Nanomedicine Applications of Hybrid Nanomaterials Built from Metal

Review pubs.acs.org/CR

Nanomedicine Applications of Hybrid Nanomaterials Built from Metal−Ligand Coordination Bonds: Nanoscale Metal−Organic Frameworks and Nanoscale Coordination Polymers Chunbai He,† Demin Liu,† and Wenbin Lin* Department of Chemistry, University of Chicago, 929 East 57th Street, Chicago, Illinois 60637, United States Author Information Corresponding Author Author Contributions Notes Biographies Acknowledgments References

1. INTRODUCTION The past two decades have witnessed rapid developments and innovations in nanotechnology.1−10 Significant efforts have also been devoted to exploring clinical applications of these nanotechnologies for the detection, diagnosis, and treatment of cancer and other diseases.11,12 A variety of organic or inorganic nanoparticles with sizes ranging from several to several hundred nanometers have been developed, and many of them have shown promise in biomedical applications due to their tunable sizes, high agent loadings, tailorable surface chemistry, controllable drug release kinetics, improved biocompatibility, and enhanced tumor accumulation through passive tumor targeting, the enhanced permeability and retention (EPR) effect, or active tumor targeting.13,14 Nanoscale materials allow the implementation of highly effective imaging techniques, such as magnetic resonance imaging (MRI), positron emission tomography (PET), computed tomography, and optical imaging.15−20 Nanoparticles have also been examined for applications in many different modalities of anticancer therapy, such as chemotherapy, pohotodynamic therapy, neutron capture therapy, thermal therapy, and magnetic therapy.21−23 The vast majority of imaging and therapeutic nanomaterials developed to date can be categorized into either purely inorganic materials including quantum dots,24 gold nanoparticles,25 iron oxide nanoparticles,26 up-conversion nanophosphors,27 and zeolites,28 or purely organic materials including liposomes,29 dendrimers,30 micelles,31 and polymeric hydrogel nanoparticles.32 In this Review, we summarize recent advances in the development of hybrid nanomaterials that are constructed via metal−ligand coordination bonds and their applications in biomedical imaging and drug delivery. Hybrid nanomaterials can be prepared using a number of strategies. For example, ultrasmall gold or iron oxide nanoparticles can be mixed with biodegradable polymers or

CONTENTS 1. Introduction 2. Synthesis of Nanoscale Metal−Organic Frameworks (NMOFs) and Nanoscale Coordination Polymers (NCPs) 3. Loading of Imaging and Therapeutic Agents in NMOFs and NCPs 4. Surface Modification of NMOFs 5. NMOFs and NCPs for Cancer Therapy and Drug Delivery 5.1. Chemotherapy 5.1.1. Platinum Drugs 5.1.2. Methotrexate (MTX) 5.1.3. Doxorubicin (DOX) 5.1.4. 5-Fluorouracil (5-Fu) 5.1.5. Other Chemotherapeutic Agents 5.1.6. Future Directions 5.2. Photodynamic Therapy (PDT) 5.3. Nucleic Acid Delivery 5.4. Nitric Oxide (NO) Delivery 5.5. Delivery of Other Drugs 6. NMOFs and NCPs for Biomedical Imaging 6.1. MRI 6.2. CT 6.3. Optical Imaging 6.4. Sensing 6.4.1. Intracellular pH Sensing 6.4.2. Other Molecular Sensing 6.4.3. Future Directions 7. Degradation, Stability, and Toxicity of NMOFs and NCPs 8. Polysilsesquioxane (PSQ) Nanoparticles for Therapy and Imaging 9. Conclusions and Outlook © 2015 American Chemical Society

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Special Issue: Nanoparticles in Medicine

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Received: March 2, 2015 Published: August 27, 2015 11079

DOI: 10.1021/acs.chemrev.5b00125 Chem. Rev. 2015, 115, 11079−11108

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Figure 1. Key developments in the nanomedicine applications of NMOFs and NCPs.

Figure 2. Surfactant-free synthesis by simply mixing precursors in appropriate solvents either at room temperature (i)83 or at elevated temperature (ii).114 Room-temperature synthesis typically yields amorphous NCPs, whereas solvothermal synthesis at elevated temperatures can afford both NCPs and crystalline NMOFs. Reprinted with permission from refs 83 and 114. Copyright 2008 and 2014 American Chemical Society.

PSQs offer biocompatibility similar to that of silica-based materials, they allow higher drug loadings with prodrug molecules as the monomeric building blocks.108,109 Our discussion will not cover the polymeric micelle nanoparticles that are loaded with cisplatin or oxaliplatin prodrugs via the metal−ligand bonds, which can be considered as polymeric nanoparticles with drugs loaded in the side chains.110−112 Although this Review covers a topic similar to that of a recent review on NMOFs,87 it focuses on the application of NMOFs in nanomedicine and has a very different emphasis. This Review is organized into the following sections to illustrate the development of NMOFs/NCPs for biomedical applications (Figure 1). We will first briefly introduce the common strategies used for NMOF/NCP synthesis and the methods for incorporating imaging agents and drugs within NMOFs and NCPs. Our main focus of this Review is to summarize the applications of NMOFs and NCPs in drug delivery and therapy, imaging, and sensing that have been reported in the past 10 years. Finally, we will discuss the degradation, stability, and toxicity of this class of novel hybrid nanomaterials and provide an outlook for the NMOFs and NCPs in potential clinical applications.

biomacromolecules to form nanoscale hybrid materials.2,26,33−37 Here, we confine our discussion to nanomaterials that are constructed via metal−ligand coordination bonds, nanoscale metal−organic frameworks (NMOFs) and nanoscale coordination polymers (NCPs). Metal−organic frameworks, also known as coordination polymers, are an emerging class of hybrid materials that are built from metal ions or clusters bridged by organic linkers and have been examined for many applications, including gas storage and separations,38−49 nonlinear optics and ferroelectrics,50,51 catalysis,50−68 sensing,69−73 solar fuel conversion,74−77 and many others.78−95 When scaled down to the nanoscale regime, NMOFs and NCPs represent a unique family of hybrid nanomaterials that readily combine the beneficial features of purely organic or inorganic nanoparticles. Strictly, NMOFs refer to nanoscale MOFs that are crystalline and porous, whereas NCPs refer to amorphous coordination polymer nanoparticles that can be either porous or nonporous. We follow this distinction as much as possible in this Review, but for simplicity, we use NMOFs to represent both NMOFs and NCPs occasionally. NMOFs/NCPs possess several potential advantages over existing nanocarriers in biomedical applications: (1) compositional and structural tunability allows for the synthesis of NMOFs/NCPs with different compositions, shapes, sizes, and chemical properties; (2) highly porous and oriented structures accommodate efficient loading of diverse imaging and therapeutic cargoes; and (3) they are intrinsically biodegradable due to the relatively labile metal−ligand bonds.78,96−107 This Review also includes polysilsesquioxane (PSQ) nanoparticles that are synthesized from condensation of silanol-based monomers and can be considered as a special class of NCPs with Si as the metal-connecting point. While

2. SYNTHESIS OF NANOSCALE METAL−ORGANIC FRAMEWORKS (NMOFs) AND NANOSCALE COORDINATION POLYMERS (NCPs) As molecular nanomaterials, NMOFs and NCPs can be synthesized with an infinite array of metal/metal cluster SBUs and bridging ligands. The methods used for NMOF and NCP synthesis can be categorized into four general approaches: nanoscale precipitation, solvothermal, surfactant-templated, and reverse microemulsion. The first method generally yields 11080


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Figure 3. Surfactant-templated synthesis either at room temperature120 or at elevated temperature.121 Reprinted with permission from ref 121. Copyright 2014 American Chemical Society.

these systems could be controlled by adjusting the w value (water to surfactant molar ratio) of the microemulsion. Crystalline particles of Gd-BDC synthesized at w = 10 were 1−2 μm in length and 100 nm in diameter. Decreasing the w value to 5 gave nanorods of 100−125 nm in length and 40 nm in diameter. Gd-BTC nanoplates of the formula Gd(BTC)(H2O)3 (BTC = benzene-1,2,4-tricarboxylate) were also synthesized by this method and were 100 nm in diameter and 35 nm in thickness. The reverse microemulsion method has also been utilized to produce amorphous Zn-NCP particles recently.120 Zn(II) bisphosphonate NCPs containing the cisplatin prodrug (Zncis) and oxaliplatin prodrug (Zn-oxali) were synthesized by vigorously stirring a mixture of Zn(NO3)2 and corresponding prodrugs in the present of 1,2-dioleoyl-sn-glycero-3-phosphate sodium salt (DOPA) in the Triton X-100/1-hexanol/cyclohexane/water reverse microemulsion at room temperature for 30 min. Zn-cis and Zn-oxali have a similar morphology with diameters less than 30 nm by TEM. These uniform spherical NCPs are amorphous as indicated by the lack of peaks in PXRDs. Surfactant molecules can be used as templating agents during solvothermal synthesis of NMOFs and NCPs. Although the templating agents are not incorporated within the NMOFs or NCPs, they play an important role in defining particle morphologies. This method is different than the reverse microemulsion method described above as heating destroys the microemulsions in the system. For example, GdBHC NMOFs were synthesized by a surfactant templated solvothermal method by heating a reverse microemulsion of GdCl3 and (NH3Me)6(BHC) (BHC = benzene hexacarboxylic acid) at 120 °C. The resulting block-like crystalline NMOFs of the formula Gd2(BHC)(H2O)6 have dimensions of 25 × 50 × 100 nm. The composition and morphologies of GdBHC NMOFs could be changed by adjusting the pH values and reaction temperatures during the synthesis. A different NMOF of the formula [Gd2(BHC)(H2O)8](H2O)2 (GdBHC′) was synthesized when the same reaction was carried out at pH = 2−3. Crystalline rod-like particles of Gd-BHC′ are 100−300 nm in diameter and several micrometers in length. Truncated octahedral microparticles of Gd-BHC′ were obtained when the reaction temperature was increased to 120 °C. The formation of Gd-BHC versus Gd-BHC′ was found to be pH- but not temperature-dependent (Figure 3).121 The high-temperature surfactant-assisted method has also been demonstrated to be useful in yielding amorphous NCP particles.88 Zinc-methotrexate (Zn-MTX) NCPs with a

amorphous materials, while the latter three methods could produce both amorphous and crystalline materials. We will illustrate these general synthetic approaches in this section. In the room-temperature nanoscale precipitation method, nanoparticles are synthesized by taking advantage of the insolubility of the particles in a given solvent system where the individual precursors remain soluble (Figure 2). This strategy was used to synthesize Tb-DSCP NCPs composed of the anticancer drug disuccinatocisplatin (DSCP) and Tb3+.83 The pH value of an aqueous solution of TbCl3 and di(methylammonium)DSCP was adjusted to 5.5 with aqueous sodium hydroxide. Methanol was then added quickly to the precursor solution to instantly produce spherical particles of Tb-DSCP that is 50−60 nm by SEM and DLS. Zr-based NCP (Zr-DCSP) containing the DSCP prodrug was similarly synthesized in N,N-dimethylformamide (DMF).116 Solvothermal synthesis involves the heating of a solution of metal and ligand over time, leading to more controlled particle nucleation and growth. This method was used to synthesize a number of iron-carboxylate NMOFs.117 Fe-BDC NMOF particles with the formula Fe3(μ3-O)Cl(H2O) (BDC)3 were synthesized by heating an equimolar solution of FeCl3 and terephthalic acid (BDC) with microwave heating. FeBDC displays an octahedral morphology with an average diameter of 200 nm and adopts a highly crystalline MIL-101 structure. 2-Aminoterephthalic acid was doped into the structure of Fe-BDC to provide the orthogonal functional group for further NMOF functionalization. A variety of other iron-carboxylate NMOFs were also synthesized by solvothermal methods, using both microwave and conventional heating.86 Lin and co-workers reported the first calciumphosphonate NMOFs, which were synthesized by microwave heating of a solution of H4-Zol (Zol = zoledronate) and CaCl2·2H2O in DMF/H2O at 100 °C.113 Crystalline Ca-Zol particles adopt a rod-like morphology of ∼70 × 70 × 1000 nm dimension. Microwave heating can also afford amorphous NCP particles. For example, Mn-Zol NCP was synthesized by a microwave reaction of zoledronic acid and MnCl2 in the presence of 1,2-dioleoyl-sn-glycero-3-phosphate sodium salt (DOPA) in DMF/H2O at 140 °C for 10 min.118 Reverse, or water in oil, microemulsions are formed by using surfactants to stabilize water droplets in a nonpolar organic phase. The reactions are typically conducted at room temperature. This method was used to synthesize crystalline Gd-DBC nanorods of the formula Gd(BDC)1.5(H2O)2 by mixing two separate microemulsions containing GdCl3 or bis(methylammonium)BDC.119 The particle morphology in 11081


