nmat2608

ARTICLESPUBLISHED 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 5 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. 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 F 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 1 Institut Lavoisier (CNRS 8180) & Institut universitaire de France, Université de Versailles, 78035 Versailles Cedex, France, 2 Faculté de Pharmacie (CNRS 8612), Université Paris-Sud, 92296 Châtenay-Malabry, France, 3 CNRS 2301, 91190 Gif-sur-Yvette France and CNRS8081, Université PARIS-Sud 91405 Orsay, France, 4 Laboratoire de Neurovirologie, SPI-BIO, CEA, 92260 Fontenay aux Roses Cedex, France, 5 Catalysis Center for Molecular Engineering, Korea Research Institute of Chemical Technology (KRICT), PO Box 107, Yusung, Daejeon 305-600, Korea, 6 Laboratoire de Biochimie—Hôpital Hôtel-Dieu—AP-HP 75004 Paris, France, 7 EA 2706, Faculté de Pharmacie, Université Paris-Sud, 92296 Châtenay-Malabry, France. *e-mail: [email protected]; [email protected]. 172 NATURE MATERIALS | VOL 9 | FEBRUARY 2010 | www.nature.com/naturematerials © 2010 Macmillan Publishers Limited. All rights reserved. LD50 (trimesic acid) = 8. the nanoMOF surfaces were engineered by coating with several relevant polymers28 (see Methods). and show low toxicity values (LD50 (Fe) = 30 g kg−1 .com/naturematerials case of MIL-88A (fumarate) and MIL-100 (trimesate). iron and fumaric acid. S10) shows that. this treatment prevented aggregation of the nanoparticles but did not improve the results. The nanoparticles lose their crystallinity and release large quantities of their ligands (72 and 58 wt% of the fumaric and trimesic acids.1038/NMAT2608 ARTICLES CORONA Biodistribution Targeting ~ 200 nm CORE Biodegradable porous iron carboxylates MIL-53 8Å MIL-88 6–11 Å MIL-100 24–29 Å MIL-101 29–34 Å Controlled release of challenging drugs Busulfan Azidothimidine triphosphate Doxorubicin Cidofovir Imaging Figure 1 | Scheme of engineered core–corona porous iron carboxylates for drug delivery and imaging. a major degradation occurred after seven days of incubation at 37 ◦ C. LD50 (fumaric acid) = 10.NATURE MATERIALS DOI: 10. in the case of MIL88A. respectively). All rights reserved.7 g kg−1 . MIL-88A (centre) and PEGylated MIL-88A nanoparticles (right). The nanoMOF cytotoxicity. benzophenone 3 and benzophenone 4 (UVA and UVB filters) were also tested. Some cosmetic molecules.nature. Finally. Their efficiency as drug carriers was tested with four challenging anticancer or antiviral drugs (busulfan (Bu). For biological applications. except the latter. studied in vitro (MTT assay. was low (57 ± 11 µg ml−1 for MIL-88A) and comparable with that of the currently available nanoparticulate systems34 . urea (hydrating agent). which. such as caffeine (liporeductor). Interestingly. Their in vitro degradation under physiological conditions (see Supplementary Fig. the potential of these nanoMOFs as contrast agents is reported.4 g kg−1 (refs 29–32). The first step of the study was to evaluate the performances of the pure nanosized iron carboxylates in terms of degradability and cytotoxicity. 173 © 2010 Macmillan Publishers Limited. Acute in vivo toxicity experiments were then carried out after intravenous administration of nanoMOFs in Wistar female rats (see Supplementary Section S7). degradability and imaging properties (Figs 1 and 2). indicating a reasonable in vitro degradability of the MOF nanoparticles. could not be successfully entrapped using existing nanocarriers (Table 1). ref 33) on mouse macrophages (see Supplementary Section S8). characterized in terms of biocompatibility. are endogenous (see Supplementrary Section S7). azidothymidine triphosphate (AZT-TP). 200 nm 100 nm 200 nm MIL-100 MIL-88A MIL-88A-PEG Figure 2 | Scanning electron micrographs of MIL-100 (left). .4 g kg−1 ) and LD50 (terephthalic acid) > 6. in the NATURE MATERIALS | VOL 9 | FEBRUARY 2010 | www. cidofovir (CDV) and doxorubicin (doxo)). the degradation products. 8) CDV loading (efficiency) (%) NH2 N O N O 10.2) 41.0) - - *Bimodal distribution of sizes.6) 29 (8.9) Benzophenone 4 loading (efficiency) (%) O C O CH3 SO3H OH 12.2) Yes 6 150* 8.24 (2.0) - 22 (7. with micrometric particles.1 (11.3 (17.7 hydrophilic 14 (81) 2.6 hydrophobic - - 1.3) Caffeine loading (efficiency) (%) N N CH3 CH3 N O N CH3 O 6.9 × 9. 