Formulation of Metal-Organic Framework-Based Drug Carriers by Controlled Coordination of Methoxy PEG Phosphate: Boosting Colloidal Stability and Redispersibility.

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Metal-organic framework nanoparticles (nanoMOFs) have been widely studied in biomedical applications. Although substantial efforts have been devoted to the development of biocompatible approaches, the requirement of tedious synthetic steps, toxic reagents, and limitations on the shelf life of nanoparticles in solution are still significant barriers to their translation to clinical use. In this work, we propose a new postsynthetic modification of nanoMOFs with phosphate-functionalized methoxy polyethylene glycol (mPEG-PO3) groups which, when combined with lyophilization, leads to the formation of redispersible solid materials. This approach can serve as a facile and general formulation method for the storage of bare or drug-loaded nanoMOFs. The obtained PEGylated nanoMOFs show stable hydrodynamic diameters, improved colloidal stability, and delayed drug-release kinetics compared to their parent nanoMOFs. Ex situ characterization and computational studies reveal that PEGylation of PCN-222 proceeds in a two-step fashion. Most importantly, the lyophilized, PEGylated nanoMOFs can be completely redispersed in water, avoiding common aggregation issues that have limited the use of MOFs in the biomedical field to the wet form-a critical limitation for their translation to clinical use as these materials can now be stored as dried samples. The in vitro performance of the addition of mPEG-PO3 was confirmed by the improved intracellular stability and delayed drug-release capability, including lower cytotoxicity compared with that of the bare nanoMOFs. Furthermore, z-stack confocal microscopy images reveal the colocalization of bare and PEGylated nanoMOFs. This research highlights a facile PEGylation method with mPEG-PO3, providing new insights into the design of promising nanocarriers for drug delivery.

Cell Survival, Doxorubicin, Drug Carriers, Drug Liberation, HeLa Cells, Humans, Metal-Organic Frameworks, Molecular Dynamics Simulation, Nanoparticles, Phosphates, Polyethylene Glycols
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American Chemical Society (ACS)
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Royal Society (UF160728)
European Research Council (726380)
British Lung Foundation (MPHD17-9)
Engineering and Physical Sciences Research Council (EP/S009000/1)
Engineering and Physical Sciences Research Council (EP/R512461/1)
Engineering and Physical Sciences Research Council (EP/P024947/1)
Engineering and Physical Sciences Research Council (EP/R00661X/1)
Medical Research Council (MR/R005699/1)
Engineering and Physical Sciences Research Council (EP/S019367/1)
This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 Research and Innovation Programme (NanoMOFdeli), ERC-2016-COG 726380 and the EPSRC (EP/S009000/1). N.R. acknowledges support from the Cambridge International Scholarship and the Trinity Henry-Barlow Scholarship (honorary). X.L. acknowledges support from the British Lung Foundation and the China Scholarship Council. D.J.W. thanks EPSRC PhD studentship (EP/R512461/1). D.F.-J. thanks the Royal Society for funding through a University Research Fellowship. The XPS facility and the Tecnai F20 TEM are supported through the Cambridge Royce facilities grant EP/P024947/1 and Sir Henry Royce Institute – recurrent grant EP/R00661X/1