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Porous metal organic framework nanoscale carriers as a potential platform for drug delivery and imaging

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Porous metal organic framework nanoscale carriers as a potential platform for drug delivery and imaging, In the domain of health, one important challenge is the efficient delivery of drugs in the body using non-toxic nanocarriers. Most of the existing carrier materials show poor drug loading and or rapid release of the proportion of the drug that is simply adsorbed at the external surface of the nanocarrier. In this context, porous hybrid solids, with the ability to tune their structures and porosities for better drug interactions and high loadings, are well suited to serve as nanocarriers for delivery and imaging applications.

ARTICLES PUBLISHED ONLINE: 13 DECEMBER 2009 | DOI: 10.1038/NMAT2608 Porous metal–organic-framework nanoscale carriers as a potential platform for drug delivery and imaging Patricia Horcajada1 *, Tamim Chalati2 , Christian Serre1 , Brigitte Gillet3 , Catherine Sebrie3 , Tarek Baati1 , Jarrod F Eubank1 , Daniela Heurtaux1 , Pascal Clayette4 , Christine Kreuz4 , Jong-San Chang5 , Young Kyu Hwang5 , Veronique Marsaud2 , Phuong-Nhi Bories6 , Luc Cynober6 , Sophie Gil7 , Gérard Férey1 , Patrick Couvreur2 and Ruxandra Gref2 * In the domain of health, one important challenge is the efficient delivery of drugs in the body using non-toxic nanocarriers Most of the existing carrier materials show poor drug loading (usually less than wt% of the transported drug versus the carrier material) and/or rapid release of the proportion of the drug that is simply adsorbed (or anchored) at the external surface of the nanocarrier In this context, porous hybrid solids, with the ability to tune their structures and porosities for better drug interactions and high loadings, are well suited to serve as nanocarriers for delivery and imaging applications Here we show that specific non-toxic porous iron(III)-based metal–organic frameworks with engineered cores and surfaces, as well as imaging properties, function as superior nanocarriers for efficient controlled delivery of challenging antitumoural and retroviral drugs (that is, busulfan, azidothymidine triphosphate, doxorubicin or cidofovir) against cancer and AIDS In addition to their high loadings, they also potentially associate therapeutics and diagnostics, thus opening the way for theranostics, or personalized patient treatments F or nanocarriers, the requirements for ensuring an efficient therapy are to (1) efficiently entrap drugs with high payloads, (2) control the release and avoid the ‘burst effect’ (important release within the first minutes), (3) control matrix degradation, (4) offer the possibility to easily engineer its surface to control in vivo fate and (5) be detectable by imaging techniques Moreover, entering a new stage of molecular medicine requires the association of therapeutics and diagnostics to make personalized patient treatment a reality A step forward aims at conceiving a nanocarrier that could serve both as drug carrier and as diagnostic agent (satisfy criteria (4) and (5)), to evaluate drug distribution and treatment efficiency (theranostics) Currently, for delivery, some materials are being used (for example, liposomes, nanoemulsions, nanoparticles or micelles; refs 1–5) but are, for the most part, unsatisfactory; better routes are therefore necessary to address the limitations Very recently, our group6,7 (ibuprofen storage/long time release) and those of R Morris8,9 (gas delivery of NO for antithrombosis and vasodilatation) and Lin10–13 (imaging) introduced a new pathway by using hybrid porous solids14 (or metal–organic frameworks (MOFs)) for this purpose However, most of the materials described in these publications (that is, Co-, Ni- and Cr-based MOFs) were not compatible with biomedical and pharmaceutical applications, and, with few exceptions10–13,15–17 , they were not engineered as nanoparticles to enable controlled drug release by intravenous administration To circumvent