(Bio)polymeric Hydrogels as Therapeutic Agents

Hydrogels derived from both natural and synthetic polymers have gained significant scientific attention in recent years for their potential use as biomedical materials to treat human diseases. While a great deal of research efforts have been directed towards investigating polymeric hydrogels as matrices for drug delivery systems, examples of such hydrogels exhibiting intrinsic therapeutic properties are relatively less common. Characteristics of synthetic and natural polymers such as high molecular weight, diverse molecular architecture, chemical compositions, and modulated molecular weight distribution are unique to polymers. These characteristics of polymers can be utilized to discover a new generation of drugs and medical devices. For example, polymeric hydrogels can be restricted to the gastrointestinal tract, where they can selectively recognize, bind, and remove the targeted disease-causing substances from the body without causing any systemic toxicity that are associated with traditional small molecule drugs. Similarly hydrogels can be implanted at specific locations (such as knee and abdomen) to impart localized therapeutic benefits. The present article provides an overview of certain recent developments in the design and synthesis of functional hydrogels that have led to several polymer derived drugs and biomedical devices. Some of these examples include FDA-approved marketed products.     

Achieving High Drug Loading and Sustained Release of Hydrophobic Drugs in Hydrogels through In Situ Crystallization

Inadequate drug loading of hydrophobic drugs is a classic problem when hydrogels are utilized as sustained‐release carriers of drugs. Herein, a strategy to load plenty of hydrophobic drugs is presented. The antitumor drug 10‐hydroxycamptothecin in the thermogel of poly(d ,l ‐lactic acid‐co‐glycolic acid)‐b‐poly(ethylene glycol)‐b‐poly(d ,l ‐lactic acid‐co‐glycolic acid) is employed. The drug is soluble in an alkaline medium, yet insoluble in a neutral/acidic medium. The crystallization is triggered after adding an alkaline drug solution into an acidic copolymer solution. The concentrated copolymer aqueous solution undergoes a sol–gel transition upon heating, faster than the crystallization. As a result, plenty of evenly dispersed drug microcrystals are formed. The in vitro and in vivo experiments indicate both high drug loading and sustained release with enhanced antitumor efficacy and reduced adverse effects. The system resolves the challenge in formulation of hydrophobic drugs in hydrogels, and is stimulating for encapsulating drugs with a soluble‐insoluble transition into a material environment.

     

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.     

An Injectable System for Local and Sustained Release of Antimicrobial Agents in the Periodontal Pocket

Periodontitis treatments usually require local administration of antimicrobial drugs with the aim to reduce the bacterial load inside the periodontal pocket. Effective pharmaceutical treatments may require sustained local drug release for several days in the site of interest. Currently available solutions are still not able to fulfill the clinical need for high‐quality treatments, mainly in terms of release profiles and patients' comfort. This work aims to fill this gap through the development of an in situ gelling system, capable to achieve controlled and sustained release of antimicrobial agents for medium‐to‐long‐term treatments. The system is composed of micrometer‐sized β‐cyclodextrin‐based hydrogel (bCD‐Jef‐MPs), featured by a strong hydrophilic character, suspended in a synthetic block‐co‐polymer solution (Poloxamer 407), which is capable to undergo rapid thermally induced sol–gel phase transition at body temperature. The chemical structure of bCD‐Jef‐MPs was confirmed by cross‐correlating data from Fourier transform infrared (FTIR) spectroscopy, swelling test, and degradation kinetics. The thermally induced sol–gel phase transition is demonstrated by rheometric tests. The effectiveness of the described system to achieve sustained release of antimicrobial agents is demonstrated in vitro, using chlorhexidine digluconate as a drug model. The results achieved in this work disclose the potential of the mentioned system in effectively treating periodontitis lesions.

     

Synthesis and release profile analysis of thermo-sensitive albumin hydrogels

Novel thermo-responsive hydrophilic microspheres were prepared by free radical polymerization of methacrylate bovine serum albumin and N-isopropylacrylamide, as cross-linker and functional monomer, respectively. The incorporation of monomers in the network was confirmed by infrared spectroscopy, while the network density and shape of hydrogels strictly depend on concentration of monomers in the polymerization feed. The thermal analyses showed negative thermo-responsive behavior with pronounced water affinity of microspheres at temperature lower than lower critical solution temperature (LCST). The in vitro release studies of drug-loaded thermo-sensitive hydrogels were performed. Experimental data showed, for the copolymers with functional monomer/cross-linker ratio ≤ 1, a predominant drug release in the collapsed state, while the copolymers with functional monomer/cross-linker ratio > 1 showed prominent drug release in the swollen state. Below the hydrogel LCST, drug release through the swollen polymeric networks was observed, while a squeezing-out effect at temperature above the LCST was predominant.     