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with the active agents as either the metal centers80,86,119,121−123 or the bridging ligands.116,123−125 This strategy can achieve a very high agent loading with uniform distribution throughout the nanoparticle matrix. However, it can be difficult to control the morphology and physiochemical properties of the resulting NMOFs and NCPs. Care must be taken to ensure that the agent is not altered or degraded during the synthesis as well. In the second loading method, biomedically relevant agents are loaded within NMOFs and NCPs during synthesis via guest encapsulation or doping. In this method, a small fraction of the biomedically relevant agent is introduced during the synthesis as a dopant to impart the desired functionality, and the particles can retain the properties of the unaltered counterparts. As NMOFs and NCPs are synthesized, the agent is encapsulated through either covalent or noncovalent interactions within the framework. This method has been used to encapsulate a number of different agents with varying functionalities and properties such as optical dyes, chemotherapeutics, proteins, and smaller nanoparticles.88,115,126−131 However, only a low drug loading can be typically achieved before the properties of NMOFs and NCPs are altered. Furthermore, most NMOFs can only encapsulate guests that possess certain chemical properties. For example, lanthanidenucleotide NMOFs can only encapsulate anionic guests.129 Postsynthetic loading offers another strategy for encapsulating biomedically relevant molecules within NMOFs and NCPs. In this strategy, a NMOF with the desired physiochemical properties is first synthesized and isolated. The agent is then introduced within the framework in a subsequent step via noncovalent or covalent interactions. Noncovalent postsynthetic drug loading was first demonstrated using bulk phase MOFs,82,132 achieving impressive loading of up to 1.4 g ibuprofen/g MOF.81 Release studies showed slow and sustained drug release from the framework with minimal burst effects. Recent studies have extended this strategy to NMOF structures, which have been loaded with hydrophilic, amphiphilic, and hydrophobic drugs and show

diameter between 40 and 100 nm were synthesized by microwave heating of a reverse microemulsion containing Zn(NO3)2 and MTX dimethylammonium salt at 120 °C.

3. LOADING OF IMAGING AND THERAPEUTIC AGENTS IN NMOFs AND NCPs NMOFs and NCPs can have diverse properties due to their molecular nature. Cargo loadings in NMOFs and NCPs can be accomplished via several distinct routes. By taking advantage of tailorable properties of NMOFs and NCPs, cargo loading can be much more efficient as compared to conventional nanoparticles to allow for higher agent loadings without sacrificing the beneficial physicochemical properties of NMOFs and NCPs. Cargo loading in NMOFs and NCPs falls under two general categories: direct incorporation of cargoes during particle synthesis or postsynthetic loading. Additionally, complementary techniques can be used to incorporate multiple biomedically relevant agents to enable the development of future theranostic or multimodal nanoparticles. In the first loading strategy, biomedically relevant agents can be directly incorporated within NMOFs and NCPs (as parts of the framework structures) during their synthesis (Figure 4). Previous works have afforded NMOFs and NCPs

Figure 4. Schematics showing the direct incorporation of biomedically relevant metal connecting points or bridging ligands.

Figure 5. Schematics showing the postsynthesis encapsulation via noncovalent encapsulation (a) and covalent attachment (b). 11082


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Figure 6. Schematics showing surface coating strategies of crystalline and amorphous NMOF and NCP particles with either a thin shell of silica or a lipid bilayer.120,138,139 Reprinted with permission from refs 120, 138, and 139. Copyright 2007 and 2014 American Chemical Society and 2011 Wiley.

sustained drug release.86,89,133 However, these NMOFs usually feature much lower drug loading than bulk phase materials. This method requires highly porous materials for optimal efficiency, limiting the general applicability of this synthetic strategy. Also, encapsulation efficacy and loading will strongly depend on the drug’s properties and the stability of the original particles. The drug distribution within the material may not be uniform, leading to variable release kinetics. Drug loading is inherently reversible, so some drugs might be prematurely lost during subsequent processing of the NMOF. Because of high surface to volume ratios for small nanoparticles, therapeutic cargoes can be loaded on the surfaces of NCPs. Lin and co-workers recently reported an interesting strategy to deliver siRNAs with NMOFs or NCPs that carry cisplatin for treating resistant ovarian cancer.89,134 For example, they used cationic lipid 1,2-dioleoyl-3trimethylammonium-propane (DOTAP) to coat NCPs to yield highly positively charged particles, which then bind strongly to negatively charged siRNAs via electrostatic interactions to afford siRNA-loaded NCP particles. Covalent postsynthetic modification has also been reported, where an orthogonal functional group within the framework reacts with a biomedically relevant agent (Figure 5).114,117,135 This method loads drugs irreversibly, making subsequent particle modification and processing easier. Covalent attachment in practice would create a prodrug, so it is essential to ensure that the functionality of the agent is maintained, or the covalent linkage must be cleavable under specific biological conditions. Covalent attachment would be expected to lead to a nonuniform drug distribution with drugs found primarily on the exterior of the material, which may limit the drug loading and unfavorably alter the properties of the material.

of surface modifications including silica coating, lipid layer encapsulation, and polymer coating are discussed (Figure 6). NMOFs and NCPs have been coated with thin silica shells to stabilize the particles, increase biocompatibility and water dispersibility, and allow functionalization with a variety of silyl-derived molecules. Generally, NMOFs and NCPs are first coated with a polymer, such as polyvinylpyrrolidone (PVP), to facilitate the silica coating process. The PVP-coated particles are then treated with tetraethylorthosilicate (TEOS) in basic ethanol to afford silica coatings. The silica shell thickness can be controlled by adjusting the reaction time or/and the reactant concentrations. Release profile experiments demonstrated that a silica shell can significantly slow the rate of particle dissolution/decomposition. This method was used to successfully coat Gd-BDC,138 MnBDC,122 Tb-DSCP,83 and Zr-DSCP NMOFs.139 In another method, Fe-BDC NMOFs were coated with silica using sodium silicate under aqueous conditions.117 The surface of these core−shell structures can be further modified by grafting a silyl-derived molecule onto the silica shell through surface silanol groups to impart additional functionality, such as targeting ligands, optical contrast agents, and sensory agents.83,117,122,138 The silica coating approach appears to be a highly general method applicable to a range of materials. However, it can be rather difficult to obtain very thin silica coatings due to the low nucleation density leading to spotty surface coverage, which could lead to burst-effect release. In addition, the coating condition is slightly basic and is not compatible with the materials that are not stable under basic conditions. Lipid coatings have recently been used to modify the surfaces of NMOFs and NCPs. Lipid bilayers not only slow the cargo release kinetics but also impart biocompatibility. The compositional tunability of lipid bilayer provides a significant advantage over the silica coating. Two different strategies have been used to coat NMOFs/NCPs with lipid layers. In the first method, lipids are coated on the particle surfaces via electrostatic interactions.113 The as-synthesized calcium-pamidronate (Ca-Pam) NCP particles had a negative ζ potential of around −22 mV and were coated with single lipid bilayers (SLBs) containing 1:1 (by mol) DOTAP/DOPE (DOTAP = dioleoyl trimethylammonium, propane and DOPE = dioleoyl L-α-phosphatidylethanolamine). In this work, liposomes of 100−120 nm in diameter with a ζ potential of +55 mV were mixed with the Ca-Pam particles with a particle to liposome weight ratio of 4:1, leading to lipid-coated CaPam.

4. SURFACE MODIFICATION OF NMOFs As-synthesized particles often do not have favorable stability, dispersibility, biocompatibility, and other properties for biomedical applications. A common strategy to improve the performance of nanoparticles under physiological conditions is through surface modification,136,137 which can improve the water dispersity, reduce nonspecific plasma protein binding, avoid uptake by the mononuclear phagocytic system (MPS), and add other molecules to target specific regions of the body or to impart additional agents or functionalities. Surface modifications can also slow the degradation of the nanomaterial. NMOFs can be coated with silica, lipid layer, polymer, oligonucleotides, nucleic acids, etc. In this section, three types 11083


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method, and further coated with a thin layer of silica and a silyl-derived peptide RGD to actively target cancer cells (Figure 7).83 Tb-DSCP exhibited a spherical morphology with

Lipid coating can also be driven by the hydrophobic and hydrophobic interactions between particles terminated with a lipid monolayer and another lipid layer. For example, Zn-cis and Zn-oxali NCP particles were synthesized in the presence of DOPA to coat the NCPs with a monolayer of DOPA via metal−phosphate interactions between NCPs and DOPA molecules.116,120,134 The DOPA-coated NCPs were further coated with 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), cholesterol, and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (DSPE-PEG2k) in a 4:4:2 molar ratio to lead to selfassembled, asymmetric lipid bilayers via hydrophobic/hydrophobic interactions between DOPA and DOPC/cholesterol/ DSPE-PEG2k. Boyes and co-workers developed polymer modified Gdbased NMOFs through attachment of homopolymers or copolymers synthesized via reversible addition−fragmentation chain transfer (RAFT) polymerization. Introduction of a trithiocarbonate RAFT agent enabled the reduction of the polymer end groups to thiolates, and thus the polymers could be attached on the NMOF surface through vacant coordination sites on the Gd3+ ions. These polymer-coated Gd NMOFs were demonstrated to be biocompatible and have cancer cell targeting, bimodal imaging, and disease treatment capabilities in the in vitro studies.140,141

Figure 7. (a) Schematic representations of the synthesis, modification, and cisplatin release from Tb-DSCP. (b) Morphology of Tb-DSCP. TEM images of Tb-DSCP (A) and silica coated TbDSCP (B). Reprinted with permission from ref 83. Copyright 2008 American Chemical Society.

