Composite Dynamic Hydrogels Constructed on Boronic Ester Cross-Links with NIR-Enhanced Diffusivity

Abstract

Dynamic hydrogels with thermosensitive cross-links are highly promising platforms for “on-demand” drug delivery systems. However, there is a problem with triggering a response in their whole volume, which reduces their efficiency. To achieve better thermoresponsiveness, a graphene oxide-filled composite hydrogel based on boronic ester cross-links, composed of hyperbranched polyglycidol, HbPGL, and poly­(acrylamide-ran-2-acrylamidephenylboronic acid), poly­(AM-ran-2-AAPBA), has been constructed. The homogeneous embedment of graphene oxide (GO) in the network assured near-infrared (NIR)-photothermal response in its bulk due to the rapid light-to-heat conversion. The rate and amplitude of materials response increase with graphene oxide concentration. The temperature of the hydrogel containing graphene oxide at a concentration of 13.2 mg/mL increased from 36.6 to 41 °C in 29 s upon NIR irradiation. The network diffusivity and the extent of its change with temperature can be regulated by the length of the applied boronic acid-based cross-linking agent. The hydrogel constructed on the shorter copolymer (M n = 23 000 g/mol) displayed a significant increase in diffusivity with temperature. A diffusion ordered NMR study revealed that the diffusion coefficient determined for niacin, a model drug encapsulated in the hydrogel, increased from 6.09 × 10–10 at 25 °C to 1.28 × 10–9 m2/s at 41 °C. In the case of the hydrogel constructed on the longer acrylamide copolymer (M n = 43 000 g/mol), in which physical entanglements stabilize the network, the change of encapsulated niacin diffusion coefficient was significantly smaller, i.e., from 3.83 × 10–10 at 25 °C to 6.63 × 10–10 m2/s at 41 °C. The possibility of on-demand NIR-regulated diffusivity of the reported boronic ester-based hydrogels makes them promising candidates for controlled drug delivery platforms.

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

“…The hydrogel constructed of neat hyperbranched polyglycidol cross-linked with acrylamide copolymer equipped with 2-acrylamidephenylboronic acid moieties, poly­(AM- ran -2-AAPBA), is a reversible network thanks to the dynamic equilibrium between boronic acids, diols, and formed boronic ester species. It is known that the networks constructed of boronic ester cross-links are thermoresponsive. ,, It results from the fact that the formation of boronic esters is an exothermic process, , and thus the increase in temperature is not favorable for the network tie-points that assure the network integrity. The gradual heating of the neat HbPGL-based hydrogel from 10 to 50 °C was accompanied by a consecutive decrease of storage modulus G ′ and then dropped below G ″ at approximately 40 °C (Figure S72), which corresponds to the transition of the hydrogel to the liquid state as a result of the equilibrium shift to substrates, i.e., boronic acids and diols (Scheme ).…”

“…From one side, the recombination rate of the binding sites is crucial, whereas, from the other side, the sufficient chain dynamics of the individual macromolecules is indispensable to enable mobility of the interacting sites to ensure the cross-link reformation . The reforming ability of boronic ester cross-links in the neat HbPGL-based network is assured not only by a sufficient rate of exchange between the product (boronic ester) and substrates, i.e., boronic acid and 1,2-diol (Scheme ), but also by the high mobility of HbPGL macromolecules in the network, which assures that binding sites can meet once again. , The relaxation time (τ R ) of macromolecules engaged in the network formation gradually decreased with the increase of the hydrophobization degree of the applied HbPGL. These data input that the highly hydrophobized HbPGL macromolecules are significantly constrained in the network, and in spite of the presence of dynamic boronic ester-based cross-links, the self-healable properties of hydrogels are reduced.…”

“…Therefore, dynamic hydrogels, i.e., networks constructed of reversible cross-links, are the most suitable systems for the construction of drug carriers. The reversible character of cross-links can assure not only the (self)-healing ability, injectability, and controlled diffusivity but also the gradual decomposition, which are of great importance in view of the intravaginal applications. − …”

“…Diol groups present in the terminal units (approx. 30 mol % of all constitutional units) in the macromolecule corona can form reversible cross-links with boronic acid moieties, generating both self-healable and injectable dynamic hydrogel systems. ,, A tree-like structure of HbPGL delivers nanosized pockets for low-molecular drug molecules. ,, The efficient encapsulation of water-insoluble drug solubilization in HbPGL, however, requires the prior hydrophobization of monohydroxyl linear units (approx. 40 mol % of all constitutional units) located in the HbPGL core. − This synthetic strategy leads to the formation of unimolecular micelles, with the inner part being a reservoir for hydrophobic molecules, and a diol-rich shell that provides the solubility of the whole construct in water.…”

Boronic Acid Esters and Anhydrates as Dynamic Cross-Links in Vitrimers

“…The dynamic character of boronic ester linkages, manifested by high rates of the transesterification reaction, has also attracted polymer materials scientists as it can be used for the construction of dynamically cross-linked networks, in bulk, in organic solvents, or in aqueous media to make hydrogels. Boronic acid-based hydrogels are extensively researched for biomedical applications due to their self-healing properties and stimuli-responsiveness [ 30 , 31 , 32 , 33 , 34 , 35 ].…”