using the same crosslinkers. The optimized gels were characterized by Fourier Transform Infrared (FTIR), Scanning Electron Microscopy (SEM), and X‐ray diffraction (XRD) as well as swelling and release studies. For drug release studies, the gels were loaded with three different model antibiotics varying in size and hydrophobicity: rifampin (RM), novobiocin (NB), and vancomycin (VM), using a common solvent method. The loading efficiency was calculated and release kinetics were determined in vitro. As expected for affinity‐based mechanisms, the release of drugs, from CD‐based gels, was slower than release from dextrose gels which indicated that the antibiotics all form inclusion complexes with CD. Release kinetics were also more linear in the observed time frame when using CD‐based hydrogels versus dextrose hydrogels. This modification in release depended on the affinity‐between CD and drug, such that larger drugs and more hydrophilic ones had their release profiles altered less than small hydrophobic ones. In conclusion, affinity‐based mechanisms can be used to load antibiotics and obtain longer, more linear release profiles than purely diffusion‐based mechanisms.