5. NMOFs AND NCPs FOR CANCER THERAPY AND DRUG DELIVERY With the enormous progress made in cancer biology in the past few decades, a large number of anticancer therapeutics have been brought to the clinic including small molecule inhibitors, antibodies, chemotherapeutics, and nucleic acid drugs.13,142−144 However, current therapeutics are limited by the nonspecific distribution and unfavorable pharmacokinetics after systemic administration, leading to undesired high doses and side effects.13,14,136 NMOFs/NCPs are potential nanovectors for delivering therapeutic agents to targeted areas of the body to overcome these limitations and to achieve enhanced therapeutic efficacy with safe doses. Nanoscale dimensions of NMOFs/NCPs allow them to take advantage of the EPR effect to achieve specific and enhanced accumulation in the tumor site. The large surface areas, high porosity, and the presence of functional groups allow NMOFs/NCPs to carry drugs with high capacities, release drugs in a controllable manner, and be easily conjugated with active targeting ligands to further increase drug accumulation in the diseased sites and enhance therapeutic efficacy. Besides delivering anticancer drugs, NMOFs/NCPs have also been demonstrated to be excellent delivery systems for gaseous molecules and other small molecule drugs for the treatment of multiple diseases including inflammation, HIV, bacterial infection, etc. In this section, we will review the applications of NMOFs and NCPs in cancer therapy and drug delivery.

a diameter of ∼70 nm by DLS. Tb-DSCP decomposes in physiological media and thus slowly releases the cisplatin prodrug by diffusing out of the silica shell to induce cytotoxicity in human colon cancer cells HT29 and breast cancer cells MCF-7. A Fe-BDC NMOF with a formula of Fe3(μ3-O)Cl(H2O)2(BDC)3 was created and postsynthetically modified to carry a cisplatin prodrug, c,c,t-Pt(NH3)2Cl2(succinate) (OEt).117 The MIL-101 NMOFs were further coated with silica and targeted with the RGD peptide. SEM imaging revealed the octahedral morphology of the NMOF and an average diameter of ∼200 nm. This NMOF was also shown to be cytotoxic to HT29 cells, with an IC50 value comparable to that of free cisplatin. To further increase biocompatibility, Lin and co-workers developed a lipid coating strategy for NCPs containing platinum drugs (Figure 8).116 NCPs containing DSCP bridging ligands were constructed based on Zr4+ or La3+ metal connecting points, with a DSCP loading of 8.2 wt % and a diameter of ∼133 nm by DLS measurements. The NCPs were then coated with a lipid bilayer composed of DOPC, cholesterol, DSPE-PEG2K, and DSPE-PEG2K-anisamide. After lipid coating and active targeting, the NCPs slowly released cisplatin and showed a significantly enhanced cellular uptake and cytotoxicity in human nonsmall cell lung cancer cells H460 and A549 as compared to nontargeted NMOFs. This formulation of Zr-DSCP is however not sufficiently stable for in vivo applications. Recently, Lin and co-workers reported the self-assembly of zinc bisphosphonate NCPs carrying cisplatin or oxaliplatin prodrugs with high drug loadings (∼48 wt % cisplatin prodrug for Zn-cis or ∼45 wt % oxaliplatin prodrug for Zn-oxali) (Figure 9).120After lipid coating and pegalytion, these two NCPs showed minimal uptake by the mononuclear phagocyte system and excellent blood circulation half-lives of 16.4 ± 2.9

5.1. Chemotherapy

5.1.1. Platinum Drugs. Three FDA-approved platinumbased chemotherapeutics, cisplatin, carboplatin and oxaliplatin, are used to treat multiple types of cancers, including lung, breast, colorectal, gastric, esophageal, testicular, cervical, nonHodgkins lymphoma, and ovarian cancers.145 Lin and coworkers have developed a series of NMOF/NCP platforms to deliver platinum-based chemotherapeutics. The amorphous Tb-DSCP NCP was prepared by the nanoprecipitation 11084


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circulation and minimal mononuclear phagocyte system uptake, and enables the codelivery of two chemotherapeutics that have distinctive mechanisms of action to simultaneously disrupt multiple anticancer pathways. The enhanced anticancer efficacy of this NCP for combination therapy has been demonstrated in two human pancreatic cancer mouse models including AsPC-1 and BxPC-3. Several other attempts have been made by other groups to deliver cisplatin by NMOFs/NCPs with limited in vitro cytotoxicity information and no in vivo efficacy results. Lian et al. synthesized a Prussian Blue-based NCP (HPB) with a hollow interior and a microporous framework of the formula K3[Fe(CN)6]·3H2O.147 HPB nanoparticles showed a diameter of ∼110 nm by TEM and carried cisplatin both on the surface and in the interior via physical encapsulation. In vitro cytotoxicity assay was carried out in human bladder cancer T24 cells. Because only 5% of cisplatin could be released after 4 h, HPB nanoparticles showed moderate cytotoxicity with a cisplatin IC50 of 238.5 μM. Torad et al. synthesized ZIF-8 NMOFs with a diameter of 50 nm by SEM followed by carbonization to form MOF-NC particles.148 Cisplatin was encapsulated into the MOF-NC particles at a loading amount of 6.26 mg cisplatin/mg MOF-NC. MOF-NC particles without cisplatin loading were nontoxic to human liver cancer cells HepG2. However, no cytotoxicity result of cisplatinloaded MOF-NC was presented in this work. 5.1.2. Methotrexate (MTX). MTX is a small molecule chemotherapeutic agent that induces cell apoptosis by inhibiting dihydrofolate reductase and disrupting DNA synthesis. Many cancer types are sensitive to MTX treatment; however, the application of MTX is limited by its poor pharmacokinetics, low tolerated dose, and resistance. NMOFs and NCPs have been used as delivery vehicles for MTX and showed high cytotoxicity in the cellular level.88,141,149 Boyes and co-workers synthesized the Gd-BDC NMOFs with a nanorod morphology that were first reported by Lin and co-workers.119,121,138,141 Gd-BDC NMOFs were coated

Figure 8. Schematic showing the lipid-coated and anisamide-targeted Zr- or La-based NCPs. Cisplatin release from the NCPs is triggered by the acidic endosomal/lysosomal pH followed by the reduction of DSCP to cisplatin by endogenous reductants. Reprinted with permission from ref 116. Copyright 2013 The Royal Society of Chemistry.

and 12.0 ± 3.9 h for NCPs carrying cisplatin and oxaliplatin, respectively. In multiple subcutaneous tumor murine models including colon, lung, and pancreatic cancer, NCPs exhibited superior potency and efficacy at very low drug dose as compared to free drugs (Figure 8c and d). This synthetic strategy was recently used by Lin and coworkers to deliver multiple chemotherapeutics in a single nanoparticle. They reported a Zn NCP platform carrying both oxaliplatin and gemcitabine monophosphate (GMP) for synergistic combination therapy of pancreatic cancer (Figure 10).146 This novel NCP platform exhibits prolonged blood

Figure 9. Zn-cis with prolonged blood circulation, minimal MPS uptake, and enhanced anticancer efficacy in mouse models. (a) Schematic representation of the core−shell structure of Zn-cis. (b) Pharmacokinetics and biodistribution of Zn-cis in CT26 tumor bearing mice after intravenous injection. (c) In vivo tumor growth curves for Zn-cis, free cisplatin, and other controls on the s.c. CT26 tumor model. (d) In vivo tumor growth inhibition curves for Zn-cis, free cisplatin, and other controls on the s.c. H460 tumor model. 11085


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Figure 10. Zn NCPs for the combination of oxaliplatin and gemcitabine. (a) Schematic representation of the synthesis, endocytosis, and intracellular drug release of Zn-Oxali and GMP. (b) Pharmacokinetics and biodistribution of Zn-Oxali and GMP in CT26 tumor bearing mice after intravenous injection. (c) Tumor growth inhibition curves of Zn NCPs in asubcutaneous xenograft mouse model of human pancreatic cancer BxPC-3. Zn NCPs were intravenously injected to the mice every 4 days for a total of three injections. Reprinted with permission from ref 146. Copyright 2015 Elsevier.

chemotherapeutic agent for hematological malignancies, many types of carcinoma, and soft tissue sarcomas. The delivery of DOX by NCPs has been demonstrated in cellular level in the literature.150−154 Imaz et al. synthesized NCPs based on Zn2+ and 1,4-bis(imidazole-1-ylmethyl)benzene (bix) and loaded with doxorubicin and other anticancer molecules (Figure 11).150 TEM gave a diameter of 100−1500 nm of these nanoparticles. DOX IC50 values of these particles were 5.2 and 4.5 μM after 24 and 48 h incubation in HL60 cells, respectively, whereas free DOX showed an IC50 value of 0.3 μM after 24 h incubation. ZIF-8 NMOFs were also exploited as the delivery vehicle of DOX.88 ZIF-8 NMOFs carried 0.049 g DOX/g ZIF-8 and showed moderate cytotoxicity against three human cancer cells including NCI-H292, HT29, and HL-60 as compared to free DOX. A NCP built from Fe2+ and 1,1′-(1,4-butanediyl)bis(imidazole) was loaded with DOX, coated with a silica shell, and conjugated with folic acid as an active targeting ligand.152 The nanoparticles showed pH-responsive drug release and significant cytotoxicity against HeLa cells. Kundu et al. synthesized bulk Gd-based MOFs first and mechanically downsized the bulk MOFs via ball milling to afford NMOFs with particle sizes of ∼140 nm.153The NMOFs carried 12 wt % of DOX and exhibited moderate cytotoxicity in a leukemia cell line U937. MIL-100(Fe) NMOFs with particle sizes of ∼200 nm were loaded with DOX. 154 The authors hypothesized that up to two DOX molecules might interact

with a polymer conjugated with MTX, PNIPAM-co-PNAOSco-PFMA-MTX, and further linked with a targeting ligand GRGDS-NH2. Enhanced cytotoxicity was observed in sarcoma cells FITZ-HAS compared to nontargeted NMOFs. These Gd-BDC NMOFs were also used as MRI contrast agents. Lin and co-workers reported the incorporation of MTX as a bridging ligand in a NMOF formulation based on Zn2+, Zr4+, or Gd3+ with exceptionally high drug loading of up to 79.1 wt %.88 These NMOFs were stabilized with a lipid bilayer and targeted with anisamide to achieve improved cellular uptake and cytotoxicity in cancer cells. TEM showed the NMOFs were spherical structures with diameter ranging from 40 to 100 nm. The enhanced cellular uptake was confirmed by confocal microscopy studies, and cytotoxicity comparable to free MTX was observed for NMOFs. Xing et al. synthesized NCPs constructed from Zn2+ or Fe3+ and MTX.149 Zn-MTX and Fe-MTX particles showed diameters of ∼145 and 160 nm, respectively, by SEM. A shell of coordination polymers synthesized from Zn2+ and 1,4bis(imidazole(1-ylmethyl)benzene) (BTX) was coated on the surface of MTX-Zn and MTX-Fe to form core−shell structured nanoparticles. These particles exhibited pHresponse MTX release and enhanced cytotoxicity in HeLa cells as compared to free MTX. 5.1.3. Doxorubicin (DOX). DOX is an anthracycline antibiotic that prevents DNA replication by intercalating between base pairs in the DNA helix, and is an FDA-approved 11086


