MOF–Thermogel Composites for Differentiated and Sustained Dual Drug Delivery

Abstract

In recent years, multidrug therapy has gained increasing popularity due to the possibility of achieving synergistic drug action and sequential delivery of different medical payloads for enhanced treatment efficacy. While a number of composite material release platforms have been developed, few combine the bottom-up design versatility of metal−organic frameworks (MOFs) to tailor drug release behavior, with the convenience of temperature-responsive hydrogels (or thermogels) in their unique ease of administration and formulation. Yet, despite their potential, MOF− thermogel composites have been largely overlooked for simultaneous multidrug delivery. Herein, we report the first systematic study of common MOFs (UiO-66, MIL-53(Al), MIL-100(Fe), and MOF-808) with different pore sizes, geometries, and hydrophobicities for their ability to achieve simultaneous dual drug release when embedded within PEG-containing thermogel matrices. After establishing that MOFs exert small influences on the rheological properties of the thermogels despite the penetration of polymers into the MOF pores in solution, the release profiles of ibuprofen and caffeine as model hydrophobic and hydrophilic drugs, respectively, from MOF−thermogel composites were investigated. Through these studies, we elucidated the important role of hydrophobic matching between MOF pores and loaded drugs in order for the MOF component to distinctly influence drug release kinetics. These findings enabled us to identify a viable MOF−thermogel composite containing UiO-66 that showed vastly different release kinetics between ibuprofen and caffeine, enabling temporally differentiated yet sustained simultaneous drug release to be achieved. Finally, the MOF−thermogel composites were shown to be noncytotoxic in vitro, paving the way for these underexploited composite materials to find possible clinical applications for multidrug therapy.

Poly(l-threonine-co-l-threonine Succinate) Thermogels for Sustained Release of Lixisenatide

“…Since the pioneering research on a poly(lactide- co -glycolide)/poly(ethylene glycol) (PLGA/PEG) system as a biodegradable thermogel, various systems, such as polycaprolactone/PEG, polyphosphazene/PEG, chitosan/glycerol phosphate, glycochitosan hexanol, and PEG/polyester multiblock copolymers, and polypeptide/PEG have been reported for their characteristic transition mechanism and potential biomedical applications. − The sol-to-gel transition mechanism of PLGA/PEG thermogel involves dehydration, followed by hydrophobic aggregation of semibald micelles. , In the case of polypeptide/PEG systems, changes in polypeptide secondary structure as well as dehydration of the PEG block were reported. , Chitosan/glycerol phosphate systems undergo thermogelation through hydrophobic aggregation involving deprotonation of ammonium groups of chitosan and increased ionic strength of phosphate salts . Recently, thermogel composite systems containing nano/microparticles, such as hydroxyapatite, silica, polyhedral oligomeric silsesquioxanes (POSS), and metal–organic framework (MOF) have been investigated to control mechanical properties as well as drug release profiles. − The facile control of sol-to-gel transition temperatures and mechanical properties by variations in polymer concentration and composition, minute polymer structural changes, and the addition of external substances are other advantages of thermogels. , The sol-to-gel transition properties of an aqueous polymer solution can even be tuned by mixing polymers with different transition temperatures. , Furthermore, the simple mixing of the aqueous polymer solution and drugs for injectable formulation and microfiltration for sterilization are additional advantages of thermogels. Various thermogel applications have been reported, including drug delivery, postsurgical adhesion prevention, three-dimensional cell culture, injectable tissue engineering, long-acting anesthetics, and wound dressing. ,− As drug delivery systems, however, thermogels suffer from an initial burst release of hydrophilic drugs, such as polypeptides and protein drugs, due to the partitioning of the drug in the hydrophilic PEG domain of the gel, as well as weak interactions between the drug and polymers.…”