Reinforced Supramolecular Hydrogels from Attapulgite and Cyclodextrin Pseudopolyrotaxane for Sustained Intra‐Articular Drug Delivery

Injectable hydrogels for nonsteroidal anti‐inflammatory drugs’ (NSAIDs) delivery to minimize the side effects of NSAIDs and achieve long‐term sustained release at the targeted site of synovial joint are attractive for osteoarthritis therapy, but how to improve its mechanical strength remains a challenge. In this work, a kind of 1D natural clay mineral material, attapulgite (ATP), is introduced to a classical cyclodextrin pseudopolyrotaxane (PPR) system to form a reinforced supramolecular hydrogel for sustained release of diclofenac sodium (DS) due to its rigid, rod‐like morphology, and unique structure, which has great potential in tissue regeneration, repair, and engineering. Investigation on the interior morphology and rheological property of the obtained hydrogel points out that the ATP distributed in PPR hydrogel plays a role similar to the “reinforcement in concrete” and exhibits a positive effect on improving the mechanical properties of PPR hydrogel by regulating their interior morphology from a randomly distributed style to the well‐ordered porous frame structure. The hybrid hydrogels demonstrate good shear‐thinning and thixotropic properties, excellent biocompability, and sustained release behavior both in vitro and in vivo. Furthermore, preliminary in vivo treatment in an acute inflammatory rat model reveals that the ATP hybrid hydrogels present sustained anti‐inflammatory effect.     

Injectable Hydrogel for Sustained Protein Release by Salt‐Induced Association of Hyaluronic Acid Nanogel

A hyaluronic acid‐based anionic nanogel formed by self‐assembly of cholesteryl‐group‐bearing HA is designed for protein delivery. The HA nanogel spontaneously binds various types of proteins without denaturation, such as recombinant human growth hormone, erythropoietin, exendin‐4, and lysozyme. The HA nanogel shows unique colloidal properties, in particular that an injectable hydrogel is formed by salt‐induced association of the HA nanogel. A pharmacokinetic study in rats shows that an in situ gel formulation, prepared by simply mixing rhGH and HA nanogel in phosphate buffer, maintains plasma rhGH levels within a narrow range over one week. Therefore, HA nanogels offer a simple method for easy formulation of therapeutic proteins and are effective for sustained protein release systems.

     

超分子水凝胶作为胰岛素缓释体系的研究

利用α-环糊精(α-CD)与含有聚乙二醇(PEG)链段的聚合物Pluronic F127的超分子作用制备水凝胶.该物理交联水凝胶的交联点包括α-CD与PEG链包合物堆积形成的微晶区和聚合物疏水链段聚集区.优化水凝胶组分,得到具有较低固含量和较短凝胶化时间的体系用于胰岛素的负载和释放研究.通过X射线衍射(XRD),扫描显微镜(SEM)对水凝胶结构进行表征.通过紫外分光光度计监测胰岛素的释放过程,结果表明,水凝胶释药时间约为65 h,且释放曲线较为平缓.细胞毒性实验结果表明该水凝胶材料对细胞生长无明显抑制作用.小鼠体内释药实验结果表明该水凝胶载体对延长胰岛素的释药时间有一定效果,可作为多肽类药物的缓释体系.     

Crosslinked Networks Based on Polysaccharides and Collagen for Pilocarpine Sustained Release

The paper presents the experimental studies regarding synthesis and characterization of hydrogels based on gellan (Gel)/chitosan (CS) and collagen (Col), obtained by crosslinking with glutaraldehyde (GLA). The influence of the polysaccharide content and GLA ratio on the final composition and swelling characteristics was evaluated. Hydrogels swelling analysis, in distilled water and phosphate buffer (PBS, pH 7.2) has shown higher swelling degrees at increased concentration of polysaccharide into hydrogels. In vitro release of pilocarpine has demonstrated the possibility to use gellan-collagen and chitosan-collagen hydrogels as ophthalmic drug delivery matrix.     