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release.157 Wang et al. created MOFs with a formula of [Zn3(L)-(H2O)2]·3DMF·7H2O (H6L = 1,2,3,4,5,6-hexakis(3carboxyphenyloxymethylene)benzene), which could accommodate 5-Fu with a loading amount of 0.36 mg 5-Fu/mg MOF and lanthanide (III) cations for luminescence applications.158 He et al. showed that ZIF-8 NMOFs with a diameter of 100−200 nm by TEM could carry both 5-Fu and green fluorescent C-dots for pH-responsive drug release and fluorescence imaging.159 Liu et al. synthesized MOFs with a formula of [Cu(L)(4,4′-bipy)(H2O)]n1.5nCH3CN (H2L = diphenylmethane-4,4′-dicarboxylic acid) and loaded the MOFs with 5-Fu at a loading amount of 27.5 wt %.160 Li et al. developed three polyoxometalates (POMs) and loaded the POMs into ZIF-8 NMOFs with an average size of 50−200 nm.178 The authors demonstrated that the incorporation of POMs into the frameworks led to more efficient loadings of 5-Fu and slow release of 5-Fu from the particles. Nascimento and co-workers reported the synthesis of a Cu-BTC MOF, which incorporated 5-Fu at ∼45 wt %.105 The cytotoxicity of drug loaded MOFs was evaluated in NCI-H292, MCF-7, HT29, and HL60 cells. MOFs loaded with 5-Fu showed enhanced cytotoxicity in MCF-7 and HL60 cells as evidenced by the significantly decreased IC50 values of 5-Fu. 5.1.5. Other Chemotherapeutic Agents. Because of the versatility of NMOF synthesis, they have also been used to deliver other chemotherapeutic agents. The anticancer efficacy of these systems against different cancer types has been evaluated in some of these reports. Lin and co-workers developed two types of NCPs for the delivery of bisphosphonates to kill cancer cells in vitro.113,118 These NCPs carried high payloads of pamidronate or zoledronate, coated with lipid bilayer to stabilize the particle structure and control drug release in physiological environment, and further conjugated with the active targeting ligand anisamide to enhance specific cancer cell uptake and killing. Zhu et al. used Zr-based UiO-66 NMOFs (∼70 nm cubical shape by TEM) to deliver Alendronate (AL), a bisphosphate anticancer drug.161 Cytotoxicity assays in HepG2 and MCF-7 cells showed that AL-UiO-66 NMOFs induced enhanced cell killing than free AL. The delivery of camptothecin (CPT) and its derivative Topotecan (TPT) was achieved by ZIF-8 (∼70 nm)162 and MIL-100 (∼50−100 nm),163 respectively. Both drug loaded NMOFs exhibited enhanced cytotoxicity against cancer cells as compared to free drugs. Ke et al. incorporated Fe3O4 nanorods into nanocrystals of Cu3(BTC)2 (HKUST-1) and further loaded the nanoparticles with cyclooxygenase-2 (COX-2) at a loading amount of ∼16.7 wt %.164 Wang et al. synthesized a cytotoxic ligand, 3,5-bis(pyridine-3ylmethylamino)benzoic acid, and developed NMOFs with Zn2+ or Cu2+. These NMOFs exhibited cytotoxicity in three human cancer cell lines including NCI-H446, MCF-7, and HeLa cells.165 5.1.6. Future Directions. Although several attempts have been made to incorporate chemotherapeutic agents into NMOFs/NCPs and evaluate the drug loading and release kinetics (Table 1), the anticancer efficacy of most NMOF/ NCP-based nanotherapeutics has not been rigorously evaluated in biological assays. Only limited in vitro cytotoxicity has been reported to date, while the in vivo anticancer efficacy studies have been exclusively reported by Lin and co-workers. A few studies used computational methods to study drug−NMOF interactions and to optimize NMOF structures for drug delivery.166−168 More efforts are

Figure 11. (a) Schematic illustration describing the encapsulation of drugs into NCP. (b) SEM and (c) TEM images of a representative colloidal solution of DOX/Zn(bix) NCP. (d) Cytotoxicity of Zn(bix) NCP (blue) and DOX/Zn(bix) NCP (blue) against HL60 cells. (e) Cytotoxicity of DOX/Zn(bix) NCP (red) and free DOX (orange) against HL60 cells. Reprinted with permission from ref 150. Copyright 2010 The Royal Society of Chemistry.

with each Fe(III) trimeric unit by coordination. No information on the drug loading, release, or cytotoxicity was provided in this work. 5.1.4. 5-Fluorouracil (5-Fu). 5-Fu is a pyrimidine analogue that irreversibly inhibits thymidylate synthase, and is used in the treatment of multiple cancer types. Because of its small molecular weight and size, it can be encapsulated in the pores/channels of NMOFs. Several examples are available in the literature showing the capability of NMOFs to carry high amount of 5-Fu and slowly release the cargo. However, no information on the anticancer effects of 5-Fu loaded NMOFs was presented in most of these reports. Sun et al. created an anionic MOF from a hexadentate ligand, 5,5′,5″-(1,3,5-triazine-2,4,6-triyl)tris(azanediyl)triisophthalate and Zn2+, which carried 5-Fu at a loading amount of 33.3 wt %.155 Wang et al. used metal−organic polyhedron (MOP)-15 as a precursor to synthesize a MOF with a formula of [Cu24(5-NH2-mBDC)24(bpy)6(H2O)12]·72DMA and studied the encapsulation and release of 5-Fu from this MOF.173 Zhao et al. synthesized Cu-based MOFs and conjugated PEG5K on the MOF surface via Click chemistry.133 DLS measurements gave particle sizes of ∼50 nm for PEGylated MOFs. 5-Fu was incorporated into the MOFs and could be slowly released from the MOFs. Sun et al. loaded 5-Fu into ZIF-8 NMOFs with a loading amount of ∼39.8 wt % and showed that 5-Fu could be released from ZIF-8 in a pHsensitive manner.156 Qin et al. also demonstrated that ZIF-8 MOFs could load 5-FU with high loading amount (30.5 wt %) and 5-Fu could diffuse out of the framework without burst 11087


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evaluations in the next few years, and the clinical potential of this unique class of hybrid nanomaterials will be determined.

Table 1. Examples of NMOFs and NCPs for Cancer Therapy

5.2. Photodynamic Therapy (PDT)

chemotherapeutic agents Fe-BDC (MIL-101) ZIF-8

NMOFs cisplatin cisplatin, DOX, 5-Fu′, CPT, Topotecan

Zr-UiO-68 Gd-BDC Zn-bix Fe-imidazole Gd-BDC MIL-100(Fe) Zn-hexadentate Cu-BDC Zn-1,2,3,4,5,6-hexakis(3carboxyphenyloxymethylene)benzene Cu-bipy POM@ZIF-8 Cu-BTC Zr-UiO-66 Cu-BTC Zn/Cu-3,5-bis(pyridine-3ylmethylamino)benzoic acid

Tb-DSCP Zr-DSCP/La-DSCP Zn-cis/Zn-oxali Zn-oxali and GMP Prussian Blue Zn-MTX/Zr-MTX/Gd-MTX Ca-pamidronate/zoledronate

cisplatin MTX DOX DOX DOX DOX 5-Fu′ 5-Fu′ 5-Fu′

5-Fu′ 5-Fu′ 5-Fu′ alendronate COX-2 cytotoxic 3,5bis(pyridine-3ylmethylamino) benzoic acid NCPs cisplatin cisplatin cisplatin/oxaliplatin oxaliplatin and gemcitabine cisplatin MTX pamidronate, zoledronate

ref

Photodynamic therapy (PDT) is an effective anticancer procedure that involves the administration of a tumorlocalizing photosensitizer (PS) followed by light activation to generate highly cytotoxic reactive oxygen species (ROS), particularly singlet oxygen (1O2), which triggers cell apoptosis and necrosis and evokes antitumor immunity.169−172 By localizing both the PS and the light exposure to tumor regions, PDT can selectively kill tumor cells while preserving local tissues, presenting significant advantages over traditional treatment modalities such as surgery and radiotherapy in terms of invasiveness and general toxicity.173,174A number of nanoparticle platforms have been developed to deliver molecule- or material-based PDT agents to cancers; however, few of them achieved anticancer efficacy with clinically relevant light irradiance and dose.175−177,179−181 No particlebased PSs have yet been approved for clinical use. The difficulty in developing clinically useful nanoparticle PSs can be attributed to the following reasons: (1) the individual PSs in the particle should not stay in close proximity so that the PS excited states will not self-quench; and (2) the mean ROS diffusion length is typically within the range of 20−220 nm leading to a significant amount of ROS generated from the nanoparticles that does not contribute to cytotoxic effects.182,183 By leveraging the tunable chemical compositions, crystalline structures, and extremely high porosity structure of NMOFs, Lin and co-workers rationally designed NMOFs that can address these challenges and demonstrated the superior tumor eradication/regression by PDT. The Lin group reported the design of a Hf-porphyrin NMOF as a highly efficient nanoparticle PS for PDT of resistant head and neck cancer (Figure 12).125 This work represents the first and the only example to deliver a PDT agent using porphyrin-based NMOFs. The novel Hfporphyrin NMOF (DBP-UiO) was constructed from Hf4+ and 5,15-di(p-benzoato)-porphyrin (H2DBP). DBP-UiO displayed plate morphology with ∼100 nm diameter and ∼10 nm thickness. It carried exceptionally high PS loading of 77 wt %. DBP-UiO efficiently generated 1O2 due to site isolation

117 88, 148, 156, 157, 159, 162 89 121 150 152 153 154 155 133, 173 158 160 178 105 161 164 165

83 116 120, 134, 185 146 147 88 113, 118

needed to systematically evaluate the therapeutic efficacy of drug-loaded NMOFs in animal models and to demonstrate the safety of these delivery systems. It is foreseeable that NMOFs and NCPs will go through thorough preclinical

Figure 12. (a) Synthesis of Hf-DBP NMOF and the schematic description of singlet oxygen generation process. (b) TEM image of DBP-UiO showing nanoplate morphology; high-resolution TEM image of DBP-UiO (c) and its fast Fourier transform pattern (d). (e) Tumor growth inhibition curve after PDT treatment of DBP-UiO and H2DBP ligand. Black and red arrows refer to injection and irradiation time points, respectively. Reprinted with permission from ref 125. Copyright 2014 American Chemical Society. 11088


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Figure 13. (a) Schematic description of the singlet oxygen generation by DBC-UiO photosensitization with LED light. (b) TEM images of DBCUiO showing nanoplate morphology. Tumor growth inhibition curves after PDT treatment in CT26 (c) and HT29 (d) models. Red arrows refer to treatment time points. Reprinted with permission from ref 184. Copyright 2015 American Chemical Society.