these problems, the strategy of the present paper (Fig 1) was to take advantage of the character and performance of suitable iron(iii) carboxylate MOFs Their nontoxic nature and potential for nanoparticle synthesis (nanoMOFs), coupled with unusually large loadings of different drugs and imaging properties, make them ideal candidates for a new valuable solution in the field of drug-delivery nanocarriers MOFs result from the assembly, exclusively by strong bonds, of inorganic clusters and easily tunable organic linkers (carboxylates, imidazolates or phosphonates14 ) This huge family presents high and regular porosities (φ up to 4.7 nm; pore volume up to 2.3 cm3 g−1 ) enabling, for instance, the entrapment of large amounts of greenhouse gases18 They can show simultaneously hydrophilic and hydrophobic entities, as well as tunable pore size and connectivities, which can be adapted to the physico-chemical properties of each drug and its medical application19,20 Moreover, the high structural flexibility of some MOFs (refs 21, 22) enables the adaptation of their porosity to the shape of the hosted molecule We have synthesized, in biologically and environmentally favourable aqueous or ethanolic medium, some non-toxic iron(iii) carboxylate MOFs (MIL-53, MIL-88A, MIL-88Bt, MIL-89, MIL100 and MIL-101_NH2 ; MIL = Materials of Institut Lavoisier; refs 23–27) and have adapted the synthesis conditions to obtain these materials as nanoparticles (see Methods and Supplementary Sections S1 and S7; Figs S1–S5 and S11–S12), which were Institut Lavoisier (CNRS 8180) & Institut universitaire de France, Université de Versailles, 78035 Versailles Cedex, France, Faculté de Pharmacie (CNRS 8612), Université Paris-Sud, 92296 Châtenay-Malabry, France, CNRS 2301, 91190 Gif-sur-Yvette France and CNRS8081, Université PARIS-Sud 91405 Orsay, France, Laboratoire de Neurovirologie, SPI-BIO, CEA, 92260 Fontenay aux Roses Cedex, France, Catalysis Center for Molecular Engineering, Korea Research Institute of Chemical Technology (KRICT), PO Box 107, Yusung, Daejeon 305-600, Korea, Laboratoire de Biochimie—Hôpital Hôtel-Dieu—AP-HP 75004 Paris, France, EA 2706, Faculté de Pharmacie, Université Paris-Sud, 92296 Châtenay-Malabry, France *e-mail: horcajada@chimie.uvsq.fr; ruxandra.gref@u-psud.fr 172 NATURE MATERIALS | VOL | FEBRUARY 2010 | www.nature.com/naturematerials © 2010 Macmillan Publishers Limited All rights reserved NATURE MATERIALS DOI: 10.1038/NMAT2608 ARTICLES CORONA ~ 200 nm Biodistribution Targeting CORE Biodegradable porous iron carboxylates MIL-53 8Å MIL-88 6–11 Å MIL-100 24–29 Å MIL-101 29–34 Å Azidothimidine triphosphate Doxorubicin Controlled release of challenging drugs Busulfan Cidofovir Imaging Figure | Scheme of engineered core–corona porous iron carboxylates for drug delivery and imaging 200 nm MIL-100 100 nm MIL-88A 200 nm MIL-88A-PEG Figure | Scanning electron micrographs of MIL-100 (left), MIL-88A (centre) and PEGylated MIL-88A nanoparticles (right) characterized in terms of biocompatibility, degradability and imaging properties (Figs and 2) Their efficiency as drug carriers was tested with four challenging anticancer or antiviral drugs (busulfan (Bu), azidothymidine triphosphate (AZT-TP), cidofovir (CDV) and doxorubicin (doxo)), which, except the latter, could not be successfully entrapped using existing nanocarriers (Table 1) Some cosmetic molecules, such as caffeine (liporeductor), urea (hydrating agent), benzophenone and benzophenone (UVA and UVB filters) were also tested For biological applications, the nanoMOF surfaces were engineered by coating with several relevant polymers28 (see Methods); this treatment prevented aggregation of the nanoparticles but did not improve the results Finally, the potential of these nanoMOFs as contrast agents is reported The first step of the study was to evaluate the performances of the pure nanosized iron carboxylates in terms of degradability and cytotoxicity Their in vitro degradation under physiological conditions (see Supplementary Fig S10) shows that, in the case of MIL-88A (fumarate) and MIL-100 (trimesate), a major degradation occurred