Highly Porous Hybrid Metal–Organic Nanoparticles Loaded with Gemcitabine Monophosphate: a Multimodal Approach to Improve Chemo‐ and Radiotherapy

Abstract

Nanomedicine recently emerged as a novel strategy to improve the performance of radiotherapy. Herein we report the first application of radioenhancers made of nanoscale metal‐organic frameworks (nanoMOFs), loaded with gemcitabine monophosphate (Gem‐MP), a radiosensitizing anticancer drug. Iron trimesate nanoMOFs possess a regular porous structure with oxocentered Fe trimers separated by around 5 Å (trimesate linkers). This porosity is favorable to diffuse the electrons emitted from nanoMOFs due to activation by γ radiation, leading to water radiolysis and generation of hydroxyl radicals which create nanoscale damages in cancer cells. Moreover, nanoMOFs act as “Trojan horses”, carrying their Gem‐MP cargo inside cancer cells to interfere with DNA repair. By displaying different mechanisms of action, both nanoMOFs and incorporated Gem‐MP contribute to improve radiation efficacy. The radiation enhancement factor of Gem‐MP loaded nanoMOFs reaches 1.8, one of the highest values ever reported. These results pave the way toward the design of engineered nanoparticles in which each component plays a role in cancer treatment by radiotherapy.

Drug-Loaded Lipid-Coated Hybrid Organic-Inorganic “Stealth” Nanoparticles for Cancer Therapy

“…This is in line with previous studies showing the efficient internalization of nanoMOFs bearing or not a lipid coating in pancreatic, breast, or bladder cancer cell lines (Rodriguez-Ruiz et al, 2015;Wuttke et al, 2015;Li et al, 2019a). It was recently shown that nanoMOFs acted as "Trojan horses" internalized by cancer cells, carrying their Gem-MP cargo to interfere with DNA (Li et al, 2019a). In this study it was shown that interestingly, the presence of a lipid coating (PEGylated or not) did not reduce the nanoMOF anticancer efficacy on SKOV3 ovarian cancer cells.…”

“…At equivalent Gem-MP concentrations, whatever the drug loading (8 or 20 wt%) and the amount of nanoMOF in contact with the cells (10 to 100 µg/mL), the drug-loaded nanoMOFs outperformed the free drug in terms of toxicity on cancer cells (Figure 7 and Supplementary Figure S5). This is in line with previous studies showing the efficient internalization of nanoMOFs bearing or not a lipid coating in pancreatic, breast, or bladder cancer cell lines (Rodriguez-Ruiz et al, 2015;Wuttke et al, 2015;Li et al, 2019a). It was recently shown that nanoMOFs acted as "Trojan horses" internalized by cancer cells, carrying their Gem-MP cargo to interfere with DNA (Li et al, 2019a).…”

“…After incubation at room temperature under gentle stirring for several hours (12 h for Amox and 4 h for Gem-MP), the nanoMOFs were recovered by centrifugation at 10,000 g for 10 min. The non-encapsulated drug in the supernatant was quantified by adapting previously described High Performance Liquid Chromatography (HPLC) methods ( Li et al, 2019a , b ). Specifically, HPLC analysis was performed on an Agilent system using a tunable UV absorbance detector.…”

“…Iron (III) trimesate nanoMOFs ( Figure 1 upper panel) are among the most widely studied MOFs for drug delivery ( Horcajada et al, 2010 ; Agostoni et al, 2013 ; Baati et al, 2013 ; Simon-Yarza et al, 2016 ; Li et al, 2019a ). Recently, they were shown to display several intrinsic properties of main interest in the nanomedicine field: radio-enhancement properties when submitted to γ-irradiation ( Li et al, 2019a ); they behaved as T 2 -weighted MRI imaging contrast agents ( Horcajada et al, 2010 ) and they had intrinsic antibacterial effects killing intracellular bacteria ( Li et al, 2019b ).…”

Deciphering the Structure and Chemical Composition of Drug Nanocarriers: From Bulk Approaches to Individual Nanoparticle Characterization

“…Organic compounds remain the most employed materials for drug incorporation and for engineering multifunctional shells. Additionally, the presence of metals in drug nanocarriers' composition offers new functionalities, such as antibacterial or antifungal properties, [7] radioenhancement [8] or imaging abilities for personalized therapies. [9] More recently, nanoscale hybrid metal-organic frameworks (MOFs) emerged as versatile Drug nanocarriers (NCs) with sizes usually below 200 nm are gaining increasing interest in the treatment of severe diseases such as cancer and infections.…”