Figure 14. (a) Schematic showing the composition of the self-assembled NCP@pyrolipid core−shell nanoparticle with PEG and pyrolipid in the outer lipid layer. (b) Schematic showing endocytosis of NCP@pyrolipid and subsequent apoptosis/necrosis achieved by combined chemotherapy and photodynamic therapy. (c) Pharmacokinetics and biodistribution of Zn-cis@pyrolipid in CT26 tumor bearing mice after intravenous injection. (d) In vivo anticancer efficacy of Zn-cis@pyrolipid. PBS, Zn-cis, porphysome, or Zn-cis@pyrolipid was intravenously injected to human head and neck cancer SQ20B subcutaneous xenograft murine models at a cisplatin dose of 0.5 mg/kg or pyrolipid dose of 0.5 mg/kg followed by irradiation (670 nm, 100 mW/cm2) for 30 min 24 h post injection. Mice receiving Zn-cis@pyrolipid without irradiation also served as a control. The drug administration and irradiation were performed once a week for twice total. Data expressed as means ± SD (N = 5). Black and red arrows in (a) and (d) represent the time of drug administration and irradiation, respectively. “+” and “−” in the figure legends refer to with and without irradiation, respectively. Reprinted with permission from ref 185. Copyright 2015 American Chemical Society.

highly efficient PDT efficacy in vitro/vivo as evidenced by a complete tumor eradication in half of the mice receiving a single DBP-UiO dose (3.5 mg DBP/kg, local administration)

of DBP ligands, enhanced intersystem crossing by Hf metal centers, and facile 1O2 diffusion through the porous and extremely thin nanoplates. As a result, DBP-UiO exhibited 11089


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Figure 15. UiO NMOFs carrying a cisplatin prodrug and siRNA exhibited capabilities to escape endosomal entrapment upon entering the cells and induce significant apoptosis in cisplatin-resistant ovarian cancer cells. (a) Schematic presentation of siRNA/UiO-Cis synthesis and drug loading. (b) TEM image of siRNA/UiO-Cis. (c) CLSM image showing that siRNA (TAMRA-labeled, red) successfully escaped from endosomes (Lysotracker Green stained, green). Nuclei was stained with DAPI. Bar = 5 μm. (d) CSLM image showing the apoptosis induced by siRNA/ UiO-Cis in human ovarian cancer cell SKOV-3. The apoptotic cells were stained with Alexa Fluor 488 Annexin V conjugate, and the nuclei were stained with DAPI. Bar = 10 μm. (e) Cytotoxicity of siRNA/UiO-cis in SKOV-3 cells after 72-h incubation. Reprinted permission from ref 89. Copyright 2014 American Chemical Society.

Figure 16. (a) Synthesis of UiO-66-N3 NMOFs. (B) DNA functionalization of UiO-66-N3 NMOFs, utilizing DNA functionalized with dibenzylcyclooctyne. (c) Powder X-ray diffraction of simulated UiO-66-N3 (black) and as-synthesized UiO-66-N3 540 nm NMOFs (red). (d) Cell uptake by flow cytometry. (e) Confocal microscopy of cells treated with 14 nm NMOF-DNA conjugates. Bar = 10 μm. (f) NMOF uptake per cell determined by ICP-MS. (g) Cell viability assay showing no significant cell toxicity for NMOF-DNA conjugates. Reprinted with permission from ref 186. Copyright 2014 American Chemical Society.

and single light irradiation at 100 mW/cm2 for 30 min (630 nm LED light source). Lin and co-workers recently reported the first chlorin-based NMOFs, DBC-UiO, with much improved photophysical properties over DBP-UiO (Figure 13).184 A solvothermal

reaction between HfCl4 and 5,15-di(p-benzoato)chlorin (H2DBC) in DMF led to the dark purple powdery product of DBC-UiO. DBC-UiO effectively induced PDT cytotoxicity in two colorectal cancer cells, HT29 and CT26, at lower NMOF doses and LED light irradiation doses as compared to 11090


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Figure 17. (a) Schematic presentation of the core−shell structure of Zn-cis/siRNAs. (b) Zn-cis/siRNAs promoted the efficient endosomal escape of siRNA (red fluorescence). The endosome and nuclei were stained with Lysotracker Green (green fluorescence) and DAPI (blue), respectively. Bar = 20 μm. (c) Tumor growth inhibition curve of Zn-cis/siRNAs. After local administration, Zn-cis/siRNAs showed significant tumor regression in a subcutaneous xenograft mouse model of cisplatin-resistant ovarian cancer. (d) The expression of drug-resistant genes in the tumors of mice treated with Zn-cis/siRNAs was significantly down-regulated. Reprinted with permission from ref 134. Copyright 2015 Elsevier.

(amino-TPDC) as bridging ligands and Zr4+ as metal connecting points. Cisplatin and a pool of siRNAs targeting multidrug resistant genes were loaded into UiO NMOFs with high loading amounts via encapsulation into the NMOF channels and surface coordination between the phosphate groups of siRNAs and Zr4+ metal ions, respectively. siRNA/ UiO-Cis NMOFs exhibited hexagonal plate like morphology with ∼100 nm diameter and ∼30 nm thickness. siRNA/UiOCis NMOFs efficiently delivered both siRNA and cisplatin to human ovarian cancer cells and dramatically decreased the cisplatin IC50 values by an order of magnitude as compared to free cisplatin in four cisplatin-resistant human ovarian cancer cells including ES-2, OVCAR-3, SKOV-3, and A2780/CDDP. The enhanced anticancer efficacy is a result of effective drugresistant gene silencing mediated by siRNA/UiO-Cis NMOFs that resensitized the ovarian cancer cells to cisplatin treatment. This work suggests that NMOFs hold great promise in the codelivery of multiple therapeutic agents including nucleic acid drugs for effective treatment of difficultto-treat cancers. Mirkin and co-workers demonstrated the ability of UiO-66 NMOFs to deliver DNA to HeLa cells (Figure 16).186 UiO66-N3 NMOFs with a formula of Zr6O4(OH)4(C8H3O4-N3)6 were first synthesized and covalently functionalized with oligonucleotides through a strain-promoted click reaction between DNA appended with dibenzylcyclooctyne and azidefunctionalized UiO-66-N3. UiO-66-N3 NMOFs with three different particle sizes of 540, 19, and 14 nm were synthesized via a solvothermal method, and the 19 and 14 nm NMOFs were further conjugated with DNA. Similar to the spherical nucleic acids (SNAs) developed in the Mirkin group, these DNA conjugated UiO-66 NMOFs exhibited increased stability and cellular uptake in HeLa cells when compared to unfunctionalized UiO-66 NMOFs with comparable sizes.

DBP-UiO. Apoptosis/necrosis and immunogenic cell death were involved in the efficient cancer cell killing mechanism. The superior PDT efficacy of DBC-UiO was demonstrated against HT29 and CT26 subcutaneous mouse tumor models, as evidenced by the significant tumor regression observed in mice treated with DBC-UiO at low doses (1 mg DBC/kg) by local injection and light irradiation (650 nm) at 90 J/cm2. Lin and co-workers also developed Zn-cis-based core−shell nanoparticles carrying high payloads of cisplatin and the photosensitizer pyrolipid, Zn-cis@pyrolipid, for combined chemotherapy and PDT.185 Zn-cis@pyrolipid releases cisplatin and pyrolipid in a triggered manner and synergistically induced cancer cell apoptosis and necrosis. In a subcutaneous xenograft mouse model of resistant head and neck cancer, Zncis@pyrolipid showed superior efficacy in tumor regression (83% reduction in tumor volume) at low drug doses (Figure 14). 5.3. Nucleic Acid Delivery

Unlike most of the small molecule drugs that can enter the cells through passive diffusion or via translocation by membrane transporters, nucleic acids are not taken up by cells in their free forms due to their hydrophilicity and high molecular weights. Nanoparticle platforms such as liposomes, polyplexes, gold nanoparticles, iron oxide nanoparticles, etc., have been used for the delivery of nucleic acids including plasmid DNA (pDNA), small interfering RNA (siRNA), microRNA, and small hairpin RNA (shRNA). Recently, NMOFs have been used to deliver nucleic acids with high efficiency.89,134,186 Lin and co-workers reported the first use of NMOFs for the codelivery of cisplatin and pooled siRNA and demonstrated the enhanced therapeutic efficacy in cisplatin-resistant ovarian cancer cells (Figure 15).89 In this work, UiO NMOFs were synthesized with amino triphenyldicarboxylic acid 11091


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Figure 18. Schematic showing the whole activation/loading/delivery cycle of NO and MOFs. Carbon, oxygen, water oxygen, metal centers, and nitrogen are colored gray, red, pink, light blue, and dark blue, respectively. Reprinted with permission from ref 202. Copyright 2010 Elsevier.

Lin and co-workers recently demonstrated the in vivo anticancer efficacy of NCPs loaded with a chemotherapeutic agent cisplatin and pooled siRNAs targeting multidrug resistant genes in a subcutaneous xenograft mouse model of cisplatin-resistant human ovarian cancer (Figure 17).134 The Zn-cis NCP was first coated with a cationic lipid layer. Pooled siRNAs including siRNAs targeting drug-resistant genes Pglycoprotein, Bcl-2, and survivin were adsorbed onto the nanoparticle surface via electrostatic interaction to yield nanoparticles carrying both cisplatin and siRNAs (Zn-cis/ siRNAs) with particle sizes of ∼150 nm and near neutral surface charge. The resulting nanoparticles increased the cellular uptake of cisplatin and siRNAs, enabled efficient endosomal escape, and mediated effective gene silencing in cisplatin-resistant ovarian cancer cells. As a result, the Zn-cis/ siRNAs significantly enhanced the chemotherapeutic efficacy as evidenced by the dramatically decreased cisplatin IC50 values (by 2 orders of magnitude as compared to free cisplatin) in cisplatin-resistant ovarian cancer cells. Local injection of Zn-cis/siRNAs led to a tumor regression (∼60% reduction in tumor volume) in the cisplatin-resistant SKOV-3 subcutaneous xenograft mouse model. While several nanoparticle systems, including liposomes, carbon nanotubes, and polymer micelles, have recently been used to codeliver siRNA and cisplatin to cancer cells to enhance therapeutic responses,187−189 this work showed the first example of the codelivery of a chemotherapeutic agent and siRNAs by NCPs with the demonstration of dramatically enhanced anticancer efficacy in a cisplatin-resistant tumor bearing mouse model. These three examples represent all of the efforts made in using NMOFs/NCPs as the delivery vehicle for nucleic acids alone or the combination of chemotherapeutic agents and siRNAs. They indicate that NMOFs/NCPs have the potential in serving as the effective delivery vehicle for nucleic acid drugs. The strategy of loading nucleic acids into NMOFs/ NCPs needs to be further investigated and optimized for achieving favorable balance between drug binding and release

in vivo. Future efforts are needed to optimize NMOF-based nucleic acid therapeutics for systemic administration, which is preferable clinically. Given that nucleic acid drugs can be used to treat many other diseases including inflammation, virus infection, and diabetes, the successful application of NMOFs in the nucleic acid delivery will open a new window in the field of nanobiomedicine. 5.4. Nitric Oxide (NO) Delivery

Because of their high porosity, MOFs are excellent candidates for gas adsorption. The gas molecules would interact strongly with the materials such that they could be stored in the frameworks for a required time period.190−194 MOFs have been demonstrated to have the capability to store H2,40,195,196 CO2,197 NO,198−203 etc., among which NO plays an important role in biological signaling. NO delivery has been achieved using polymers, dendrimers, functionalized silica nanoparticles, and zeolites as vehicles.204−207 Morris and co-workers synthesized a series of MOFs that can efficiently adsorb, store, and deliver NO and demonstrated its biological functions in animal tissue in situ (Figure 18).198−203 Two porous MOFs of the formula [M2(C8H2O6)(H2O)2]·8H2O (M = Co, Ni) exhibited extremely high NO adsorption capacity (∼7 mmol of NO/g of MOF) with good stability.200,203 The activity of the NO delivered by MOFs was proved in myography experiments. NO-releasing MOFs caused relaxation of porcine arterial tissue. Morris and co-workers further loaded another chemotherapeutic agent, [Ru(p-cymene)Cl2(pta)] (RAPTA-C), along with NO into the same MOF by direct interaction with the Ni open metal sites and physically entrapment, respectively. The loading efficiency of NO and RAPTA-C was not affected by the presence of each other. However, the presence of RAPTA-C in the MOFs significantly retarded the desorption of NO under a humid flowing gas. MIL-88(Fe) MOFs were also exploited as the delivery vehicle for NO by Morris and co-workers.201 A significant amount of NO was adsorbed at room temperature by the nontoxic, biodegradable, 11092


