Nanostructured metal–organic frameworks and their bio

Review

Nanostructured metal–organic frameworks and their bio-related applications

Highlights

MOFs have emerged as promising candidates for biomedical applications.

Relevant bioapplications deal with drug release, imaging, biocatalysis or sensing.

Nanometric MOFs are more suitable for the different administration routes.

MOF miniaturization governs their in vivo fate and toxicity and/or activity.

Specific synthetic and shaping methods are required for a bioapplications.

Abstract

Miniaturization of metal–organic frameworks (MOFs) results of great interest in order to integrate these materials in strategic applications such as sensing or drug delivery. This emerging class of nanoscaled MOFs (nanoMOFs), combining the intrinsic properties of the porous materials and the benefits of nanostructures, are expected to improve in some cases the performances of classical bulk crystalline MOFs. In the field of biomedicine, the benefits of MOF miniaturization have already been proved to be effective, not only because establishes a strong influence over the choice of the administration route but also governs their in vivo fate and therefore, their toxicity and/or activity.

The scope of this review focuses on the preparation of nanostructured MOFs and their related biomedical applications. We will cover all aspects concerning the various synthetic methods reported so far, as well as the shaping and surface engineering routes required for their use in biomedicine.

Introduction

The field of hybrid ordered porous materials has been growing very rapidly within the past decade not only as a result of the still increasing number of new structures and compositions, but also due to important efforts to introduce new or optimized functionalities. Metal–organic frameworks (MOFs) or porous coordination polymers (PCPs) are a specific type of hybrid inorganic–organic solids, built up from the assembly of inorganic secondary building units (SBUs), and easily tuneable polycomplexant organic linkers, which present permanent pores in their structure [1]. In the early stages of the field, their foremost potential applications were based on storage and separations of fluid mixtures due to their regular and large porous structure. More recently, these applications have been extended to energy storage, sensors, magnetic and electronic devices, heterogeneous catalysis and biomedicine.

The miniaturization of MOFs results of great interest in order to integrate these materials in strategic applications such as sensing or drug delivery. This emerging class of nanoscaled MOFs (nanoMOFs), combining the intrinsic properties of the porous materials and the benefits of nanostructures, are expected to improve in some cases the performances of classical bulk crystalline MOFs. In the field of biomedicine, the benefits of MOF miniaturization have already been proved to be effective, not only because establishes a strong influence over the choice of the administration route but also governs their in vivo fate and therefore, their toxicity and/or activity [2]. For instance, when considering the use of nanoparticles (NPs) as nanocarriers, the large (external) surface area of NPs may not only favor an enhanced bioactivity but also permit an efficient surface modification, facilitating their circulation, targeting properties and improving their chemical and colloidal stability [3]. In particular, these features govern their in vivo fate. Thus, particles smaller than 500

nm usually enter the cells by endocytosis against likely phagocytosis for larger ones [4], [5]. Also, it is known that the size plays a decisive role on the splenic and renal clearance: particles larger than 200

nm are more likely removed through the splenic filtration system, whereas those smaller than 10

nm are cleared through kidney's filtering system [6]. Finally, the size strongly impacts the circulating time in the bloodstream, modifying the interaction with the endothelium and then, their biodistribution [7]. As an example, particles smaller than 250

nm exhibit a higher crossing through the leaky endothelium (i.e. extravasation), being useful for tumor targeting [8], [9]. Finally, depending on the targeted functionalities, these nanomaterials must meet a series of pre-requisites such as minimal toxicity, good blood compatibility, low immunogenicity together with a tunable degradation and, often, suitable mechanical properties [10], [11].

The scope of this review focuses on the preparation of nanostructured MOFs and their related biomedical applications. We will cover all aspects concerning the various synthetic methods reported so far, as well as the shaping and surface engineering routes required for their use in biomedicine. In spite of the recommended definition of a nanomaterial, typically accepted as materials within the 1–100

nm range (at least one dimension and for ≥50% of the particles in the number size distribution), in nanomedicine, larger particles (>500–1000

nm) are often considered as nanoparticles [12]. Therefore, we will cover both submicronic (<1000

nm) and nanometric (1–100

nm) particles often using the same terminology of nanoparticles.

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Section snippets

Synthesis of MOF nanoparticles

In the last years, the development of suitable synthetic methodologies and novel approaches for the preparation of nanoMOFs have enabled to gain understanding on the crystal growth as well as a better control over the size of the material without hampering their intrinsic porous characteristics [13], [14], [15], [16], [17]. Consequently, advanced engineered nanoMOFs displaying improved performances and novel functionalities have been obtained [18], [19]. We report here the preparation of

MOF formulation

As previously established, the control of the particle size is a limiting factor in the field of biomedicine, especially when considering their administration via the most common pathways (i.e. oral, intravenous, intranasal, cutaneous, ocular, otic, and so on) [69]. The physicochemical properties of the NPs (i.e. particle size, surface charge, rheological properties, colloidal stability) will determine the NPs affinity by different biological structures and/or matrices (formulations), their

Biomedical applications

Recent reports demonstrate that MOFs are of potential interest in biomedical applications, acting as new therapeutic and/or diagnostic materials, among others. When considering a material for biological applications, particularly for in vivo medical uses, very strict demands are subjected for commercial activity. In the particular case of MOFs, these needs involve toxicological considerations, its chemical stability and a convenient biodistribution. Although far away from clinical applications,

Concluding remarks

This review offers an extensive overview of the recent advances concerning the miniaturization of MOFs and its related biomedical applications, ranging from synthetic procedures and shaping of nanoMOFs to the foremost uses towards their integration in biomedicine.

In the first section, we summarize the most employed methodologies for the preparation of nanoMOFs, including typical procedures as hydro–solvothermal synthesis but also more innovative ones, which imply for instance continuous flow

Acknowledgements

This work was partially supported by the UVSQ, CNRS and by two public grants overseen by the French National Research Agency (ANR), the ANR 2010-MatePro VirMIL and the Laboratoire d'Excellence NanoSaclay (ref: ANR-10-LABX-0035) as part of the “Investissements d’Avenir” program. Also, M.G.-M. thanks the EU for a Marie Sklodowska-Curie postdoctoral fellowship (H2020-MSCA-IF-EF-658224).

The manuscript was written through contributions of all authors. M. Giménez-Marqués and T. Hidalgo equally

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These authors contributed equally to this work.

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