174 NATURE MATERIALS | VOL 9 | FEBRUARY 2010 | www.7) Urea loading (efficiency) (%) O H2N C NH2 4.1038/NMAT2608 Table 1 | Structure description.8 (4.5) Benzophenone 3 loading (efficiency)(%) OH O O 12. All rights reserved. .8) - 5 (7.1 hydrophilic - - 69.0 (90.0 × 7.nature. wt%) in several porous iron(III) carboxylate nanoparticles.5) 42.1) - HO P O HO OH Doxorubicin loading (efficiency)(%) O OH O MeO O OH O O NH2 HO OH OH 15. particle size.1 × 5.2 hydrophilic - - 15.5 (74.5 (1.2 (2.6 amphiphilic - - 24.2 (85.6 350* 14.3) No 25 (5.0 (3.1 × 7.60 (6.ARTICLES NATURE MATERIALS DOI: 10.2 (16.1 (15.9) No 29 (12) 34 (16) 120 Yes 8.1 (46.5) - 23.6 (12) 16.2) - - Ibuprofen loading (efficiency) (%) O OH 10 × 5 hydrophobic - - 33 (11.1 hydrophilic - 0.com/naturematerials © 2010 Macmillan Publishers Limited.1 × 3.4) 0.5 amphiphilic 9.6) 200 25.3 × 11.4 × 3. drug loading (wt%) and entrapment efficiency (below the drug loading values in parentheses.9) Bu loading (efficiency) (%) O O s O O s O O AZT-TP loading (efficiency) (%) OH O OH O OH P O P O OH P HO O O O OH N N N N NH2 11.5 (31.4) 21.9 hydrophobic - - 9.9 (68.1) - 63.8 × 7.2 (22. MIL-89 MIL-88A MIL-100 MIL-101 _NH2 MIL-53 Organic linker HO Muconic O acid OH O HO Fumaric acid O O Trimesic acid OH HO O HO O OH O Amino terephthalic acid NH O 2 Terephthalic acid O O OH HO O HO OH Crystalline structure Flexibility Pore size (Å) Particle size (nm) Yes 11 50–100 13. Moreover. Figs S13 and S14). or from a hydrophobic aromatic linker. 25% of paediatric cancer patients go uncured. but significantly larger than for the existing materials. refs 37. No significant toxic effects were observed up to ten days after administration (see Supplementary Figs S15–S17). Some nanocarriers were previously developed to circumvent these inconveniences. Bu-loaded nanoMOFs could avoid the use of toxic organic solvents (N . respectively. This result is five times higher than the best system of polymer nanoparticles (5–6 wt%. MIL-53. Moreover. In this context. with no ‘burst effect’. Bu solution in N . The non-toxicity of the iron nanoMOFs. MIL-100 nanoparticles load up to 25. three out of four children can now be cured.NATURE MATERIALS DOI: 10. AZT-TP. for four days. we have confirmed the total absence of cytotoxicity of the empty MIL-100 nanoparticles in the same cell lines. in agreement with their high polarity. compared with 1 wt% values reported in the literature for these drugs in usual nanocarriers41 . body and organ weights and serum parameters) were evaluated up to three months after injection (see Supplementray Section S7. ref. The performance of iron carboxylates therefore indicated major promise for the entrapment of all the above important drugs (Table 1). Indeed. Thanks to its efficiency. All experiments were carried out in quadruplicate. 39). is not satisfactory because loading never exceeds 5–6 wt% (ref.39 ) owing to the entrapment of Bu in its molecular form within the pores. Doses up to the highest possible injectable amounts were administrated (220 mg kg−1 for MIL-88A and MIL-100. 40). Moreover. 3). 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. attributed to the fast sequestration by the reticuloendothelial organs of the nanoMOFs not protected by a PEG (polyethylene glycol) coating. the nanoMOFs act as remarkable molecular ‘sponges’. All rights reserved. 38). the absence of activation of cytochrome P-450 suggests a direct excretion of the polyacids. respectively. S18). They include the monophosphorylated form of the antiviral phosphonate cidofovir. 38) and 60 times higher than with liposomes (0. As all the body organ weights were back to normality one to three months after injection (see Supplementary Figs S13 and S14). Supplementary Section S10 and S11. Chemotherapy indeed plays a key role in the treatment of cancer in children. fumarate (MIL-88A).43 .1038/NMAT2608 100 CDV AZT-TP Doxo ARTICLES as liposomes or polymeric nanoparticles. led us to investigate their ability to entrap anticancer and antiviral drugs. Bu entrapment in microporous flexible structures (MIL88A. the phenomenon was fully reversible. Nevertheless. considering the actual intravenous dosage of Bu (Busilvex. such as the consortium Innovative Therapies for Children with Cancer (ITCC). Table S3–S5).nature. 