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Figure 19. Scheme of engineered core−corona porous iron carboxylates for drug delivery and imaging. Reprinted with permission from ref 86. Copyright 2010 Nature Publishing Group.

and flexible MIL-88(Fe) MOFs at a high loading amount of 1−2.5 mmol/g. NO was released from MOFs over a long period of time (>16 h), suggesting these MOFs can adsorb NO with high efficiency and release NO in a controlled manner. Reynolds and co-workers utilized MOFs for the catalytic production of NO by using Cu3(BTC)2 as a catalyst and biologically existing S-nitrosocysteine as a substrate.207 Long and co-workers synthesized an iron(II)-based MOF with coordinatively unsaturated redox-active metal cation sites, Fe2(1,4-dioxido-2,5-benzenedicarboxylate).208 This MOF absorbed one NO molecule per iron center, yielding NO adsorption capacity greater than 16 wt %, and gradually released NO under humid conditions over the course of more than 10 days. NO is a critical gas messenger and plays important roles in biological functions, and can be used as a therapeutic agent for antibacterial, antithrombotic, and wound healing applications.209−211 While MOFs have been shown to have the capability of adsorption−storage−delivery of vastly different amounts of NO, their biomedical applications are still limited by the particle size and modest NO delivery efficiency. Further efforts are needed in the development of NMOFs as delivery vehicles for NO and the evaluation of their therapeutic efficacy in other diseases. Since Morris and coworkers also showed the capability of MOFs to codeliver NO and another chemotherapeutic agent,203 the interactions between the payloads and the potential synergistic effects of the payloads are also worthy of further studies.

5.5. Delivery of Other Drugs

The highly tunable functional groups and pore/channel sizes of NMOFs make them applicable for the delivery of a variety of other drugs with diverse physicochemical properties and biological functions. In particular, NMOFs have been shown to be promising vehicles for many drugs that have antiinflammatory, antiarrhythmia, antibacterial, anti-HIV, and other biological functions. In 2010, Férey and co-workers reported the use of nontoxic MIL series MOFs as nanocarriers for the controlled delivery of drugs against cancer and AIDS, including busulfan, azidothymidine triphosphate, doxorubicin, and cidofavir (Figure 19).86 The authors demonstrated that these drugs could be incorporated into MIL NMOFs via encapsulation with relatively high efficiency and be released in the biologically relevant media without significant burst release. Further efforts have been made by Férey and co-workers as well as other groups to evaluate drug loading and release using NMOFs. Ibuprofen is a nonsteroidal anti-inflammatory drug used for alleviating pain and fever as well as reducing inflammation. It is a small hydrophobic drug with a molecular weight of 206 g/mol. Férey and co-workers utilized this small molecule as a model drug to study the incorporation and release properties of MIL series of MOFs in 2006.81 Two MOFs, MIL-100 and MIL-101, were synthesized and ibuprofen was adsorbed by the dehydrated powdered MOFs from a solution in hexane, yielding drug loadings of 0.347 g ibuprofen/g MIL-100 MOFs and 1.376 g ibuprofen/g MIL-101 MOFs. Drug release studies 11093


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peroxidation, causing rupture of the bacterial membrane, and finally inactivating the bacterial activity. The antibacterial effect could last as long as 4 weeks. Silver has long been recognized as an effective antibacterial. Lu et al. synthesized two Ag-based MOFs [Ag 2 (O-IPA)(H 2 O)·(H 3 O)] and [Ag5(PYDC)2(OH)] (HO-H2IPA = 5-hydroxyisophthalic acid and H2PYDC = pyridine-3,5-dicarboxylic acid).217 Both MOFs slowly released Ag+ leading to excellent and long-term antibacterial activity toward both Gram-negative and Grampositive bacteria, E. coli and S. aureus, respectively, by rupturing the bacterial membrane. Hematological study showed that these two MOFs had good biocompatibility in mice. Serre and co-workers synthesized MIL series and UiO series MOFs for the delivery of nicotinic acid and caffeine.124,218 Nicotinic acid is an endogenous acid, which lowers the total cholesterol and triglyceride levels. The medical use of caffeine includes the prevention and treatment of bronchopulmonary dysplasia in premature infants, the primary treatment of apnea of prematurity, and the treatment of orthostatic hypotension. A biodegradable MOF based on iron and a bioactive molecule, nicotinic acid, was synthesized and named as BioMIL-1.124 BioMIL-1 carried a high payload of nicotinic acid of 75 wt %, rapidly degraded in physiological conditions such that nicotinic acid could be released efficiently within a few hours. Another two MOFs, MIL-100 and UiO66, were synthesized and loaded with caffeine at (49.5 ± 1.9) wt % and (22.4 ± 3.4) wt %, respectively.218 Both MOFs released caffeine in a sustained manner in the simulated physiological media. Deferiprone chelates iron and is used to treat thalassaemia major and hemochromatosis in the clinic. Burrows et al. constructed a series of zinc-based MOFs and loaded deferiprone into the two- or three-dimensional networks after deprotonation.219 Deferiprone can be released from the zinc-based MOFs in PBS or in acidic environment.

showed that ibuprofen could be released from both MIL MOFs. Férey and co-workers later synthesized two flexible MOFs, MIL-53(Cr) and MIL-53(Fe), and showed that both MOFs could carry ∼20 wt % of ibuprofen.82 The authors further demonstrated a slow and complete release of ibuprofen from both MOFs under physiological conditions in 3 weeks with a zero-order release kinetics. Recently, Hu et al. synthesized a positively charged submicrometer MOF-74Fe(III) with a rod-like morphology.212 This cationic MOF showed low cytotoxicity on rat pheochromocytoma PC12 cells. Ibuprofen anions were loaded into MOF-74-Fe(III) with a high loading amount (∼15.9 wt %) through ion exchange and salt penetration. The author hypothesized that the ibuprofen release from MOFs exhibited two distinct stages due to the two interactions of drug anions with the carriers, encapsulation and coordination. To achieve better controlled ibuprofen release and multifunctional MOFs, Wu et al. loaded MIL-53(Al) with superparamagnetic γ-Fe2O3 NPs and ibuprofen sequentially.213 The submicrometer MIL-53(Al) achieved the adsorption capacity of ibuprofen ∼0.11 g/g MIL53(Al) loaded with iron oxide nanoparticles. A three-phase release of ibuprofen from MOFs was observed, and the MOFs retained their magnetic properties after releasing the drugs. Procainamide is an antiarrhythmic drug for the treatment of cardiac arrhythmias. An et al. created an anionic bio-MOF-1 constructed from zinc-adeninate and biphenyldicarboxylate and loaded the bio-MOF-1 with cationic procainamide hydrochloride at a loading amount of 0.22 g procainamide/ g bio-MOF-1. Because of the ionic interactions between procainamide and bio-MOF-1, cations such as Na+ could be used to trigger drug release from the framework. Ananthoji et al. encapsulated procainamide into a zeolite-like MOF with a formula of ([In48(HImDC)96]48−)n and further embedded the drug loaded MOFs in polymeric hydrogel (P(HEMA/ DHPMA/VP/EGDMA) copolymer hydrogel) to achieve slow and sustained drug release in physiological environment.214 In the work reported by Agostoni et al., a MIL-100 NMOF was generated by the spontaneous coordination of oxocentered Fe(III) trimers and trimesic acid, and loaded with a hydrophilic anti-HIV drug, azidothymidine tryphosphate (AZT-TP).215 MIL-100 NMOFs showed high loading capacity with a loading amount of 24 wt % and particle size of 238 ± 22 nm by DLS measurements. The authors also demonstrated the efficient penetration and release of AZT-TP from MIL-100 NMOFs inside major HIV target cells, human PHA-P-activated PBMC, thus providing effective protection against HIV infection. This work reported the first example of using NMOFs to deliver anti-HIV drugs, demonstrating the in vitro anti-HIV effect of NMOFs. Bacterial infection can be a serious health issue, and there is a need to develop antibacterial agent with high potency and long-term stability. The antibacterial effects induced by NMOFs can be achieved by constructing the frameworks with metal ions of antibacterial activity, such as cobalt and silver. Zhuang et al. created a Co MOF where cobalt served as a central element and tetrakis [(3,5-dicarboxyphenyl)oxamethyl] methane (TDM8−) served as an octa-topic carboxylate ligand. This Co MOF displayed distinctive grain boundaries and a well-developed periodic structure.216 Antibacterial studies on Gram-negative bacteria, Escherichia coli (strain DH5alpha and XL1-Blue), revealed that the release of Co from the frameworks rapidly catalyzed the lipid

6. NMOFs AND NCPs FOR BIOMEDICAL IMAGING Nanomaterials have been extensively studied as new imaging probes in the field of biomedical imaging. For example, quantum dots have been used as optical imaging agents, whereas superparamagnetic iron oxide nanoparticles have been used as contrast agents for magnetic resonance imaging (MRI). As hybrid materials, NMOFs can be tailored to function as contrast agents for many imaging modalities, including MRI, CT, and optical imaging (OI).99,102 NMOFs offer some interesting and distinct advantages over other nanoparticles in delivering imaging contrast agents. 6.1. MRI

MRI is a noninvasive imaging technique based on the detection of nuclear spin reorientations in a magnetic field. MRI is able to differentiate diseased tissues from normal tissues on the basis of the different water proton NMR signals. MRI provides excellent spatial resolution, high soft tissue contrast, and unlimited penetration depth, but with low sensitivity.78 A contrast agent is typically used to further improve the image quality. The ability of the contrast agent to modify the relaxation times of water protons when a magnetic field is applied is directly related to the relaxivity of the material. Paramagnetic metal ions such as Gd(III) are typically utilized to improve image contrast by increasing longitudinal water proton relaxation (r1) rates. However, small molecule 11094


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Figure 20. (a) T1-weighted MR phantoms of Gd-BDC in water with 0.1% xanthan gum at 3T. (b) r1 and r2 relaxivity curves of Gd-BDC of ∼100 nm in length by ∼40 nm in diameter. Reprinted with permission from ref 119. Copyright 2008 American Chemical Society.

