Conventional drug delivery approaches are plagued by issues pertaining to systemic toxicity and repeated dosing. Hydrogels offer convenient drug delivery vehicles to ensure these disadvantages are minimized and the therapeutic benefits from the drug are optimized. With exquisitely tunable physical properties that confer them great controlled drug release features and the merits they offer for labile drug protection from degradation, hydrogels emerge as very efficient drug delivery systems. The versatility and diversity of the hydrogels extend their applications beyond targeted drug delivery also to wound dressings, contact lenses and tissue engineering to name but a few. They are 90% water, and highly porous to accommodate drugs for delivery and facilitate controlled release. Herein we discuss hydrogels and how they could be manipulated for targeted drug delivery applications. Suitable examples from the literature are provided that support the recent advancements of hydrogels in targeted drug delivery in diverse disease areas and how they could be suitably modified in very different ways for achieving significant impact in targeted drug delivery. With their enormous amenability to modification, hydrogels serve as promising delivery vehicles of therapeutic molecules in several disease conditions, including cancer and diabetes.

https://www.mdpi.com/1420-3049/24/3/603/pdf

Hydrogels and Their Applications in Targeted Drug Delivery.

Low molecular weight gels, or supramolecular gels, are formed when small molecules self-assemble into fibrous structures Above a critical concentration, the entanglement and cross-linking of these structures leads to the formation of a self-supporting gel There are many examples where a single component is used to form such gels There is however an ever-increasing interest in using multiple components Here, if each component is able to form a gel by itself, a range of fibre types are possible, formed by either random or specific associations between the low molecular weight gelators (LMWG) The properties of the networks will depend on how the LMWG assemble into the primary fibrous structures and then how these primary structures entangle As such, to understand these gels, it is necessary to understand the networks across multiple length scales Here, we discuss the current state of the art, the effectiveness of the different techniques that have been used, and hopefully provide the impetus for the field to move away from the cartoon-level discussion of assembly

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How should multicomponent supramolecular gels be characterised

Natural polymer hydrogels are one of the best biomaterials for soft tissue repair because of their excellent biocompatibility, biodegradability and low immune rejection. However, they lack mechanical strength matching that of natural tissue and desired functionality (e.g., self-healing and 3D-printability). To solve these problems, we developed a host–guest supramolecule (HGSM) with three arms covalently crosslinked with a natural polymer to construct a novel hydrogel with non-covalent bonds integrated into a covalently crosslinked network. This unique structure enabled the hydrogel to exhibit improved mechanical properties and show both self-healing and 3D printing capabilities. The three-armed HGSM was first prepared via efficient non-covalent host–guest inclusion interactions between isocyanatoethyl acrylate-modified β-cyclodextrin (β-CD-AOI2) and acryloylated tetra-ethylene glycol-modified adamantane (A-TEG-Ad). Subsequently, a host–guest supramolecular hydrogel (HGGelMA) was obtained through copolymerization between the arms of the HGSM and gelatin methacryloyl (GelMA) to form a covalently crosslinked network. The HGGelMA was robust, fatigue resistant, reproducible and rapidly self-healing. In the HGGelMA, the covalent crosslinking maintained its overall shape, whereas the weak reversible non-covalent host–guest interactions reinforced its mechanical properties and enabled it to rapidly self-heal upon fracturing. The reversible non-covalent interactions could be re-established upon breaking, so as to heal the hydrogel and dissipate energy to prevent catastrophic fracture propagation. Furthermore, the precursors of the HGGelMA were sufficiently viscous and could be rapidly photocrosslinked to produce a robust scaffold with an exquisite internal structure through 3D printing. The 3D-printed HGGelMA hydrogel scaffold was biocompatible, promoted cell adhesion and proliferation, and supported tissue in-growth. Our strategy of integrating a non-covalently linked HGSM into a covalently linked hydrogel network represents a new approach to the development of natural polymers into biocompatible hydrogels with improved strength as well as desired self-healing and 3D-printability.

3D-printable self-healing and mechanically reinforced hydrogels with host–guest non-covalent interactions integrated into covalently linked networks

Although in situ restoration of blood supply to the infarction region and attenuating pre-existing extracellular matrix degradation remain potential therapeutic approaches for myocardial infarction (MI), local delivery of therapeutics has been limited by low accumulation (inefficacy) and unnecessary diffusion (toxicity). Here, a dual functional MI-responsive hydrogel is fabricated for on-demand drug delivery to promote angiogenesis and inhibit cardiac remodeling by targeting upregulated matrix metalloproteinase-2/9 (MMP-2/9) after MI. A glutathione (GSH)-modified collagen hydrogel (collagen-GSH) is prepared by conjugating collagen amine groups with GSH sulfhydryl groups and the recombinant protein GST-TIMP-bFGF (bFGF: basic fibroblast growth factor) by fusing bFGF with glutathione-S-transferase (GST) and MMP-2/9 cleavable peptide PLGLAG (TIMP). Specific binding between GST and GSH significantly improves the amount of GST-TIMP-bFGF loaded in collagen-GSH hydrogel. The TIMP peptide enclosed between GST and bFGF responds to MMPs for on-demand release during MI. Additionally, the TIMP peptide is a competitive substrate of MMPs that inhibits the excessive degradation of cardiac matrix by MMPs after MI. GST-TIMP-bFGF/collagen-GSH hydrogels promote the recovery of MI rats by enhancing vascularization and ameliorating myocardium remodeling. The results suggest that on-demand growth factor delivery by synchronously controlling binding and responsive release to promote angiogenesis and attenuate cardiac remodeling might be promising for the treatment of ischemic heart disease.