after seven days of incubation at 37 ◦ C The nanoparticles lose their crystallinity and release large quantities of their ligands (72 and 58 wt% of the fumaric and trimesic acids, respectively), indicating a reasonable in vitro degradability of the MOF nanoparticles Interestingly, in the case of MIL88A, the degradation products, iron and fumaric acid, are endogenous (see Supplementrary Section S7), and show low toxicity values (LD50 (Fe) = 30 g kg−1 , LD50 (fumaric acid) = 10.7 g kg−1 ; LD50 (trimesic acid) = 8.4 g kg−1 ) and LD50 (terephthalic acid) > 6.4 g kg−1 (refs 29–32) The nanoMOF cytotoxicity, studied in vitro (MTT assay; ref 33) on mouse macrophages (see Supplementary Section S8), was low (57 ± 11 µg ml−1 for MIL-88A) and comparable with that of the currently available nanoparticulate systems34 Acute in vivo toxicity experiments were then carried out after intravenous administration of nanoMOFs in Wistar female rats (see Supplementary Section S7) NATURE MATERIALS | VOL | FEBRUARY 2010 | www.nature.com/naturematerials © 2010 Macmillan Publishers Limited All rights reserved 173 NATURE MATERIALS DOI: 10.1038/NMAT2608 ARTICLES Table | Structure description, particle size, drug loading (wt%) and entrapment efficiency (below the drug loading values in parentheses, wt%) in several porous iron(III) carboxylate nanoparticles Organic linker MIL-89 MIL-88A Muconic O acid Fumaric acid HO OH OH HO O O O MIL-100 MIL-101 _NH2 MIL-53 Trimesic acid Amino terephthalic acid NH Terephthalic acid HO O HO O OH O O HO O O OH HO O OH Crystalline structure Flexibility Pore size (Å) Yes 11 Yes Particle size (nm) 50–100 13.4 × 3.5 amphiphilic Bu loading (efficiency) (%) O O s O O s O O 150* No 25 (5.6) 29 (8.6) 200 No 29 (12) 34 (16) 120 Yes 8.6 9.8 (4.2) 8.0 (3.3) 25.5 (31.9) - 14.3 (17.9) 11.9 × 9.1 hydrophilic - 0.60 (6.4) 21.2 (85.5) 42.0 (90.4) 0.24 (2.8) 10.8 × 7.7 hydrophilic 14 (81) 2.6 (12) 16.1 (46.2) 41.9 (68.1) - 15.3 × 11.9 hydrophobic - - 9.1 (11.2) - - 10 × hydrophobic - - 33 (11.0) - 22 (7.3) 6.1 × 7.6 amphiphilic - - 24.2 (16.5) - 23.1 (15.7) 4.1 × 3.1 hydrophilic - - 69.2 (2.1) - 63.5 (1.9) 12.0 × 7.2 hydrophilic - - 15.2 (22.8) - (7.5) 12.1 × 5.6 hydrophobic - - 1.5 (74.0) - - 350* AZT-TP loading (efficiency) (%) OH O OH P O P O OH P HO O O O OH N N N N NH2 OH O CDV loading (efficiency) (%) NH2 O N N HO P O HO OH O Doxorubicin loading (efficiency)(%) OH O OH O OH MeO O OH O O NH2 HO Ibuprofen loading (efficiency) (%) O OH Caffeine loading (efficiency) (%) N N CH3 CH3 N O N CH3 O Urea loading (efficiency) (%) O H2N C NH2 Benzophenone loading (efficiency) (%) O OH C O CH3 SO3H Benzophenone loading (efficiency)(%) OH O O *Bimodal distribution of sizes, with micrometric particles 174 NATURE MATERIALS | VOL | FEBRUARY 2010 | www.nature.com/naturematerials © 2010 Macmillan Publishers Limited All rights reserved NATURE MATERIALS DOI: 10.1038/NMAT2608 100 Released drug (%) Doxo AZT-TP CDV ARTICLES 50 0 Time (days) 11 12 13 14 Figure | CDV (black), doxo (red) and AZT-TP (green) delivery under simulated physiological conditions (PBS, 37 ◦ C) from MIL-100 nanoparticles All experiments were carried out in quadruplicate Three different loaded porous iron(iii) carboxylate nanoparticles were used They were built up either from a hydrophilic aliphatic linker, fumarate (MIL-88A), from a hydrophilic aromatic linker, trimesate (MIL-100), or from a hydrophobic aromatic linker, tetramethylterephthalate (MIL-88Bt) (see Methods) Doses up to the highest possible injectable amounts were administrated (220 mg kg−1 for MIL-88A and MIL-100, and 110 mg kg−1 for MIL-88Bt) Different indicators (the animal behaviour, body and organ weights and serum parameters) were evaluated up to three months after injection (see Supplementray Section S7; Figs S13 and S14) Their comparison with control groups did not show significant differences between them, except a slight increase in the spleen and liver weights, attributed to the fast sequestration by the reticuloendothelial organs of the nanoMOFs not protected by a PEG (polyethylene glycol) coating As all the body organ weights were back to normality