Figure 21. (a) In vitro MR images of HT-29 cells incubated with Mn-BTC@silica (left), nontargeted Mn-BTC@silica (middle), and c(RGDfK)targeted Mn-BTC@silica (right). Confocal images of HT-29 cells incubated with no particle (b) nontargeted Mn-BTC@silica (c), and c(RGDfK)-targeted Mn-BTC@silica (d). The cell nuclei were stained with DRAQ5 (blue), and the particles were detected with rhodamine B (green). Scale bars represent 20 μm. Reprinted with permission from ref 122. Copyright 2008 American Chemical Society.

the size of Gd(III) NMOFs and compared the relaxivities of NMOFs with different particle sizes. They found that the relaxivity values of the NMOFs are dependent on nanoparticle size, with smaller NMOFs exhibiting larger r1 relaxivities. This can be attributed to the fact that smaller particles possess higher surface to volume ratios to enhance the exchange between Gd(III) bound water and bulk water, and corroborated the earlier observations by the Lin group.221 Boyes and co-workers further tuned the relaxivities of Gd(III)-based NMOFs by surface modification with polymers, showing that hydrophilic polymers would contribute to an increased r1 relaxivity while hydrophobic polymers could increase the r2 relaxivity.140,141 To improve the stability and efficiency of NMOFs, other efforts have been made to coat the NMOFs with polymers or further conjugate an active targeting ligand to enhance the tumor accumulation. Chelebaeva et al. synthesized a magnetoluminescent cyano-bridged NCP with a formula of Ln0.333+Gdx3+/[Mo(CN)8]3−. These ultrasmall nanoparticles of 3−4 nm in diameter were further wrapped by the chitosan polymer and were shown to have low toxicity in human cancer and normal cells including HCT-116, Capan-1, and HUVEC cells. These nanoparticles showed slightly higher r1 and r2 relaxivities than those of the clinically used Gd-DTPA or Omniscan.222 Zhou et al. created magneto-phosphorescent NCPs composed of carboxyl-functionalized iridium complexes as building blocks and magnetic Gd(III) ions as metallic nodes.223 These nanoparticles were further coated with polyvinylpyrolidone (PVP) and exhibited a hollow sphere morphology with an average diameter of ∼60 nm and PVP thickness of ∼10 nm. The nanoparticles showed an intense red phosphorescence, a moderate r1 value of 8.0 mM−1 s−1 on a per Gd(III) basis, and low cytotoxicity in HeLa cells. Yang

contrast agents such as Gd(III) chelates used in the clinic typically have modest r1 values. Therefore, large doses of contrast agents are used in clinical scans to enhance the contrast between normal and diseased tissues, which would potentially lead to significant toxicity in some populations of patients.220 To enhance the sensitivity and lower the toxicity of MRI contrast agents, efforts have been made to deliver imaging agents by nanomaterials including NMOFs. The effectiveness of Gd(III)-containing NMOFs as T1weighted contrast agents was first demonstrated by Lin and co-workers.119,121 For example, Gd-BDC nanorods of ∼100 nm length and ∼40 nm diameter gave a longitudinal relaxivity (r1) of 35.8 mM−1 s−1 on a per Gd3+ basis and ∼1.6 × 107 mM−1 s−1 on a per NMOF basis in an aqueous xanthan gum suspension (Figure 20).119 The per Gd3+ relaxivity is almost an order of magnitude higher than that of the commercially available contrast agent Omniscan. Gd-BDC also exhibited a transverse relaxivity (r2) of 55.6 mM−1 s−1 on a per Gd3+ basis and ∼2.5 × 107 mM−1 s−1 on a per nanorod basis. Similar relaxivities were obtained for Gd-BHC NMOFs synthesized using a surfactant-mediated method. When measured using a 9.4T MR scanner, the Gd-BHC NMOF exhibited a modest r1 of 1.5 mM−1 s−1 on a per Gd3+ basis and an exceptionally high r2 of 122.6 mM−1 s−1 on a per Gd3+ basis. This magnitude of r2 relaxivity is very large as compared to other Gd-containing nanoscale contrast agents and indicates its potential application in T2-weighted MRI.121 The dependence of r1 and r2 relaxivities on the particle sizes of NMOFs was also established by Lin and co-workers. Boyes and co-workers further refined and modified the Gd NMOFs reported by Lin and co-workers with polymers and studied their performance as MRI contrast agents. They used hydrotropes including NaSal, SalAc, and 5-mSalAc to control 11095


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et al. recently developed a NCP based on Gd3+ as metal connecting points and 1,1′-dicarboxyl ferrocene (Fc) as building blocks.224 The nanoparticles were further coated with SiO2 and covalently conjugated with RGD peptide as tumor targeting ligand to afford Fc-Gd@SiO2-RGD NCPs. The r1 and r2 relaxivities were determined to be 5.1 and 21.7 mM−1 s−1, respectively. By intravenous injection of Fc-Gd@ SiO2-RGD NCPs to subcutaneous xenograft mouse models of U87 glioblastoma, T1-weighted MRI was enhanced 47 ± 5% and T2-weighted MRI was decreased 33 ± 5%. Although Gd-NMOFs have been successfully utilized as MRI contrast agents, they would unfortunately leach significant amounts of Gd(III) ions, severely limiting their clinical utility due to the toxicity of free Gd(III) ions.225 To address this issue, the Lin group and others have synthesized Mn(II)-based NMOFs and evaluated their applications as MRI contrast agents (Figure 21).122 Mn(II) ions have been shown to be potent MRI contrast agents with lower toxicity as compared to free Gd(III). Nanorods of Mn(BDC)(H2O)2 were found to have an r1 and r2 of 5.5 and 50.0 mM−1 s−1 on a per Mn(II) basis at 3 T, respectively, whereas nanorods of Mn2(BTC)3(H2O)6 exhibited an r1 and r2 of 7.8 and 70.8 mM−1 s−1 per Mn(II) basis, respectively. Mn-BTC NMOFs were further coated with a silica shell and functionalized with a cancer targeting peptide c(RGDfK) to stabilize the NMOFs in biological environment and endow the tumor targeting capability. This NMOF was evaluated in vivo and demonstrated an enhancement in T1-weighted signals in the liver, spleen, and aorta 1 h post intravenous injection at a 10 μmol/kg Mn dose, which was caused by the Mn(II) ions released from the NMOFs. The Lin group recently reported a theronostic NCP for MRI and bisphosphonate delivery.118 The Mn-bisphosphonate NCPs were self-assembled from Mn2+ and zoledronate with exceptionally high loadings of zoledronate (63 ± 5 wt %) and Mn2+ ions (13 ± 4 wt %) and were further coated with lipid and pegylated to achieve controlled drug release, improved stability, and functionalization of anisamide as an active targeting ligand. The Mn NCPs with pegylation and anisamide conjugation exhibited an r1 value of 7.6 and an r2 value of 70.3 mM−1 s−1 and were demonstrated to have higher signals in T1-weighted images after incubation with human breast cancer MCF-7 cells when compared to nontargeted particles at the 24 h time point. The r1 value of Mn NCPs was estimated to be ∼8 mM−1 s−1 in MCF-7 cells, suggesting the ability of this NCP to act as an efficient T1-weighted MRI contrast agent in vitro. Horcajada and coworkers synthesized a series of MIL series NMOFs as T2weighted contrast agents with sizes ranging from 50 to 350 nm. Negative enhancement of the liver and spleen was observed after injection of these NMOFs to Wistar rats.86

adequate contrast, large doses (tens of grams) of CT contrast agents are usually required in the clinic, which sometimes cause side effects on the patients.226 Lin and co-workers developed a series of NMOFs and demonstrated their potential applications as CT contrast agents. Five NMOFs were synthesized using 2,3,5,6-tetraiodo1,4-benzenedicarboxylic acid (I4-BDC-H2) as bridging ligands and Cu(II) or Zn(II) as metal connecting points as CT imaging contrast agents.123 CT phantom studies showed that these NMOFs possessed slightly higher X-ray attenuation factors than commercially used contrast agent iodixanol. Additionally, these NMOFs are biodegradable as evidenced by the complete degradation observed after incubating in phosphate buffered saline (PBS, pH 7.4) at 37 °C for 46 h with a half-life of ∼1.5 h. This result suggested that the NMOFs are biodegradable while still stable enough to allow for prolonged circulation as compared to molecular iodinated contrast agents. In another example, instead of incorporating the high-Z element into the bridging ligand of the structure, Lin and co-workers incorporated high-Z elements (Hf and Zr) into the M6(μ3-O4)(μ3-OH)4(RCO2)12 (M = Zr or Hf) secondary building units of UiO-66 NMOFs with high Hf (57 wt %) and Zr (37 wt %) contents.80 Hf-NMOFs exhibited an average size of 169 nm by dynamic light scattering measurements and were coated with silica and poly(ethylene glycol) (PEG) to enhance biocompatibility. After being coated with SiO2 and PEG, Hf-NMOFs were ∼246 nm and their potential applications in the in vivo CT imaging were evaluated in mice. Hf-NMOFs were intravenously injected to mice and showed increased attenuation in the liver and spleen and no increase in attenuation in the bloodstream (Figure 22). 6.3. Optical Imaging

Optical imaging has emerged as a powerful imaging modality due to its ability to noninvasively differentiate between healthy tissues and tumors or other diseased tissues based on the differential dye accumulations. A number of luminescent

6.2. CT

CT is a noninvasive imaging technique that utilizes computerprocessed X-ray absorption data to generate tomographic images of specific areas of the scanned object for diagnostic purpose in the clinic. CT imaging is based on attenuation of X-rays by a specimen to provide three-dimensional images with high spatial resolution.226 High Z number elements such as iodine, barium, and bismuth are chosen as CT contrast agents. However, the application of small molecule contrast agents in CT imaging is limited by the unspecific tissue distribution and rapid clearance from body. To achieve

Figure 22. Sagittal (A and B) and axial (C and D) CT slices of a mouse precontrast and 15 min after injection of Hf-NMOFs coated with silica and PEG. The areas of increased attenuation are outlined, and the labels are (1) spleen (+131 HU), (2) liver (+86 HU), (3) heart, and (4) lungs. Reprinted with permission from ref 80. Copyright 2014 The Royal Society of Chemistry. 11096


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Figure 23. (a) SEM image of anisamide-targeted and silica-coated particles of Zr-based NMOF. The inset shows the schematic of such core− shell nanoparticles. (b) Confocal microscopy image of H460 cell after being incubated with anisamide-targeted and silica-coated particles of Zrbased NMOF. Reprinted with permission from ref 139. Copyright 2011 Wiley.

Figure 24. (a) Schematic presentation of F-UiO synthesis. (b) PXRD patterns of UiO, F-UiO, and F-UiO after incubating in Hanks’s Balanced Salt Solution (HBSS) for 12 h. TEM images showing the morphology of F-UiO (c) and F-UiO after incubating in HBSS for 12 h (d). Bar = 200 nm. (e) High-resolution TEM image showing the distribution and structural integrity of UiO NMOFs in the endosomes of H460 cells. Inset is a zoomed-in view showing one intact UiO NMOF inside endosome. CLSM image was obtained from live cell imaging video, showing the overlay of green fluorescence (488 nm channel), red fluorescence (435 nm channel), and DIC. The pH of different endosomes or particles outside the cells was calculated on the basis of the pH calibration curve obtained on live cells. Reprinted with permission from ref 114. Copyright 2014 American Chemical Society.