Myocardial-Infarction-Responsive Smart Hydrogels Targeting Matrix Metalloproteinase for On-Demand Growth Factor Delivery.

Over the past decade, tissue-engineering strategies, mainly involving injectable hydrogels and epicardial biomaterial patches, have been pursued to treat myocardial infarction. However, only limited therapeutic efficacy is achieved with a single means. Here, a combined therapy approach is proposed, that is, the coadministration of a conductive hydrogel patch and injectable hydrogel to the infarcted myocardium. The self-adhesive conductive hydrogel patch is fabricated based on Fe3+-induced ionic coordination between dopamine-gelatin (GelDA) conjugates and dopamine-functionalized polypyrrole (DA-PPy), which form a homogeneous network. The injectable and cleavable hydrogel is formed in situ via a Schiff base reaction between oxidized sodium hyaluronic acid (HA-CHO) and hydrazided hyaluronic acid (HHA). Compared with a single-mode system, injecting the HA-CHO/HHA hydrogel intramyocardially followed by painting a conductive GelDA/DA-PPy hydrogel patch on the heart surface results in a more pronounced improvement of the cardiac function in terms of echocardiographical, histological, and angiogenic outcomes.

Coadministration of an Adhesive Conductive Hydrogel Patch and an Injectable Hydrogel to Treat Myocardial Infarction.

Curcumin (Cur), a phenolic anti-oxidant compound obtained from Curcuma longa plant, possesses a variety of therapeutic properties. However, it is suffered from its low water solubility and low bioavailability property, which seriously restricts its clinical application. In this study, we developed a glycyrrhetinic acid (GA) modified curcumin supramolecular pro-gelator (GA-Cur) and a control compound Nap-Cur by replacing GA with the naphthylacetic acid (Nap). Both compounds showed good water solubility and could form supramolecular gels by disulfide bond reduction triggered by glutathione (GSH) in vitro. Both formed gels could sustainedly release Cur in buffer solutions. We also investigated the cytotoxicity of pro-gelators to HepG2 cells by a MTT assay and determined the cellular uptake behaviours of them by fluorescence microscopy and LC-MS. Due to the over expression of GA receptor in liver cancer cells, our pro-gelator of GA-Cur showed an enhanced cellular uptake and better inhibition capacity to liver tumor cells than Nap-Cur. Therefore, the GA-Cur could significantly inhibit HepG2 cell growth. Our study provides a novel nanomaterial for liver tumor chemotherapy.

A Glycyrrhetinic Acid-Modified Curcumin Supramolecular Hydrogel for liver tumor targeting therapy.

Myocardial infarction (MI) remains the major cause of death and disability in the world, and intramyocardial administration of biomaterials (e.g., hydrogels) along the perimeter of MI region is demonstrated as an effective way for the treatment of MI. The curcumin has anti-inflammation, antioxidation, and antiapoptosis properties, and nitric oxide (NO) molecules are favorable for angiogenesis. This study prepares a mixed component hydrogel capable of releasing both bioactive curcumin and NO for the treatment of MI. The study shows that the combinational treatment of curcumin and NO can remarkably reduce collagen deposition, improve cardiac function, ameliorate adverse myocardium remodeling, suppress apoptosis, and hypertrophy as well as attenuate the expression of matrix metalloproteinases (MMPs) and transforming growth factor-β1 (TGF-β1) and upregulate the expression of silent information regulator 1 than curcumin alone, because of the synergistic action of both molecules and the angiogenesis promotion ability of NO. The results indicate that codelivery of curcumin and NO in a controllable manner by hydrogels might be considered as a promising option for treatment of cardiovascular disease.

A Mixed Component Supramolecular Hydrogel to Improve Mice Cardiac Function and Alleviate Ventricular Remodeling after Acute Myocardial Infarction

Effect of Rosiglitazone, the Peroxisome Proliferator-Activated Receptor (PPAR)-γ Agonist, on Apoptosis, Inflammatory Cytokines and Oxidative Stress in pentylenetetrazole-Induced Seizures in Kindled Mice

Jinliang Li

Papers

A Glycyrrhetinic Acid-Modified Curcumin Supramolecular Hydrogel for liver tumor targeting therapy.

A Mixed Component Supramolecular Hydrogel to Improve Mice Cardiac Function and Alleviate Ventricular Remodeling after Acute Myocardial Infarction

Effect of Rosiglitazone, the Peroxisome Proliferator-Activated Receptor (PPAR)-γ Agonist, on Apoptosis, Inflammatory Cytokines and Oxidative Stress in pentylenetetrazole-Induced Seizures in Kindled Mice