PUBLISHEDONLINE:13DECEMBER2009 | DOI:10.1038/NMAT2608
Porousmetal–organic-frameworknanoscale carriersasapotentialplatformfordrug deliveryandimaging
Jong-SanChang5,YoungKyuHwang5,VeroniqueMarsaud2,Phuong-NhiBories6,LucCynober6, SophieGil7,GérardFérey1,PatrickCouvreur2 andRuxandraGref2*
Inthedomainofhealth,oneimportantchallengeistheefﬁcientdeliveryofdrugsinthebodyusingnon-toxicnanocarriers.Most of the existing carrier materials show poor drug loading (usually less than 5wt% 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 thatspeciﬁcnon-toxicporousiron(III)-basedmetal–organicframeworkswithengineeredcoresandsurfaces,aswellasimaging 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 patienttreatments.
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, enteringanewstageofmolecularmedicinerequirestheassociation of therapeutics and diagnostics to make personalized patient treatmentareality.Astepforwardaimsatconceivingananocarrier thatcouldservebothasdrugcarrierandasdiagnosticagent(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 15) 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 Lin1013 (imaging) introduced a new pathway by using hybrid porous solids14 (or metalorganic frameworks (MOFs))forthispurpose.However,mostofthematerialsdescribed in these publications (that is, Co-, Ni- and Cr-based MOFs) were not compatible with biomedical and pharmaceutical applications, and, with few exceptions1013,1517, 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 non-toxic 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 solutioninthefieldofdrug-deliverynanocarriers.
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 ( up to 4.7nm; pore volume up to 2:3cm3 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, thehighstructuralflexibilityofsomeMOFs(refs21,22)enablesthe adaptationoftheirporositytotheshapeofthehostedmolecule.
We have synthesized, in biologically and environmentally favourableaqueousorethanolicmedium,somenon-toxiciron(iii) carboxylate MOFs (MIL-53, MIL-88A, MIL-88Bt, MIL-89, MIL-100 and MIL-101_NH2; MIL D Materials of Institut Lavoisier; refs 2327) and have adapted the synthesis conditions to obtain these materials as nanoparticles (see Methods and Supplementary Sections S1 and S7; Figs S1S5 and S11S12), which were
1Institut Lavoisier (CNRS 8180) & Institut universitaire de France, Université de Versailles, 78035 Versailles Cedex, France, 2Faculté de Pharmacie (CNRS 8612), Université Paris-Sud, 92296 Châtenay-Malabry, France, 3CNRS 2301, 91190 Gif-sur-Yvette France and CNRS8081, Université PARIS-Sud 91405 Orsay,France,4LaboratoiredeNeurovirologie,SPI-BIO,CEA,92260FontenayauxRosesCedex,France,5CatalysisCenterforMolecularEngineering,Korea Research Institute of Chemical Technology (KRICT), PO Box 107, Yusung, Daejeon 305-600, Korea, 6Laboratoire de Biochimie—Hôpital
Hôtel-Dieu—AP-HP 75004 Paris, France, 7EA 2706, Faculté de Pharmacie, Université Paris-Sud, 92296 Châtenay-Malabry, France. *e-mail:firstname.lastname@example.org; email@example.com.
172 NATUREMATERIALS j VOL 9 j FEBRUARY 2010 j www.nature.com/naturematerials © 2010 Macmillan Publishers Limited. All rights reserved.
Biodistribution ~ 200 nm
Biodegradable porous iron carboxylates
8 Å 6–11 Å
Controlled release of challenging drugs
200 nm 100 nm 200 nm
MIL-100 MIL-88A MIL-88A-PEG
characterized in terms of biocompatibility, degradability and imaging properties (Figs 1 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 notbesuccessfullyentrappedusingexistingnanocarriers(Table 1). Some cosmetic molecules, such as caffeine (liporeductor), urea (hydrating agent), benzophenone 3 and benzophenone 4 (UVA and UVB filters) were also tested. For biological applications, the nanoMOFsurfaceswereengineeredbycoatingwithseveralrelevant polymers28 (see Methods); this treatment prevented aggregation of the nanoparticles but did not improve the results. Finally, the potentialofthesenanoMOFsascontrastagentsisreported.
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
NATUREMATERIALS j VOL 9 j FEBRUARY 2010 j www.nature.com/naturematerials
case of MIL-88A (fumarate) and MIL-100 (trimesate), a major degradation occurred after seven days of incubation at 37C. The nanoparticles lose their crystallinity and release large quantities of their ligands (72 and 58wt% of the fumaric and trimesic acids, respectively), indicating a reasonable in vitro degradability of the MOF nanoparticles. Interestingly, in the case of MIL-88A, the degradation products, iron and fumaric acid, are endogenous(seeSupplementrarySectionS7),andshowlowtoxicity values (LD50(Fe) D 30gkg 1, LD50(fumaric acid) D 10:7gkg 1; LD50(trimesic acid) D 8:4gkg 1) and LD50(terephthalic acid) >6:4gkg 1 (refs 2932).
The nanoMOF cytotoxicity, studied in vitro (MTT assay; ref 33) on mouse macrophages (see Supplementary Section S8), was low (5711gml 1 for MIL-88A) and comparable with that of the currently available nanoparticulate systems34. Acute in vivo toxicity experimentswerethencarriedoutafterintravenousadministration ofnanoMOFsinWistarfemalerats(seeSupplementarySectionS7).
© 2010 Macmillan Publishers Limited. All rights reserved.
terephthalic O NH2
Flexibility Pore size (Å)
Particle size (nm)
Bu loading (efficiency) (%)
s O O s
(efficiency) (%) OH OH
OH O O P OH HO P
O OH N
CDV loading (efficiency) (%)
N N O
HO P O
Doxorubicin loading (efficiency)(%)
O OH O OH OH
MeO O OHO O
Ibuprofen loading (efficiency) (%)
Caffeine loading (efficiency) (%)
CH N N O
CH3 O CH3
Urea loading (efficiency) (%) O
H2N C NH2
Benzophenone 4 loading (efficiency) (%)
O OH C
O CH SO3H
Benzophenone 3 loading (efficiency)(%)
25 (5.6) 29 (8.6) 200