Drug-delivery and biological activity in colorectal cancer of a supramolecular porous material assembled from heptameric chromium-copper-adenine entities

Abstract

The therapeutic application of drugs often faces challenges due to non-specific distribution, inadequate dosification and degradation, which limits their efficacy. Two primary strategies are employed to overcome these issues: the use of derivatives of the active substances and incorporation of those into porous materials. The latter, involving materials such as zeolites, metal-organic framewoks (MOFs), and hydrogels, has shown promising results in protecting the active ingredients from degradation and enabling a controlled release. This study focuses on supramolecular metal-organic frameworks (SMOFs), which leverage supramolecular interactions for enhanced pore size control. [Cu6Cr(μ-adeninato-κN3:κN9)6(μ3-OH)6(μ-OH2)6](SO4)1.5⋅nH2O (Cu6Cr) was chosen for its flexible porous structure, water-stability, and paramagnetic properties. Magnetic sustentation studies showed this compound was able to capture several drug molecules (5-fluorouracil, 5-aminosalicylic acid, 4-aminosalicylic acid and theophylline). Their release follows a pseudo-first-order kinetic with desorption half-lives ranging from 2.2 to 4.7 hours. In these sense, a novel approach is proposed using bulkier raffinose and cholesterol as pore-blocking molecules. Cholesterol exhibited the best performance as blocking molecule increasing the desorption half-life up to 8.2 hours. Cytotoxicity and RNA-seq transcriptomics assays carried out on human colorectal cancer cell culture showed on one hand, that Cu6Cr porous material shows a proliferative effect, probably coming from the over-expression of MIR1248 and SUMO2 genes, and on the other hand, that there is a delay on the emergence of the cytoxicity of 5-fluorouracil as expected for a slower release.