PH and ultrasound dual-responsive drug delivery system based on PEG–folate-functionalized Iron-based metal–organic framework for targeted doxorubicin delivery

Abstract

In recent years, the use of metal–organic frameworks (MOFs) as drug nanocarriers has gained attention because of their extraordinary physical and chemical properties. In this work, dual-responsive iron-based MOFs were synthesized via the microwave-assisted method using FeCl 3 .6 (H 2 O) as the metal cluster and 2-aminoterephthalic acid (NH 2 -BDC) as the organic linker (namely NH 2 -Fe-BDC) and loaded with the anti-cancer drug doxorubicin (DOX). The DOX-loaded MOFs were further functionalized with polyethylene glycol-folate (PEG–FA), yielding PEG–FA-NH 2 -Fe-BDC. The folate moiety is used to specifically target several cancers overexpressing the folate receptor (FR). These nanoparticles were characterized using Fourier-Transform Infrared Spectroscopy (FTIR), X-ray Diffraction (XRD), Thermogravimetric Analysis (TGA), and Dynamic Light Scattering (DLS). The FTIR confirmed the PEG–FA conjugation to the MOFs, while the XRD patterns confirmed the crystallinity of the nanoparticles. TGA results demonstrated the thermal stability of the MOFs. Moreover, the DLS analysis showed that regular MOFs had a particle diameter of 577 nm, while the PEG–FA-functionalized MOF had a particle diameter of 461 nm, which demonstrates the improved colloidal stability of the functionalized MOF. The DOX encapsulation efficiency was determined to be approximately 97%, while the encapsulation capacity was around 14.5 wt%. Furthermore, the in-vitro release profiles were studied under different pH values (5.3 and 7.4) with and without low-frequency ultrasound (LFUS, at 40 kHz). The results confirmed the sonosensitivity of the nanovehicles, with US-triggered release efficiency reaching up to 90% after 280 min (at a pH of 5.3). The MTT study revealed that these nanocarriers are non-toxic at lower concentrations. Their toxicity increases at higher concentrations. Furthermore, the cellular uptake was investigated via flow cytometry, and the results showed that the conjugation of the PEG-FA moiety to the MOF’s surface significantly enhanced uptake by cancer cells. Accordingly, this study showed the pH/US dual-responsive capability of NH 2 -Fe-BDC and PEG–FA-NH 2 -Fe-BDC.