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

J Mater Chem B. 2024 Nov 6;12(43):11156-11164. doi: 10.1039/d4tb01521e.

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)63-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.

MeSH terms

  • Adenine* / chemistry
  • Adenine* / pharmacology
  • Antineoplastic Agents* / chemistry
  • Antineoplastic Agents* / pharmacology
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Chromium* / chemistry
  • Colorectal Neoplasms* / drug therapy
  • Colorectal Neoplasms* / metabolism
  • Colorectal Neoplasms* / pathology
  • Copper* / chemistry
  • Drug Carriers / chemistry
  • Drug Delivery Systems
  • Drug Screening Assays, Antitumor
  • Fluorouracil / chemistry
  • Fluorouracil / pharmacology
  • Humans
  • Metal-Organic Frameworks* / chemistry
  • Metal-Organic Frameworks* / pharmacology
  • Molecular Structure
  • Particle Size
  • Porosity
  • Surface Properties

Substances

  • Copper
  • Antineoplastic Agents
  • Metal-Organic Frameworks
  • Adenine
  • Chromium
  • Fluorouracil
  • Drug Carriers