21. Research in paediatric oncology is now encouraged and supported by European legislation (Paediatric Use Marketing Authorization. rendering our search of efficient nanocarriers an attractive challenge. Fig. proved above. because it represents a good alternative to total-body irradiation35. tetramethylterephthalate (MIL-88Bt) (see Methods). the current encapsulation of Bu in known drug nanocarriers. except a slight increase in the spleen and liver weights. S19). Even if the concentration of the drug in the solution was low. Their comparison with control groups did not show significant differences between them. and 110 mg kg−1 for MIL-88Bt). the total amount of MIL-88A or MIL-100 to be administered would be around 100 and 20 mg kg−1 d−1 . 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 ). The comparison between kinetics of drug delivery and the degradation profiles suggests that the delivery 175 Released drug (%) 50 0 0 1 2 3 4 Time (days) 5 11 12 13 14 Figure 3 | CDV (black). especially in paediatrics. ref. the clinical use of nucleoside analogues is limited by their poor stability in biological media. We have verified on cell culture experiments that the nanoMOFs were able to release Bu in its active form. Table 1 shows the maximum amounts of drug adsorbed in several porous iron carboxylates. from a hydrophilic aromatic linker. Fig. For instance. However.com/naturematerials © 2010 Macmillan Publishers Limited. An unprecedented capacity of 42 wt% can be achieved for AZT-TP and CDV with MIL-101_NH2 nanoparticles (Table 1. The absence of immune or inflammatory reactions after nanoparticle administration supports their lack of toxicity. doxo (red) and AZT-TP (green) delivery under simulated physiological conditions (PBS. such NATURE MATERIALS | VOL 9 | FEBRUARY 2010 | www. 37 ◦ C) from MIL-100 nanoparticles. but show poor efficiencies together with ‘burst effects’44 . MIL-89) is lower than for MIL-100. Finally. this was achieved by simply soaking the preformed dried nanoMOFs in aqueous solutions of the drugs. CDV and doxo) is observed using MIL-100 nanoparticles (Fig.4 wt%. 16 and 29 wt% of Bu.36 . Different indicators (the animal behaviour. Consequently. and the triphosphorylated form of azidothymidine. In the case of AZT-TP and CDV. Three different loaded porous iron(iii) carboxylate nanoparticles were used. and doxorubicin. The Bu loading in the rigid mesoporous MIL-100 may be considered as exceptionally high (25 wt%). which are the active forms of these anti-cytomegalovirus and anti-HIV compounds. However. PUMA) and new international organizations. In addition to alkylating agents such as Bu.N -dimethylacetamide. one of the most effective agents in the treatment of breast cancer. Owing to their lower pore volumes. The important hydrophilic character of nucleoside analogues also strongly limits their intracellular penetration owing to their low membrane permeability42. A progressive release of the three active molecules (AZT-TP. the active molecules could be loaded with high efficiency (in most cases. the amphiphilic antitumoural drug busulfan (Bu) is widely used in combination high-dose chemotherapy regimes for leukaemias.N -dimethylacetamide) during administration and reduce the liver toxicity mentioned above (hepatic veno-occlusive disease37. and chemotherapy-induced long-term side effects justify the continued development of new strategies to fight childhood cancer. higher than 80%). nucleoside analogues are also of major importance in the treatment of cancer and viral infections. trimesate (MIL-100). 