分子印迹智能水凝胶的研究进展

智能水凝胶可以响应外界环境(如温度、pH、溶剂、离子强度、电场、磁场、光、压力和特异分子等)的变化,发生可逆体积相变,从而具有控制释放的能力.将分子印迹技术引入智能水凝胶,制备分子印迹智能水凝胶,不仅可以保持其环境响应性,更赋予其对特异分子的识别性能,从而可以根据外界环境的变化控制其对特定分子记忆功能的开关,实现自动识别并结合或释放特定分子.它有望应用于药物控释、生物传感和免疫分析等领域.本文综述了分子印迹智能水凝胶的研究现状,讨论了其目前所面临的挑战,并展望了其发展前景.     

Competitive Affinity Release for Long‐Term Delivery of Antibodies from Hydrogels

With increased clinical use of antibodies, long‐term delivery strategies are needed to decrease injection frequency and improve health outcomes. A three‐component drug‐delivery system was developed for competitive affinity release of a streptavidin–antibody conjugate from agarose–desthiobiotin hydrogels via controlled dissolution of sparingly soluble biotin derivatives. The antibody conjugate was localized in the hydrogel through streptavidin–desthiobiotin complexation. Dissolution of sparingly soluble biotin derivatives disrupts streptavidin–desthiobiotin complexation for controlled release of the antibody conjugate. Release was tuned by altering the total biotin derivative concentration without further hydrogel or antibody modification. First‐order tunable release of bioactive Avastin, a therapeutic anti‐VEGF antibody, was demonstrated from a non‐cytotoxic system for over 100 days.     

Structural Selection in G‐Quartet‐Based Hydrogels and Controlled Release of Bioactive Molecules

A guanosine‐5′‐hydrazide can entrap biologically interesting molecules such as acyclovir, vitamin C, and vancomycin into its hydrogel network. Controlled release of these molecules was monitored by ¹H NMR spectroscopy. The hydrazide may potentially form mixed G–G quartets with analogous compounds containing a guanine group. ¹H NMR spectroscopy was used to study the inclusion of various guanine derivatives into the hydrogel. The structural selectivity was found to depend strongly on both the shape and the charge of the additive and may arise from the strong cohesion of the supramolecular architecture of the gel and the resulting resistance to perturbation by foreign bodies. Hydrogels thus offer a promising medium for highly selective, controlled release of bioactive substances.     

Elucidation of the Mechanism of Enhanced Insulin Uptake and Release from pH Responsive Hydrogels

Summary: Environmentally responsive hydrogels composed of poly(methacrylic acid-g-ethylene glycol) (P(MAA-g-EG)) have shown promise for oral insulin delivery due to their pH responsive complexation behavior. A series of hydrogel formulations were polymerized with varying amounts of crosslinker and varying monomer volume fraction. The mesh size of the network depended primarily on pH, varying from 8.0 to 27.2 nm. Insulin loading efficiency varied directly with crosslink density, ranging from 42.7 to 84.9% of available insulin loaded into the hydrogels. The release of insulin was performed with each polymer formulation at 5 pH levels ranging from 2.7 to 6.8. Insulin release was less than 20% for all formulations tested with insulin for the duration of the 3 hour release study for all pH levels considered except when the pH was 6.8, at which point the release occurred as a burst. Loading studies performed with insulin glargine, an insulin analog with an increased pI, showed the same trends as native insulin. However, the release of insulin glargine only occurred at a pH level above that of the pI of the protein. These results indicate that hydrogen bonds and ionic interactions between the protein and P(MAA-g-EG) may strongly influence its loading and release behavior in vitro.     

Preparation of Biomimetic Zwitterionic Core Cross-Linked Nanocarriers for Control Release of Bioactive Agents

Biomimetic core cross-linked nanocarriers (CCL-NCs) with zwitterionic shell was constructed from an amphiphilic block copolymer poly(2-(dimethylamino) ethyl methacrylate-co-carboxybetaine)-b-polystyrene ((PDMAEMA-co-PCB)-b-PS) via mini-emulsion RAFT polymerization. CCL-NCs present in this report possess properties of redox-sensitivity, limited unspecific protein adsorptions and low cytotoxicity, which highly enhance their potential application in drug delivery. Morphology of CCL-NCs was characterized by transmission electron microscopy (TEM) and dynamic light scattering (DLS) measurements. The control release process has also been investigated under three different conditions with or without dithiothreitol (DTT) at pH 5.4, 6.5 and 7.4.     

