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

Xu Chen,Han Yu,Oren A Scherman,Clare P Grey,Nakul Rampal,Jonathan J Powell,Xiewen Liu,Giorgio Divitini,Rachel Hewitt,Daniel J Whitaker,Ravin Jugdaohsingh,Yunhui Zhuang,David Fairen-Jimenez,Christopher A O’Keefe,John W Wills

doi:10.1021/jacs.1c03943

Abstract

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.

Highlights

Metal−organic frameworks (MOFs) have shown great potential in a variety of applications such as gas storage and separation,[1,2] sensing,[3] catalysis,[4] and drug delivery[5−7] due to their welldefined, tunable structures and permanent porosities
With nanosized PCN-222 as a model example, we systematically studied the PEGylation process with mPEG−PO3 using ex situ time-dependent techniques combined with molecular dynamics (MD) simulations
We examined the generality and drug storage capabilities of our formulation strategy by successfully extending it to other nanosized Zr−MOFs, including UiO-66, MOF-808, NU-901, and PCN-128 using doxorubicin hydrochloride (DOX) as a model drug

Summary

■ INTRODUCTION

Metal−organic frameworks (MOFs) have shown great potential in a variety of applications such as gas storage and separation,[1,2] sensing,[3] catalysis,[4] and drug delivery[5−7] due to their welldefined, tunable structures and permanent porosities. When performing the drug encapsulation on the lyophilized MOF@PEG−PO3, we found negligible amounts (less than 1 wt %) of DOX loaded This suggests that the infiltrated mPEG−PO3 molecules block access to the internal porosities.

■ ACKNOWLEDGMENTS

Findings

■ REFERENCES