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. especially because smaller amounts of solids would be required to deliver the needed dose of this drug. . Bu was loaded in the preformed nanoMOFs by soaking in saturated drug solutions (Supplementary Table S2. In the same way. They were built up either from a hydrophilic aliphatic linker. the use of porous iron carboxylates as nanocarriers could represent important progress for Bu therapy. CDV and doxo. often resulting in short half-lives and low bioavailabilities37 . as well as sometimes partial resistance to the drug41 . The promising data obtained with AZT-TP in MIL-100 nanoparticles incited us to evaluate. li. three months after injection. f) regions.1038/NMAT2608 d 220 mg kg¬1 MILL-88A_nano st li b dm e st li c dm f s k Figure 4 | Magnetic resonance images. The higher the quantity and the mobility of the metal coordinated water in the first and second coordination spheres. In parallel. a–c) and rats injected with 220 mg kg−1 MIL-88A (right. CDV. the drug was adsorbed only onto the external surface and not within the pores (see Supplementary Information. to the best of our knowledge. the liver and spleen returned to a similar appearance to that of the untreated animals (results not shown). kidney. 4 and Supplementary Section S14). The adaptive internal microenvironment (for example. as discussed previously. our MOF nanoparticles possess not only paramagnetic iron atoms in their matrix. e) sequence of control rats (left. this represents the first example for iron-based MOFs. Both gradient echo and spin echo sequences show that the treated organs are darker than the normal ones (Fig. the total delivery of AZT-TP occurred within 3 days. 44 and 22 mg kg−1 suspensions of MIL-88A nanoparticles (Fig. S20). d. Also. e) and spleen (c. 176 Finally. in liver (a. (dm. 4a–c.nature.ARTICLES a CONTROL dm NATURE MATERIALS DOI: 10. The images were acquired with gradient echo (a. liver. but also an interconnected porous network filled with metal coordinated NATURE MATERIALS | VOL 9 | FEBRUARY 2010 | www. b. the anti-HIV activity of AZT-TP. 12) or Mn (ref. Fig. product effect is observable on the liver and spleen. The favourable in vivo detection of the iron carboxylate MOF nanoparticles makes them interesting candidates for contrast agents. tests carried out in nanoparticles with smaller pore size than the drug dimensions have shown very low drug capacities and ‘burst’ release kinetics. s. spleen. not only hydrophilic (AZT-TP. This suggests that. dorsal muscle. 4d–f versus Fig. The efficiency of our ironbased nanoMOFs is directly related to their relaxivity.com/naturematerials © 2010 Macmillan Publishers Limited. This is in accordance with the temporary accumulation of the nanoparticles in these organs. We first proved by Mössbauer spectroscopy that the MOFs themselves (and not eventual iron oxide and/or hydroxide degradation products) act as contrast agents. Their unprecedented encapsulation capacities apply to a large number of challenging drugs. urea and benzophenone 4) but also hydrophobic (doxorubicin. even at the highest tested dose (10 µg ml−1 of nanoparticles). in other words their capacity to modify the relaxation times of the water protons in the surrounding medium when a magnetic field is applied. f) or spin echo (b. the higher the relaxivity. The resulting aspects of the liver and the spleen are indeed different between control and treated rats (Supplementary Figs S21 and S22). Magnetic resonance imaging measurements have been made on Wistar female rats 30 min after injection of 220. However. st. ibuprofen and benzophenone 3) and amphiphilic (busulfan and caffeine) molecules (Table 1. 30 min after injection. in this last case.) process is governed mainly by diffusion from the pores and/or drug–matrix interactions and not by the MOF degradation. in vitro in human peripheral blood mononuclear cells infected by HIV-1-LAI (see Supplementary Section S10). and. 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. From the above results. All rights reserved.). Indeed. Moreover. some examples of MOFs based on Gd (ref. it is clear that porous iron(iii) carboxylates currently represent the best nanocarriers for the drug release of important drugs. stomach. d. c. 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. the empty nanoparticles demonstrated no cytotoxic effects. when only approximately 10% of MIL-100 was degraded. In this sense. see Supplementary Section S13. . d–f). Table S6). we have investigated the potential of the nanoMOFs as contrast agents. 14) as potential contrast agents have been recently reported. k. Peer. PEGylated or not. 15. 