one to three months after injection (see Supplementary Figs S13 and S14), the phenomenon was fully reversible The absence of immune or inflammatory reactions after nanoparticle administration supports their lack of toxicity Moreover, the absence of activation of cytochrome P-450 suggests a direct excretion of the polyacids, in agreement with their high polarity Finally, in vivo subacute toxicity assays were carried out by injecting up to 150 mg of MIL-88A kg−1 d−1 during four consecutive days No significant toxic effects were observed up to ten days after administration (see Supplementary Figs S15–S17) The non-toxicity of the iron nanoMOFs, proved above, led us to investigate their ability to entrap anticancer and antiviral drugs Chemotherapy indeed plays a key role in the treatment of cancer in children Thanks to its efficiency, three out of four children can now be cured Nevertheless, 25% of paediatric cancer patients go uncured, and chemotherapy-induced long-term side effects justify the continued development of new strategies to fight childhood cancer Research in paediatric oncology is now encouraged and supported by European legislation (Paediatric Use Marketing Authorization, PUMA) and new international organizations, such as the consortium Innovative Therapies for Children with Cancer (ITCC) In this context, the amphiphilic antitumoural drug busulfan (Bu) is widely used in combination high-dose chemotherapy regimes for leukaemias, especially in paediatrics, because it represents a good alternative to total-body irradiation35,36 However, Bu possesses a poor stability in aqueous solution and an important hepatic toxicity due to its microcrystallization in the hepatic microvenous system (hepatic veno-occlusive diseases37 ) Moreover, the current encapsulation of Bu in known drug nanocarriers, such as liposomes or polymeric nanoparticles, is not satisfactory because loading never exceeds 5–6 wt% (ref 38), rendering our search of efficient nanocarriers an attractive challenge Bu was loaded in the preformed nanoMOFs by soaking in saturated drug solutions (Supplementary Table S2, Fig S18) Table shows the maximum amounts of drug adsorbed in several porous iron carboxylates The Bu loading in the rigid mesoporous MIL-100 may be considered as exceptionally high (25 wt%) This result is five times higher than the best system of polymer nanoparticles (5–6 wt%; ref 38) and 60 times higher than with liposomes (0.4 wt%; refs 37, 39) Owing to their lower pore volumes, Bu entrapment in microporous flexible structures (MIL88A, MIL-53, MIL-89) is lower than for MIL-100, but significantly larger than for the existing materials Consequently, the use of porous iron carboxylates as nanocarriers could represent important progress for Bu therapy, especially because smaller amounts of solids would be required to deliver the needed dose of this drug Indeed, considering the actual intravenous dosage of Bu (Busilvex, Bu solution in N ,N -dimethylacetamide; ref 40), the total amount of MIL-88A or MIL-100 to be administered would be around 100 and 20 mg kg−1 d−1 , respectively, for four days Moreover, Bu-loaded nanoMOFs could avoid the use of toxic organic solvents (N ,N -dimethylacetamide) during administration and reduce the liver toxicity mentioned above (hepatic veno-occlusive disease37,39 ) owing to the entrapment of Bu in its molecular form within the pores We have verified on cell culture experiments that the nanoMOFs were able to release Bu in its active form Studies on human leukaemia and human multiple myeloma cells in culture have shown that Bu has the same activity whether it is in its free form or entrapped in the nanoMOFs (see Supplementary Section S9; Fig S19) In the same way, we have confirmed the total absence of cytotoxicity of the empty MIL-100 nanoparticles in the same cell lines In addition to alkylating agents such as Bu, nucleoside analogues are also of major importance in the treatment of cancer and viral infections They include the monophosphorylated form of the antiviral phosphonate cidofovir, and the triphosphorylated form of azidothymidine, which are the