Advanced Delivery of Therapeutics Using Metal-Organic Frameworks (MOFs) in 3D In Vitro Respiratory and Cancer Cell Models

Therapeutics used in the treatment of various types of cancer and respiratory diseases present significant drawbacks such as limited efficacy and severe off-target toxicity. These issues hinder their success and support the current need to develop enhanced formulations to improve the prognosis of patients. Metal-organic frameworks (MOFs) have attracted much attention for biomedical applications since they can encapsulate and thus enhance the safety and efficacy of therapeutics. MOFs are a class of biocompatible nanoporous materials with exceptionally high surface area (&gt;8,000 m²/g) and drug loading capabilities (&gt;70% drug weight).<br/><br/>In this work, molecular simulations were performed to find a MOF structure with a porosity compatible with different chemotherapeutics. PCN-222, a zirconium-based MOF with mesopore size (&gt; 2 nm), was selected due to its high porosity and biocompatibility. Chemotherapeutics used to treat breast and lung cancer (fulvestrant and temozolomide, respectively) were then loaded into PCN-222. Subsequently, a PEG coating was applied to drug-loaded PCN-222 to improve stability and slow-release profile. The resulting PEGylated drug-loaded MOFs were characterized for drug loading capacity and physiochemical properties, including size, aqueous stability, crystalline structure, and porosity. Drug loaded-PCN-222 was tested using <i>in vitro</i> models of breast and lung cancer (MCF7 and A549 cells, respectively). The effects of this nanomaterial’s characteristics (including size, composition, and surface characteristics) on toxicity were assessed by metabolic activity. Live-cell imaging and confocal microscopy were used to analyze internalization and cellular interactions of PCN-222.<br/><br/>PCN-222 characterization showed nanoparticles of 120-150 nm in a homogenous dispersion. Drug loading of fulvestrant and temozolomide into PCN-222 was successful for both chemotherapeutics, achieving a loading efficiency of more than 30%. The effect of this nanomaterial on cell toxicity was assessed by a metabolic activity assay and live cell imaging, showing that breast and lung cancer cells tolerated high concentrations of PCN-222. These results highlight the biocompatibility of PCN-222. The PEG coating improved intracellular stability and delayed drug-release capability. PCN-222 showed a high cell internalization efficacy in MCF7 and A549 cells, as seen by confocal microscopy.<br/><br/>PCN-222 showed biocompatibility, high loading capabilities, delayed drug-release, and efficacious cell internalization. Further works using <i>in vivo</i> mouse models are expected to confirm the previous <i>in vitro</i> data. Finally, PCN-222 is a promising nanocarrier able to increase the efficacy and safety of current standard-of-care chemotherapeutics and facilitate the progress of nanomaterials for medical applications.