9024–9025 (2006).. P. P. Chem. 27) were optimized by an appropriate choice of the reaction conditions (conventional solvothermal or microwave synthesis. M. thermogravimetric analysis and infrared spectroscopy. These complementary properties might open new opportunities to use nanoMOFs for the eventual goal as theranostic agents. Science 263. Chem.nature. measured at 9. Soc.. Chem. The presence of this last type of water molecule should induce an effect on the relaxation times of the water protons. W.428 0. et al. Flexible porous metal–organic frameworks for a controlled drug delivery. Surfactant-assisted synthesis of nanoscale gadolinium metal–organic-framework for potential multimodal imaging. 2) porous iron(iii) carboxylates (labelled MIL-n) with different topologies and compositions (iron trans. Taylor..1016/j. they are obtained in aqueous or ethanolic solutions. trimesate (MIL-100. tetramethylterephthalate (MIL-88Bt. PEG led to the formation of a superficial PEG ‘brush’ sterically protecting the nanoparticles from aggregation. Chem. 5. The structure and composition of the resulting nanoparticles were analysed using X-ray powder diffraction. Ed. 6.or tri-carboxylate linkers. 19. Jhung. B.. but also to the size of the nanoparticles. et al. Angew. & Morris. Selective nucleation and growth of metal–organic open framework thin films on patterned COOH/CF3 -terminated self-assembled monolayers on Au(111). J. Nanoparticules hybrides organiques inorganiques à base de carboxylates de fer. Their framework contains (1) water molecules strongly coordinated to the Lewis acid metal sites. Relaxivity values r1 could not be measured. In conclusion. et al. A. M. Horcajada. PEG was successfully bound to the nanoparticles’ surface. 14358–14359 (2008). Zeta-potential measurements clearly indicated that neutral PEG chains were located at the surface of the nanoparticles. 5777–5779 (2008). An. 11584–11585 (2008). PCT applications PCT/FR2008/001366. Gref. Férey. Chem. 4. of the same order of magnitude as those described as being sufficient to ensure ‘stealth’ properties (see Supplementary Section S2). Effect of the microencapsulation of nanoparticles on the reduction of burst release.. MIL-89. The PEG coating may modify the nanoparticle relaxivities in two opposite ways46 : increasing the size of individual nanoparticles and decreasing their aggregation. All rights reserved. Chem. In terms of synthesis. 3. Am. the synthesis could be carried out in water or ethanol. Moreover. was lower than 200 nm. Hermes. as well as cosmetic agents. NATURE MATERIALS | VOL 9 | FEBRUARY 2010 | www. A. & Lin. & Lin. MIL-89. In the biomedical sense. ref..trans-muconate (MIL-89. To control crystal growth. supporting the fact that it was firmly bound to the nanoparticles through coordination of its amino or carboxyl end-group with the metal centres. 191–241 (2008). 5974–5978 (2006). ref. These results show that the iron-based core is responsible for the favourable relaxivities and imaging properties of the MOF nanoparticles. 53–61 (2007). Taylor. H. MIL-101 _NH2 ) (Fig. 8. refs 21–24)).. 1). Gref. Zeta-potential values of uncoated MIL-100 (−14 mV) were shifted to almost neutral values (−2 mV) in the case of PEGylated MIL-100. Llewellyn.4 T magnetic field.micromeso. Jin. 1. 128. Thus. 6774–6780 (2008). sizes and functional groups by immersion in corresponding solutions. Hinks.04. Taylor. J. when PEG with two non-reactive monomethoxy end-groups was added to the reaction mixture. K. R. leading either to microporous flexible solids (MIL-88. Biodegradable long-circulating polymeric nanospheres. K. Gref. High uptakes of CO2 and CH4 in mesoporous metal–organic-frameworks MIL-100 and MIL-101. K. Rev. G.. A. Am. refs 21–24). & Couvreur. concentrations. Wheatley. Gabizon. The relaxivity values are related not only to the iron content. determined by both scanning electron microscopy and quasi-elastic light scattering investigations. diffusing through the interconnected pores. C. Thus. MIL-101 _NH2 ) or chains of corner sharing octahedra (MIL-53) and di. Chemically blockable transformation and ultraselective low-pressure gas adsorption in a non-porous metal organic framework. Chem. 13744–13745 (2005).1038/NMAT2608 Table 2 | Transversal (r2) relaxivities of MIL-88A and MIL-100 nanoparticles. Int. M. PEG chains with only one terminal reactive group (amino or carboxyl) were added during the course of the synthesis process (see Supplementary Section S2). L.2009.. Received 16 December 2008. Microporous Mesoporous Mater. 