active forms of these anti-cytomegalovirus and anti-HIV compounds, and doxorubicin, one of the most effective agents in the treatment of breast cancer However, the clinical use of nucleoside analogues is limited by their poor stability in biological media, often resulting in short half-lives and low bioavailabilities37 , as well as sometimes partial resistance to the drug41 The important hydrophilic character of nucleoside analogues also strongly limits their intracellular penetration owing to their low membrane permeability42,43 Some nanocarriers were previously developed to circumvent these inconveniences, but show poor efficiencies together with ‘burst effects’44 The performance of iron carboxylates therefore indicated major promise for the entrapment of all the above important drugs (Table 1) In the case of AZT-TP and CDV, this was achieved by simply soaking the preformed dried nanoMOFs in aqueous solutions of the drugs Even if the concentration of the drug in the solution was low, the active molecules could be loaded with high efficiency (in most cases, higher than 80%); the nanoMOFs act as remarkable molecular ‘sponges’ For instance, MIL-100 nanoparticles load up to 25, 21, 16 and 29 wt% of Bu, AZT-TP, CDV and doxo, respectively An unprecedented capacity of 42 wt% can be achieved for AZT-TP and CDV with MIL-101_NH2 nanoparticles (Table 1; Supplementary Section S10 and S11; Table S3–S5), compared with wt% values reported in the literature for these drugs in usual nanocarriers41 A progressive release of the three active molecules (AZT-TP, CDV and doxo) is observed using MIL-100 nanoparticles (Fig 3), with no ‘burst effect’ The comparison between kinetics of drug delivery and the degradation profiles suggests that the delivery NATURE MATERIALS | VOL | FEBRUARY 2010 | www.nature.com/naturematerials © 2010 Macmillan Publishers Limited All rights reserved 175 NATURE MATERIALS DOI: 10.1038/NMAT2608 ARTICLES a d CONTROL 220 mg kg¬1 MILL-88A_nano dm st li b e dm st li c f dm s k Figure | Magnetic resonance images The images were acquired with gradient echo (a, c, d, f) or spin echo (b, e) sequence of control rats (left; a–c) and rats injected with 220 mg kg−1 MIL-88A (right; d–f), in liver (a, b, d, e) and spleen (c, f) regions 30 after injection, product effect is observable on the liver and spleen (dm, dorsal muscle; k kidney; li, liver; s, spleen; st, stomach.) process is governed mainly by diffusion from the pores and/or drug–matrix interactions and not by the MOF degradation Indeed, the total delivery of AZT-TP occurred within days, when only approximately 10% of MIL-100 was degraded Moreover, tests carried out in nanoparticles with smaller pore size than the drug dimensions have shown very low drug capacities and ‘burst’ release kinetics This suggests that, in this last case, the drug was adsorbed only onto the external surface and not within the pores (see Supplementary Information, Fig S20) The promising data obtained with AZT-TP in MIL-100 nanoparticles incited us to evaluate, in vitro in human peripheral blood mononuclear cells infected by HIV-1-LAI (see Supplementary Section S10), the anti-HIV activity of AZT-TP A significant anti-HIV activity was observed only for (AZT-TP)-charged nanoparticles (about 90% inhibition of HIV replication) for a concentration of 200 nM in AZT or AZT-TP In parallel, the empty nanoparticles demonstrated no cytotoxic effects, even at the highest tested dose (10 µg ml−1 of nanoparticles) From the above results, it is clear that porous iron(iii) carboxylates currently represent the best nanocarriers for the drug release of important drugs Their unprecedented encapsulation capacities apply to a large number of challenging drugs, not only hydrophilic (AZT-TP, CDV, urea and benzophenone 4) but also hydrophobic (doxorubicin, ibuprofen and benzophenone 3) and amphiphilic (busulfan and caffeine) molecules (Table 1; see Supplementary Section S13; Table S6) The adaptive internal microenvironment (for example, amphiphilic polar metal and non-polar linker) of the pores of this family of solids could probably explain the exceptional qualities