Tailoring drug release profile of low-molecular-weight hydrogels by supramolecular co-assembly and thiol–ene orthogonal coupling

Abstract

We describe a general user-friendly platform for fine-tuning the drug release properties of low-molecular-weight hydrogels by a combination of supramolecular co-assembly of complementary molecular structures and controlled photochemical thiol-ene cross-linking.Other critical features such as thermomechanical stability and morphology of the nanostructured hydrogels are also tailored by this approach.Molecular functional gels able to immobilize a large number of solvent molecules have been a subject of study for well over a century. 1 These hierarchical, self-assembled, and viscoelastic materials may be considered to be either hard or soft based on their rheological characteristics, 2 and can be categorized into two major types according to their driving forces for molecular aggregation: chemical gels, 3 based on covalent bonds, and physical gels, 1,4 based on non-covalent bonds. 'Bottom-up' processing of stable and stimuliresponsive gels has allowed their use in important applications (e.g. regenerative medicine, sensors, nanoelectronics, etc.). 5 Nevertheless, the search for a universal platform to fine-tune their functional properties, especially in the case of gels made of low-molecularweight-gelators (LMWGs), continues being a great scientific challenge for the creation of shape-controlled and robust functional soft-materials. 6-8 On the other hand, Sharpless and co-workers introduced, early in this decade, the valuable concept of 'click' chemistry, 9 exemplified by the copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC). 10 After the first 'boom' caused by the versatility of the CuAAC, 11 the century-old thiol-ene coupling (TEC) 12 has emerged as a competitive orthogonal strategy for the high-yield synthesis of complex functional networks under mild conditions. 13,14 In this communication, we report the supramolecular co-assembly (SMCA) of complementary structures followed by controlled TEC as a new user-friendly strategy for fine-tuning the drug release kinetics of self-assembled hydrogels made of LMWGs. In addition, its effect on the sol-to-gel transition temperature (T gel ) and morphology of the materials is also described.The hydrogelation ability of LMW hydrogelator dibenzoyl-L-cystine (1) at very low concentrations (0.2 wt%) was already noted in 1892 15 and revisited by Menger and Caran in the late 90's. 16 The gelation phenomenon is driven here by a favorable backbone orientation (CH 2 -S-S-CH 2 dihedral angle $87 to 99 ) enhanced by cooperative hydrogen-bonding and p-p stacking interactions (Fig. 1). Inspired by our previous studies directed towards the mechanical stabilization of organogels via CuAAC, 17 pseudocomplementary compounds 2-4 were synthesized by incorporation of terminal alkene units. 18 In contrast to other LMWGs, 19 the simple co-assembly process of LMWG 1 at 0.2 wt% in water with the corresponding alkene-containing analogues 2, 3 or 4 (under optimized molar ratio 1 : (2-4) ¼ 10 : 1) did not improve the mechanical strength of the fragile original hydrogel. 18 The stability of the h...

“A novel highly stable and injectable hydrogel based on a conformationally restricted ultrashort peptide”

“…For release study, 5 mL of PBS was placed on top of the gels and 1.0 mL of samples were withdrawn from the release medium at different time intervals (2 hr, 4 hr, 8 hr, 16 hr, 24 hr, 48 hr, 72 hr, 96 hr and 120 hr) and replaced with fresh PBS. Contents of both hydrophilic and hydrophobic drugs into the overlying PBS was monitored by methods reported earlier 13 52 53 54 55 56 using UV-vis spectroscopy. The percentage release was calculated using an equation: Percentage Release = (Absorbance of drug released in PBS/Absorbance of total drug encapsulated in gel) X 100.…”

“…The relative diffusion coefficient (D) of drugs in the gel matrix was calculated by using the non-steady state diffusion model equation given as: M t /M ∞ = 4 X (D t /π λ 2 ) 1/2 , where, M t is the total amount of drug released at the time of measurement, M ∞ is the total amount of drug that was kept in the matrix, λ represents the hydrogel thickness, t is the time of measurement, and D is the diffusion coefficient of the drug 55 . The ClogP values of the drugs were obtained from “drug bank” and “pubchem”.…”

Self-assembled sorbitol-derived supramolecular hydrogels for the controlled encapsulation and release of active pharmaceutical ingredients

“…17 Other reports have controlled gelation using (e.g.) pH, 18 photoirradiation, 19 or crosslinking reactions 20 to trigger or inhibit drug release. Recently, we have worked with gelators based on the 1,3:2,4-dibenzylidene sorbitol (DBS) framework.…”

Isosteric Substitution of 4H-1,2,4-Triazole by 1H-1,2,3-Triazole in Isophthalic Derivative Enabled Hydrogel Formation for Controlled Drug Delivery

“…Concentrations above this valuewere not evaluated in this work. In a previous report, we demonstrated the use of a supramolecular co-assembly strategy for fine-tuning the properties of hydrogels for drug delivery applications 51. With this in mind, we checked that stable gels could also be made of mixtures click-TIA:5-TIA at different molar ratios being click-TIA always the major component (see below).…”