Self-Healable, Injectable Hydrogel with Enhanced Clotrimazole Solubilization as a Potential Therapeutic Platform for Gynecology

Abstract

Injectable, self-healing hydrogels with enhanced solubilization of hydrophobic drugs are urgently needed for antimicrobial intravaginal therapies. Here, we report the first hydrogel systems constructed of dynamic boronic esters crosslinking unimolecular micelles, which are a reservoir of antifungal hydrophobic drug molecules. The selective hydrophobization of hyperbranched polyglycidol with phenyl units in the core via ester or urethane bonds enabled the solubilization of clotrimazole, a water-insoluble drug of broad antifungal properties. The encapsulation efficiency of clotrimazole increases with the degree of the HbPGL core modification; however, the encapsulation is more favorable in the case of urethane derivatives. In addition, the rate of clotrimazole release was lower from HbPGL hydrophobized via urethane bonds than with ester linkages. In this work, we also revealed that the hydrophobization degree of HbPGL significantly influences the rheological properties of its hydrogels with poly(acrylamide-ran-2-acrylamidephenylboronic acid). The elastic strength of networks (G N ) and the thermal stability of hydrogels increased along with the degree of HbPGL core hydrophobization. The degradation of the hydrogel constructed of the neat HbPGL was observed at approx. 40 °C, whereas the hydrogels constructed on HbPGL, where the monohydroxyl units were modified above 30 mol %, were stable above 50 °C. Moreover, the flow and selfhealing ability of hydrogels were gradually decreased due to the reduced dynamics of macromolecules in the network as an effect of increased hydrophobicity. The changes in the rheological properties of hydrogels resulted from the engagement of phenyl units into the intermolecular hydrophobic interactions, which besides boronic esters constituted additional cross-links. This study demonstrates that the HbPGL core hydrophobized with phenyl units at 30 mol % degrees via urethane linkages is optimal in respect of the drug encapsulation efficiency and rheological properties including both self-healable and injectable behavior. This work is important because of a proper selection of a building component for the construction of a therapeutic hydrogel platform dedicated to the intravaginal delivery of hydrophobic drugs.

Cross-linkable star-hyperbranched unimolecular micelles for the enhancement of the anticancer activity of clotrimazole

“…Contrary to previously published reports on hydrogels constructed on unimolecular micelles made of hyperbranched polyglycidol hydrophobized directly underneath the terminal units by modification of the monohydroxyl groups, 15 the star-hyperbranched amphiphiles in this study formed both injectable (ESI,† Video film) and self-healable hydrogels (Fig. 8).…”

“…[11][12][13] In recent years, there has been growing interest in unimolecular micelles capable of both encapsulating water-insoluble drugs and forming hydrogels. 14,15 This combination of features offers great potential for unimolecular micelles for applications in topical therapies requiring the controlled, prolonged, but infrequent delivery of a drug that must be released at the target site. 14,15 Hydrogels, because of their swollen state along with elastic properties, mimic the properties of the extracellular matrix of most tissues, with minimal irritation of the surrounding tissues when applied in vivo.…”

“…14,15 This combination of features offers great potential for unimolecular micelles for applications in topical therapies requiring the controlled, prolonged, but infrequent delivery of a drug that must be released at the target site. 14,15 Hydrogels, because of their swollen state along with elastic properties, mimic the properties of the extracellular matrix of most tissues, with minimal irritation of the surrounding tissues when applied in vivo. [16][17][18] Furthermore, the highly porous structure of hydrogels facilitates the encapsulation of significant amounts of drugs, making them of great interest as drug-delivery platforms.…”

“…Recently, we synthesized hydrogels based on single-molecule micelles composed of hyperbranched polyglycidol, the inner part of which, directly under the 1,2-diol-rich corona of the macromolecules, was hydrophobized with phenyl groups. 15 This was achieved by modifying the monohydroxyl groups of the linear constitutive units, while the 1,2-diol molecules remained intact and were used to form a hydrogel with polyacrylamide with 2-acrylamide-phenylboronic acid motifs. The water solubility of these constructs was, however, strictly dependent on the degree of hydrophobization, which reduced their biomedical potential.…”

Hydrophobized Hydrogels: Construction Strategies, Properties, and Biomedical Applications

“…To overcome this limitation, unimolecular micelles have been used, however, as the main building component in the construction of hydrogels. [54,70,71] For this goal, unimolecular micelles can be embedded in a thermogelating aqueous solution of triblock copolymer [70] or participate in the network formation thanks to the presence of an active binding site in the micelle' corona. [54,71] Chen et al distributed multiarm star amphiphilic poly(amidoamine)-poly(valerolactone)-poly(ethylene glycol), PAMAM-PVL-PEG (Scheme 6b) in 23 wt% aqueous solution of a triblock copolymer of poly(lactide-co-glycolide)-poly(ethylene glycol)-poly(lactide-co-glycolide) at low temperature (10 °C), which in vivo conditions formed the hydrogel.…”