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 frameworks (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 that this compound was able to capture several drug molecules: 5-fluorouracil (5-FU), 5-aminosalicylic acid (5-ASA), 4-aminosalicylic acid (4-ASA) and theophylline (THEO). Their release follows a pseudo-first-order kinetics with desorption half-lives ranging from 2.2 to 4.7 hours. In this sense, a novel approach is proposed using bulkier raffinose and cholesterol as pore-blocking molecules. Cholesterol exhibited the best performance as a blocking molecule increasing the desorption half-life up to 8.2 hours. Cytotoxicity and RNA-seq transcriptomic assays carried out on human colorectal cancer cell cultures showed, on one hand, that the Cu6Cr porous material exhibits a proliferative effect, probably coming from the over-expression of MIR1248 and SUMO2 genes, and on the other hand, that there is a delay in the emergence of the cytotoxicity of 5-FU as expected for a slower release.