of these porous materials 176 Finally, we have investigated the potential of the nanoMOFs as contrast agents We first proved by Mössbauer spectroscopy that the MOFs themselves (and not eventual iron oxide and/or hydroxide degradation products) act as contrast agents Magnetic resonance imaging measurements have been made on Wistar female rats 30 after injection of 220, 44 and 22 mg kg−1 suspensions of MIL-88A nanoparticles (Fig and Supplementary Section S14) Both gradient echo and spin echo sequences show that the treated organs are darker than the normal ones (Fig 4d–f versus Fig 4a–c.) The resulting aspects of the liver and the spleen are indeed different between control and treated rats (Supplementary Figs S21 and S22) Also, three months after injection, the liver and spleen returned to a similar appearance to that of the untreated animals (results not shown) This is in accordance with the temporary accumulation of the nanoparticles in these organs, as discussed previously The favourable in vivo detection of the iron carboxylate MOF nanoparticles makes them interesting candidates for contrast agents, and, to the best of our knowledge, this represents the first example for iron-based MOFs However, some examples of MOFs based on Gd (ref 12) or Mn (ref 14) as potential contrast agents have been recently reported The efficiency of our ironbased nanoMOFs is directly related to their relaxivity, in other words their capacity to modify the relaxation times of the water protons in the surrounding medium when a magnetic field is applied The higher the quantity and the mobility of the metal coordinated water in the first and second coordination spheres, the higher the relaxivity In this sense, our MOF nanoparticles possess not only paramagnetic iron atoms in their matrix, but also an interconnected porous network filled with metal coordinated NATURE MATERIALS | VOL | FEBRUARY 2010 | www.nature.com/naturematerials © 2010 Macmillan Publishers Limited All rights reserved NATURE MATERIALS DOI: 10.1038/NMAT2608 Table | Transversal (r2) relaxivities of MIL-88A and MIL-100 nanoparticles, PEGylated or not, measured at 9.4 T MIL-88 A MIL-88 A + PEG MIL-100 MIL-100 + PEG Fe (mmol l−1 ) PEG (wt%) r2 (s−1 mM−1 ) 0.428 0.364 0.187 0.15 13.6 13.3 56 95 73 92 and/or free water molecules Table shows the relaxivity of the iron fumarate MOF (MIL-88A) nanoparticles under a 9.4 T magnetic field Relaxivity values r1 could not be measured, but r2 of MIL88A nanoparticles are of the order of 50 s−1 mM−1 , which can be considered as sufficient for in vivo use45 The relaxivity values are related not only to the iron content, but also to the size of the nanoparticles The PEGylated nanoparticles showed slightly higher r2 values than the non-PEGylated ones The PEG coating may modify the nanoparticle relaxivities in two opposite ways46 : increasing the size of individual nanoparticles and decreasing their aggregation These results show that the iron-based core is responsible for the favourable relaxivities and imaging properties of the MOF nanoparticles Their framework contains (1) water molecules strongly coordinated to the Lewis acid metal sites, as well as (2) free water molecules, probably in exchange with these bound water molecules, diffusing through the interconnected pores The presence of this last type of water molecule should induce an effect on the relaxation times of the water protons, resulting in good imaging properties In conclusion, our porous iron carboxylate nanoMOFs have many advantages when used as non-toxic and biocompatible drug nanocarriers In terms of synthesis, they are obtained in aqueous or ethanolic solutions, instead of using organic solvents, and provide an example of what ‘green’ technology can afford for biomedical applications In the biomedical sense, they act as molecular sponges, encapsulating drugs with different polarities, sizes and functional groups by immersion in corresponding solutions This simple entrapment method has been applied to previously challenging antitumoural and antiviral drugs, as well as cosmetic agents Progressive release was obtained