A non-covalent “click chemistry” strategy to efficiently coat highly porous MOF nanoparticles with a stable polymeric shell

Highlights

• A non-covalent “click chemistry” strategy was developed to coat nanoMOFs.

• Phosphorylated β-cyclodextrin derivatives efficiently coat nanoMOFs postsynthetically.

• The higher the phosphate grafting density, the higher the coating stability.

• The versatile coating does not affect the nanoMOF porosity, adsorption and release abilities.

Abstract

Background

Metal-organic framework nanoparticles (nanoMOFs) are biodegradable highly porous materials with a remarkable ability to load therapeutic agents with a wide range of physico-chemical properties. Engineering the nanoMOFs surface may provide nanoparticles with higher stability, controlled release, and targeting abilities. Designing postsynthetic, non-covalent self-assembling shells for nanoMOFs is especially appealing due to their simplicity, versatility, absence of toxic byproducts and minimum impact on the original host-guest ability.

Methods

In this study, several β-cyclodextrin-based monomers and polymers appended with mannose or rhodamine were randomly phosphorylated, and tested as self-assembling coating building blocks for iron trimesate MIL-100(Fe) nanoMOFs. The shell formation and stability were studied by isothermal titration calorimetry (ITC), spectrofluorometry and confocal imaging. The effect of the coating on tritium-labeled AZT-PT drug release was estimated by scintillation counting.

Results

Shell formation was conveniently achieved by soaking the nanoparticles in self-assembling agent aqueous solutions. The grafted phosphate moieties enabled a firm anchorage of the coating to the nanoMOFs. Coating stability was directly related to the density of grafted phosphate groups, and did not alter nanoMOFs morphology or drug release kinetics.

Conclusion

An easy, fast and reproducible non-covalent functionalization of MIL-100(Fe) nanoMOFs surface based on the interaction between phosphate groups appended to β-cyclodextrin derivatives and iron(III) atoms is presented.

General significance

This study proved that discrete and polymeric phosphate β-cyclodextrin derivatives can conform non-covalent shells on iron(III)-based nanoMOFs. The flexibility of the β-cyclodextrin to be decorated with different motifs open the way towards nanoMOFs modifications for drug delivery, catalysis, separation, imaging and sensing. This article is part of a Special Issue entitled “Recent Advances in Bionanomaterials” Guest Editors: Dr. Marie-Louise Saboungi and Dr. Samuel D. Bader.

Introduction

The use of nanotechnology for drug delivery applications is changing the landscape of pharmaceutical and biotechnology industries opening new opportunities for more efficient and personalized treatments. Among the large variety of nanomaterials explored for this purpose, metal-organic frameworks (MOFs) [1] keep attracting a growing interest due to their useful applications in gas storage, separation, catalysis, sensing, etc. [2], [3], [4] and, more recently, in biomedicine [3], [4], [5], [6], [7], [8], [9], [10], [11]. Some of the key advantages of MOFs are their easily tunable and versatile composition, as well as their large variety in terms of pore sizes and shapes. In particular, nanosized MOFs (nanoMOFs) based on porous iron(III) polycarboxylates emerged as a new class of biodegradable and non-toxic nanomaterials [12]. Various challenging therapeutic molecules could be entrapped within the interconnected porous structure reaching unprecedented loadings (within the 20–70 wt% range). In addition, a controlled release in simulated body fluid was achieved, while the iron(III) nanoMOFs exhibited high relaxivities making these particles interesting candidates for teranostics [5].

The use of nanomaterials in biomedicine has risen new challenging goals such as: (i) targeted drug delivery; (ii) bypassing across biological barriers; (iii) delivery of drugs to intracellular targets and (iv) imaging of sites of drug delivery. To address these challenges, the use of nanoparticles with engineered shells is mandatory since the in vivo fate of nanoparticles (biodistribution, pharmacokinetics and targeting abilities) is intimately related to their surface physicochemical properties [13], [14]. Engineered core-shell nanoparticles should be able not only to contain high drug payloads (preferably, > 20 wt%) and release the drugs in a controlled fashion, but they should be also easily coated through a “green” versatile process without altering neither the drug payloads nor the drug integrity. Besides, the coating shell should be stable enough in biological media to exert its therapeutic activity.