16. Andrieux. instead of using organic solvents.. Stealth liposomes and tumor targeting: One step further in the quest for the magic bullet. Am. J. MIL-53) or mesoporous rigid frameworks (MIL-100. 01 October 2008. & Lin. 1600–1603 (1994). 223–225 (2001). & Lin. fumarate (MIL-88A. they act as molecular sponges. T. which can be considered as sufficient for in vivo use45 . Progressive release was obtained under simulated physiological conditions. In the case of MIL-53. P. Soc. present. K. Rieter. Chem. R. but r2 of MIL88A nanoparticles are of the order of 50 s−1 mM−1 . Int. et al. 11.187 0. Solid State Chem. 14. encapsulating drugs with different polarities. & Bein. published online 13 December 2009 References 1. Directing the structure of metal–organic frameworks by oriented surface growth on an organic monolayer. R. C.4 T..15 PEG (wt%) 0 13.3 r2 (s−1 mM−1 ) 56 95 73 92 ARTICLES In most cases. 26) and aminoterephthalate (MIL-101 _NH2 . 7245–7250 (2008). C. Soc. additives. Am. resulting in good imaging properties. H. 25). Soc. which makes these nanoparticles candidates for magnetic resonance imaging (contrast) agents. Nanoscale metal–organic frameworks as potential multimodal contrast enhancing agents. Férey. W. Angew. Finally. K.. 37. 47. MIL-88A. ref. Horcajada. Pharm. W. Soc. Couvreur. 2. iron source. This is in accordance with previously reported data on PEG-coated nanoparticles2 . J. temperature and time) (see supplementary Section S1). terephthalate (MIL-53. 289–294 (2009). 130. 18.NATURE MATERIALS DOI: 10. probably owing to the competition between nucleation and growth during the crystallization process and to an aggregation of the particles. . 127. Indeed. Xiao. L. probably in exchange with these bound water molecules. Soc. Hybrid porous solids: Past. P. 13. 12. MIL-100 and MIL-101 _NH2 . P. 17. Nanocarriers as an emerging platform for cancer therapy. Nature Chem. S. P. et al. a negligible surface modification occurred.031 (2009) (in the press). Nanoscale coordination polymers for platinum-based anticancer drug delivery. J. Xiao. Clin. Ed. Rieter. 19. Taylor. D. The nanoparticle size distribution of MIL-53 and MIL-88A was bimodal. our porous iron carboxylate nanoMOFs have many advantages when used as non-toxic and biocompatible drug nanocarriers. 751–760 (2007). W. compatible with the intravenous route of administration (see Table 1). G. and/or free water molecules. B. 130. 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). K. Int. et al. 7. Metal–organic frameworks as efficient materials for drug delivery. Table 2 shows the relaxivity of the iron fumarate MOF (MIL-88A) nanoparticles under a 9. the iron-based cores are endowed with good relaxivities. 10. 34. et al. 121–124 (2007). Prog.6 0 13. 45. et al. S. E. Microwave synthesis of chromium terephthalate MIL-101 and its benzene sorption ability. future. Cancer Res. anti-HIV activity of AZT-TP loaded nanoMOFs has been proven. Bound PEG could be removed only after particle degradation under acidic conditions.com/naturematerials © 2010 Macmillan Publishers Limited. Angew. J. Scherb. N. J. the nanoparticles’ mean diameter. Chem. as well as (2) free water molecules. A. Nature Nanotech. W. L. Metal organic frameworks as NO delivery materials for biological applications. M. & Malvy. 9. Horcajada. refs 21–24). Langmuir 24. L. Sheikh Hasan. solvent. These porous iron(iii) carboxylates are built up from the assembly of either oxo-centred trimers of iron octahedra (MIL-88. McKinlay. MIL-100. L. Rieter. Mater. and from 17 to 2 mV in the case of PEGylated MIL-88A. accepted 11 November 2009. P. 7. C. Int.. MIL-89. R. J. doi:10. This simple entrapment method has been applied to previously challenging antitumoural and antiviral drugs. Am. Fe (mmol l−1 ) MIL-88 A MIL-88 A + PEG MIL-100 MIL-100 + PEG 0. M. The PEGylated nanoparticles showed slightly higher r2 values than the non-PEGylated ones. 2. Pott.364 0. energy. et al. and PEG contents up to 17 wt% were obtained. 177 Methods The syntheses of nanoscale (Fig. Manganese-based nanoscale metal–organic frameworks for magnetic resonance imaging. 47. J.. Ed. Adv. 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