under simulated physiological conditions Moreover, anti-HIV activity of AZT-TP loaded nanoMOFs has been proven These results open new perspectives for improved treatment with anticancer and antiviral drugs and for the development of adapted formulations in paediatrics (using Bu nanoMOFs) Finally, the iron-based cores are endowed with good relaxivities, which makes these nanoparticles candidates for magnetic resonance imaging (contrast) agents These complementary properties might open new opportunities to use nanoMOFs for the eventual goal as theranostic agents Methods The syntheses of nanoscale (Fig 2) porous iron(iii) carboxylates (labelled MIL-n) with different topologies and compositions (iron trans,trans-muconate (MIL-89; refs 21–24)), fumarate (MIL-88A; refs 21–24), tetramethylterephthalate (MIL-88Bt; refs 21–24), terephthalate (MIL-53; ref 25), trimesate (MIL-100; ref 26) and aminoterephthalate (MIL-101 _NH2 ; ref 27) were optimized by an appropriate choice of the reaction conditions (conventional solvothermal or microwave synthesis, solvent, additives, iron source, concentrations, energy, temperature and time) (see supplementary Section S1) These porous iron(iii) carboxylates are built up from the assembly of either oxo-centred trimers of iron octahedra (MIL-88, MIL-89, MIL-100, MIL-101 _NH2 ) or chains of corner sharing octahedra (MIL-53) and di- or tri-carboxylate linkers, leading either to microporous flexible solids (MIL-88, MIL-89, MIL-53) or mesoporous rigid frameworks (MIL-100, MIL-101 _NH2 ) (Fig 1) The structure and composition of the resulting nanoparticles were analysed using X-ray powder diffraction, thermogravimetric analysis and infrared spectroscopy In the case of MIL-53, MIL-88A, MIL-89, MIL-100 and MIL-101 _NH2 , the synthesis could be carried out in water or ethanol ARTICLES In most cases, the nanoparticles’ mean diameter, determined by both scanning electron microscopy and quasi-elastic light scattering investigations, was lower than 200 nm, compatible with the intravenous route of administration (see Table 1) The nanoparticle size distribution of MIL-53 and MIL-88A was bimodal, probably owing to the competition between nucleation and growth during the crystallization process and to an aggregation of the particles To control crystal growth, PEG chains with only one terminal reactive group (amino or carboxyl) were added during the course of the synthesis process (see Supplementary Section S2) Thus, PEG led to the formation of a superficial PEG ‘brush’ sterically protecting the nanoparticles from aggregation Zeta-potential measurements clearly indicated that neutral PEG chains were located at the surface of the nanoparticles Zeta-potential values of uncoated MIL-100 (−14 mV) were shifted to almost neutral values (−2 mV) in the case of PEGylated MIL-100, and from 17 to mV in the case of PEGylated MIL-88A This is in accordance with previously reported data on PEG-coated nanoparticles2 Bound PEG could be removed only after particle degradation under acidic conditions, supporting the fact that it was firmly bound to the nanoparticles through coordination of its amino or carboxyl end-group with the metal centres Indeed, when PEG with two non-reactive monomethoxy end-groups was added to the reaction mixture, a negligible surface modification occurred Thus, PEG was successfully bound to the nanoparticles’ surface, and PEG contents up to 17 wt% were 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Couvreur, drug encapsulation and delivery, toxicity assays, surface modification of nanoparticles; R.G., drug encapsulation and delivery, toxicity assays, surface modification of nanoparticles, imaging. .. release Int J Pharm 344, 53–61 (2007) Horcajada, P et al Metal organic frameworks as efficient materials for drug delivery Angew Chem Int Ed 45, 5974–5978 (2006) Horcajada, P et al Flexible porous. .. that, in the case of MIL-8 8A (fumarate) and MIL-100 (trimesate), a major degradation occurred after seven days of incubation at 37 ◦ C The nanoparticles lose their crystallinity and release large

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