Encapsulation and Sustained Release of Curcumin using Superparamagnetic Silica Reservoirs

For controlled release and targeted delivery of curcumin in an aqueous medium a method of encapsulating curcumin and magnetic nanoparticles inside porous silica matrix has been developed. Curcumin and superparamagnetic nanoparticles are loaded inside porous silica in a single process. The graphic shows the TEM image of microtomed sample of Fe₃O₄ particles surrounded by a silica matrix.

     

Imaging Therapeutic Proteins in Gelatin for Controlled Drug Release

Preliminary results from this study show that x-ray microcomputed tomography can be used to image model proteins for bone inducing growth factors. Small quantities (<1 μg protein/mg gelatin) of soybean trypsin inhibitor labeled with either gold nanoparticles or nonradioactive iodine were detected using synchrotron radiation. These results could lead to a new method of measuring the release profile of therapeutic proteins.     

Injectable Supramolecular Hydrogel/Microgel Composites for Therapeutic Delivery

Shear‐thinning hydrogels are useful for biomedical applications, from 3D bioprinting to injectable biomaterials. Although they have the appropriate properties for injection, it may be advantageous to decouple injectability from the controlled release of encapsulated therapeutics. Toward this, composites of hydrogels and encapsulated microgels are introduced with microgels that are fabricated via microfluidics. The microgel cross‐linker controls degradation and entrapped molecule release, and the concentration of microgels alters composite hydrogel rheological properties. For the treatment of myocardial infarction (MI), interleukin‐10 (IL‐10) is encapsulated in microgels and released from composites. In a rat model of MI, composites with IL‐10 reduce macrophage density after 1 week and improve scar thickness, ejection fraction, cardiac output, and the size of vascular structures after 4 weeks when compared to saline injection. Improvements are also observed with the composite without IL‐10 over saline, emphasizing the role of injectable hydrogels alone on tissue repair.     

壳聚糖-聚丙烯酸复合水凝胶的药物控制释放行为

以壳聚糖(Cs)和丙烯酸(AA)为原料,利用自由基聚合法制备了具有孔洞结构的复合水凝胶Cs-PAA,并研究了AA的量、交联剂的量、聚合温度和AA的中和度对水凝胶溶胀度的影响以及复合水凝胶对烟酸的控制释放。 结果表明,Cs-PAA复合水凝胶具有良好的pH值、离子强度敏感性,且溶胀度最高达1228 g/g,其在pH=686的缓冲溶液中的烟酸累积释放率明显大于其在pH=1.80的缓冲溶液,因此Cs-PAA水凝胶可作为肠口服药物的载体。     

Injectable Polypeptide Hydrogel Depot System for Assessment of the Immune Response–Inducing Efficacy of Sustained Antigen Release Alone

Vaccines typically contain an antigen, delivery system (vehicle), and adjuvant, all of which contribute to inducing a potent immune response. Consequently, design of new vaccines is difficult, because the contributions and interactions of these components are difficult to distinguish. Here, it is aimed to develop an easy‐to‐use, non‐immunogenic, injectable depot system for sustained antigen release that will be suitable for assessing the efficacy of prolonged antigen exposure per se for inducing an immune response. This should mimic real‐life infections. Recombinant elastin‐like polypeptides with periodic cysteine residues (cELPs) are selected, which reportedly show little or no immunogenicity, as carriers and tetanus toxoid (Ttd) as an antigen. After subcutaneous injection of the mixture, cELP rapidly forms a disulfide cross‐linked hydrogel in situ, within which Ttd is physically incorporated, affording a biodegradable antigen depot. A series of Ttd‐containing hydrogels is examined. A single injection induces high levels of tetanus antibody with high avidity for at least 20 weeks in mice. The chain length of cELP proves critical, whereas differences in hydrophobicity has little effect, although hydrophilic cELPs are more rapidly biodegraded. This system's ability to distinguish the contribution of sustained antigen release to antibody induction should be helpful for rational design of next‐generation vaccines.