An investigation on the potential of covalent organic frameworks (COFs) to be used as nanocarriers in drug delivery systems

Abstract

Covalent organic frameworks (COFs) are intrinsically designed to accommodate guest molecules in their tuneable, structurally regular pores, which are characterised by high surface areas and large pore volumes. The design of COFs with unique chemical and physical properties, can be extended to the incorporation of active pharmaceutical ingredients (APIs) as guests, to create COF drug carriers. This novel application of COFs to the field of therapeutics, provides an alternative route to (i) enhance the loading capacity of nanoparticle drug delivery systems, (ii) effectively increase drug solubility and protection from degradation in biological environments, and (iii) provide additional control on the distribution and release of the entrapped drug molecules. To date, the development of COF networks, conjugated with smart stimuli-responsive polymers, for use as drug carriers is very limited and unexplored, leaving a significant gap in literature. The aim of this project was to address this gap by structurally engineering new smart COF materials loaded with pharmaceutical molecules, and determining their sensitivity and release response to target stimuli, in simulated physiological conditions. Twelve distinctive diffraction patterns were obtained from four monomer combinations, indicating the formation of new potential COFs, which are currently at different stages of crystal structure determination. FTIR and hot stage microscopy results further confirmed new linkage formation. A fully characterised new cage-based imine and ester linked COF structure, synthesised from the 4 + 2 + 9 condensation of 2-amino-2- (hydroxymethyl)propane-1,3-diol, C6, with terephthalaldehyde, C7, and with pyridine2,5-dicarboxylic acid, C8, using LAG and catalytic amounts of 1:1 1,4-dioxane:1,3,5- trimethylbenzene, was used as the core of the nanocarrier system. Modification of its unit cell parameters and atomic coordinates upon loading of 5-fluoro-1H-pyrimidine-2,4- dione, C14, and conjugation of pH sensitive pyridine-2,6-dicarbaldehyde, C9, electro sensitive 1,1’-ferrocenedicarboxaldehyde, C10, and UV sensitive 4-[(4- aminophenyl)diazenyl]aniline, C11, indicated the physical adsorption of the molecules into the pores and onto the surface of the framework. Control on the release of the loaded API molecules was confirmed in vitro for the three final complexes, through an enhanced release at the target stimuli, with the biggest increase exhibited by the C9 conjugated complex, and a sustained release for the C10 conjugated complex. This demonstrates the application of COFs as stimuli-responsive nanocarriers in drug delivery systems, which by proof of concept can be extended to other frameworks, and API and smart molecules.