Coating preformed nanoparticles with a stable, covalent coating often involves several time consuming reaction steps and generates side products difficult to be totally removed. Traces of these side products and/or organic solvents might raise toxicological concerns in view of clinical applications. Moreover, during the coating process drugs can leak out or lose their activity. One trend for coating strategies relies on “click chemistry”, and more specifically on the copper-catalyzed azide-alkyne cycloaddition reaction, in reason of its rapidity and possibility of being carried out in aqueous media [15], [16], [17], [18]. However, yields are not always high, especially in the case of bulky molecules due to the formation of alkyne homocoupling side products, among other reasons.

As a strategy to overcome these drawbacks, we have recently reported a non-covalent procedure enabling to coat, practically instantaneously, preformed MIL-100(Fe) (MIL standing for Material from Institute Lavoisier) nanoMOFs, built up from iron(III) octahedral trimers and trimesate linkers (1,3,5-benzene tricarboxylate), with phosphate-decorated cyclooligosaccharide β-cyclodextrin (β-CD) shell (Fig. 1) [19]. The coating was achieved directly in water following a “green” method which does not involve organic solvents, nor produces side products. This strategy took advantage of the ability of polar phosphate groups to coordinatively bind the unsaturated metallic Lewis acid sites on the nanoMOFs surface, forming a stable shell.

β-CD is a naturally occurring cyclic oligosaccharide comprising seven d-glucopyranose units linked by α-(1 → 4) bonds. This biocompatible macrocycle possesses a relatively rigid torus-shaped structure, which defines an inner hydrophobic cavity rimmed by two hydrophilic openings. β-CD is well-known to form inclusion complexes in aqueous solution with a large variety of organic molecules of hydrophobic nature and suitable size and geometry [20], [21], [22] and it is a suitable scaffold for introducing functional groups for targeting and imaging purposes [23]. Due to its ability to improve the physicochemical properties of drugs (stability, solubility and bioavailability) [22] CDs are considered as “smart” components when incorporated in drug delivery devices [24].

In view of these properties, the modification of nanoMOFs cores with β-CD-based shells appears as particularly appealing. This association is feasible due to the fact that β-CD outer diameter is 15.4 Å, the average value for its radii of the hydrodynamic equivalent sphere being 7.7 Å [25]. In contrast, MIL-100(Fe) nanoMOFs shows a porous architecture delimiting large (29 Å) and small (24 Å) mesoporous cages which are accessible through microporous pentagonal (5.6 Å) or hexagonal windows (8.6 Å) [26]. Thus, bulkyer CD molecules cannot penetrate the nanoMOF tridimensional core structures (Fig. 1).

Water soluble β-CD polymers remarkably increase the solubility of hydrophobic drugs as compared to their monomers (β-CDs) [27], [28], [29]. In addition, polymeric CD shells have some advantages over the monomeric ones, such as the obtention of thicker coatings, which in turn may lead to increased stability, better control of drug release and facilitated shell functionalization with fluorescent dyes or targeting ligands. However, ensuring stable thick polymeric shells on porous MOFs, without using any organic solvent or coupling agent, is not a trivial issue. Indeed, shell stability is related to the density and accessibility of the anchoring moieties. While a high effective concentration of interacting appendages is expected in the case of persubstituted discrete β-CD derivatives resulting in a multivalent effect, additional factors may be involved in the case of β-CD polymers, including higher steric hindrance, different spatial distribution of the anchors depending on the derivatisation degree, induce-fit effects, or possitibility of cross-linking between several nanoparticles. As a result, it is difficult to predict the behavior of a given β-CD polymer as a coating shell on MOFs nanoparticles.

Despite these interesting features, the use of CD polymers to coat nanoMOFs has not been explored yet. In order to shed some light on this challenging goal, this work describes the synthesis of several phosphorylated discrete and polymeric β-CD derivatives, some of them containing functional moieties such as mannose and rhodamine. The surface functionalization of MIL-100(Fe) nanoMOFs with these compounds, drug entrapment and the characterization of the hybrid nanoassemblies are studied and compared using complementary techniques.