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internalized by the cells efficiently and remained structurally intact inside endosomes, offering the possibility of sensing the endosomal/lysosomal pH. Live cell imaging studies elucidated endocytosis and exocytosis of F-UiO and endosomal acidification in real time. The advantages of using such F-UiO NMOFs for sensing pH i in live cells were clearly demonstrated in this study; fluorescently labeled NMOFs thus represent a new class of nanosensors for sensing pHi and for investigating NMOF−cell interactions. 6.4.2. Other Molecular Sensing. MOFs have been exploited as chemical sensors for metal ions, gas molecules, enantiopurity, and pH in aqueous solution.99,138,230−238 NMOFs have also been exploited to sense some small molecules, such as nitric oxide,239 acetone molecules,240 and nitroaromatic derivatives.241 Wu et al. synthesized two NMOFs constructed from Cu2+ and tricarboxytriphenyl amine (H3TCA) or lathanide metal Eu2+ and H3TCA to form Cu-TCA and Eu-TCA, respectively, for sensing nitric oxide.239 Cu-TCA exhibited weak emission at 430 nm in the absence of nitric oxide; however, the fluorescence was enhanced by 700-fold after the addition of nitric oxide. This luminescence detection was of high selectivity as other reactive species present in biological systems including H2O2, NO3−, NO2−, ONOO−, and ClO− had no interference with the detection. The ability to sense nitric oxide of Cu-TCA was confirmed in a living human breast cancer cell line MCF-7. Eu-TCA showed lanthanidebased emission (610 nm) and triphenylamine emission (430 nm) and thus worked as a ratiometric luminescent sensor toward nitric oxide. Yang et al. fabricated nanoscale Tb-MOF-76 by microwaveassisted methods using amino acids as capping agents for sensing acetone molecules in solution.240 Tb-MOF-76 exhibited rod-like monodisperse nanocrystals with dimensions of 50 ± 15 nm in width and 100 ± 25 nm in length. The characteristic Tb3+ ions’ photoluminescence contributed to the ability of Tb-MOF-76 to sense acetone molecules in solution. Suresh et al. synthesized a NCP self-assembled from oligo(p-phenyleneethynylene)dicarboxylic acid and GdIII in polar solvent.241 The coordination polymers adopt a rod-like morphology with dimensions of 50−100 nm diameter and 0.5−0.8 μm length. Besides their potential applications as T2 contrast agents in MRI, the authors also demonstrated their capability to sense nitroaromatic derivatives like 2,4dinitrotoluene as realized by the fluorescence quenching in solution and in the gas phase. 6.4.3. Future Directions. Although NMOFs have been explored for potential anatomical imaging using several modalities, there have been few attempts to use MOFs for molecular imaging in live cells or living animals. The ready internalization of NMOFs by cells should render them applicable in sensing biologically relevant molecules such as Ca2+ and nitric oxide responsible for signal transduction, Na+/ K+ responsible for ion channels and proton pumps, Cl− responsible for osmotic pressure, and other processes in live cells. We envision that NMOFs with sufficient stability inside the cells could serve as new classes of nanosensors for monitoring intracellular pH, metal ion, and other molecules. The periodic and porous structures of NMOFs will enable high dye loadings without self-quenching; the open channels of NMOFs will allow the fast and free diffusion of molecules to allow rapid response; and the covalent conjugation of dye

nanoparticles have been synthesized, but their absorption properties and quantum yields need to be further optimized for clinical applications as contrast agents in optical imaging.99 Lin and co-workers synthesized NCPs containing a phosphorescent Ru(bpy)32+ derivative as the bridging ligand and Zn(II) or Zr(IV) as metal connecting points (Figure 23).139 Zr-based NMOFs with high dye loadings (up to 57.4 wt %) were further coated with a layer of amorphous silica, functionalized with PEG, and an active targeting moiety anisamide for enhanced uptake in cancer cells. The Z-average size and polydispersity index of this NMOF were 124 nm and 0.062, respectively. The anisamide-targeted NMOFs were demonstrated to be efficient optical imaging contrast agents with preferable cancer specificity, as demonstrated by increased cellular uptake in human lung cancer cells H460 by confocal microscopy studies and ICP-MS analysis. Besides using optical imaging agents as bridging ligands for constructing NCPs, optical dyes can also be postsynthetically incorporated within the frameworks. Kimizuka and co-workers created a series of NCPs based on lanthanide ions and nucleotides.127,129,227,228 Anionic dyes, such as perylene3,4,9,10-tertacarboxylate, were incorporated within NCPs of adenosine 5′monophosphate and Gd3+. Confocal microscopy studies showed the uptake of this NCP into the lysosomes of HeLa cells and its biodistribution and toxicity in a murine model was examined. After intravenous injection of this NCP to mice, the fluorescence coming from NCPs was only observed in liver, which might be due to recognition of NCPs by the RES. Negligible liver toxicity was noticed in mice treated with NCPs. Lanthanide-nucleotide NCPs were also used to successfully encapsulate other anionic dyes and negatively charged quantum dots. Luminescence emitted in the near-infrared (NIR) region has several advantages over those emitted in the visible spectrum, including low autofluorescence and larger tissue penetration depth. Foucault-Collet et al. created NIR-emitting NMOFs incorporating a high density of Yb3+ lanthanide cations and phenylenevinylenedicarboxylate-3 (PVDC) as bridging ligand.229 This block-like Yb-based NMOF was stable in cell lysate and had low toxicity on HeLa and NIH 3T3 cells by confocal microscopy studies. The NIR imaging was demonstrated in live cells with Yb-based NMOFs upon single-photon excitation. The NMOF luminescence was readily discerned from the cellular autofluorescence of the biological materials. 6.4. Sensing

6.4.1. Intracellular pH Sensing. Intracellular pH (pHi) plays a vital role in the regulation of physiological/ pathological process. It is of great importance to sense and monitor the real-time pHi changes inside live cells to better understand the biological processes and assist in the rational design of NMOFs for intracellular drug delivery. Although a number of nanoscale materials have been developed for pHi sensing, the Lin group recently reported the first NMOFbased pH sensor for ratiometric intracellular pH sensing in live cells with fast response and high accuracy (Figure 24).114 Fluorescein isothiocynate (FITC) was covalently conjugated to a UiO NMOF constructed from Zr4+ and aminotriphenyldicarboxylic acid (amino-TPDC) to afford F-UiO NMOFs with exceptionally high FITC loadings (up to 7 wt % without self-quenching), efficient fluorescence, and excellent ratiometric pH-sensing properties. F-UiO NMOFs were 11098


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Figure 25. (a) Histological section of spleen, brain, kidney, and heart after 1 day of the i.v. administration of MIL-88A, MIL-100, and MIL88B_4CH3 NMOFs in comparison with the control group. All sections were stained with Prussian blue, except those of the heart, stained with hematoxylin-erosin. (b) TEM images of liver after 1 day of the i.v. injection of MIL-88A, MIL-100, and MIL-88B_4Ch3 NMOFs as compared to the control group. Red arrows remark the presence of NMOFs within the lysosomes beside mitochondria. Yellow arrows indicate lipid droplets in the lysosome containing MIL-88B_4CH3. Reprinted with permission from ref 244. Copyright 2014 The Royal Society of Chemistry.

PXRD patterns, and negligible FITC dye leaching, indicating its structural stability in the intracellular environment. Importantly, the Lin group for the first time observed intact UiO NMOFs inside endosomes by TEM. This demonstrated adequate structural stability in the endosomes is one of the prerequisites for F-UiO to being a reliable intracellular pH nanosensor. The potential of NMOFs in biomedical applications depends on their cytotoxicity and general toxicity when applied in vivo. Horcajada et al. screened the cytotoxicity and general toxicity in mice of a series of NMOFs based on Fe, Zn, and Zr.86,243,244 The results demonstrated that Fe(III)based NMOFs showed a lack of severe acute and subacute toxicity in mice (Figure 25) and negligible cytotoxicity in human cancer cells HeLa and macrophage J774 cells. Ren et al. synthesized IRMOF-3 constructed from Zn2+ and NH2BDC ligand. In rat pheochromocytoma PC12 cells, IRMOF-3 showed no toxicity at a concentration of 25 μg/mL, while time- and concentration-dependent toxicity was observed at a concentration of 100 μg/mL. The authors hypothesized that the toxicity was associated with a disrupted cellular zinc homeostasis and the down-regulation of GAP-43 protein.

to NMOFs will prevent dye leaching and eliminate background interference.

7. DEGRADATION, STABILITY, AND TOXICITY OF NMOFs AND NCPs NMOFs are intrinsically biodegradable as a result of their relatively labile metal−ligand bonds. The degradation profile of NMOFs should be considered as an important parameter in the optimization of NMOF design to achieve desired therapeutic, imaging, or sensing functions. The NCPs carrying platinum-based drugs developed in the Lin group have been demonstrated to have triggered release properties after being internalized into the cells. 118 They are stable under extracellular environment in vivo; however, they will be readily reduced in the intracellular environment with high concentration of reducing agents such as glutathione and cysteine to release platinum drugs. The released drug will undergo aquation and binds to DNA to induce apoptosis. ́ Amorin-Ferré et al. compared the drug release mechanisms of NCPs with two different encapsulation methods. NCPs with a formula of [Co(bix)(3,5-dbsq)(3,5-dbcat)] were synthesized and demonstrated to exhibit spherical structures of 150−200 nm in diameter.242 Drugs loaded into the NCPs via encapsulation will be released through free diffusion, while drugs covalently conjugated to the frameworks can only be released after the nanoparticles are degraded. The stability of NMOFs in the physiological environment should be addressed before their successful applications in drug delivery, imaging, and sensing. Especially when NMOFs are utilized as nanosensors for intracellular or in vivo sensing/ detection, they need to maintain structural intactness to avoid dye leaching. However, few studies have been carried out to gather information on this critical issue. The Lin group developed a nanosensor based on FITC conjugated UiO-68 NMOFs (F-UiO) for intracellular pH sensing.114 After incubating in Hank’s Balanced Salt Solution (HBSS) for 24 h, F-UiO exhibited unaltered hexagonal plate morphology,

8. POLYSILSESQUIOXANE (PSQ) NANOPARTICLES FOR THERAPY AND IMAGING Similar to NMOFs, polysilsesquioxane (PSQ) nanoparticles are a class of hybrid nanomaterials composed of siloxane networks with organic or metal−organic bridging ligands. As cross-linked homopolymers of (R′O)3-Si-R-Si-(OR′)3, PSQ nanoparticles retain the biocompatibility of silica-based nanomaterials while allowing exceptionally high drug loadings and highly tunable physicochemical properties. The Lin group created a series of PSQ nanoparticles and demonstrated their potential applications in chemotherapy,108 chemoradiotherapy,73 and MRI imaging.109 PSQ-oxali nanoparticles carrying a platinum complex, [Pt(dach)Cl2(triethoxysilylpropyl succinate)2], were synthesized and 11099


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Figure 26. PSQ nanoparticles carrying a cisplatin prodrug and their anticancer efficacy in human lung cancer xenograft murine models by chemoradiotherapy. TEM (a) and SEM (b) images of cisplatin-PSQ. (c) In vivo chemoradiotherapy efficacy assay against mice bearing A549 xenografts. Reprinted with permission from ref 73. Copyright 2014 Elsevier.

Figure 27. (a) Schematic illustration of the preparation of size controlled PEGylated Cpt-NCs. (b) SEM images of size precisely controlled CptNCs. (c) EL4 tumors were cultured with 50 or 200 nm NCs labeled with IR783 in cell medium for 48 h. Tumors without the treatment served as control. Tumor sections were collected by cryostat and mounted on glass slides. Fluorescence images were taken by fluorescence microscope with 780 nm laser excitation. (d) Delay and inhibition of LLC tumor growth in C57Bl/6 mice with treatment of Cpt-NCs with different sizes. Reprinted with permission from refs 245 and 246. Copyright 2012 and 2013 American Chemical Society.

postsynthetically coated with PEG to stabilize the nanoparticles as well as to yield nanoparticles with long circulation property. The chemoradiotherapeutic efficacy of 150 nm nanoparticles was evaluated in vitro and in vivo in human nonsmall cell lung cancer models and subcutaneous xenograft mouse models. At a cisplatin dose of 1 mg/kg and a radiation dose of 10 Gy, the PSQ nanoparticles demonstrated anticancer efficacy superior to that of free cisplatin and radiation alone in chemoradiation in two subcutaneous xenograft mouse models of human nonsmall cell lung cancer H460 and A549, and thus represented a promising therapeutic in cancer treatment. The potential applications of PSQ nanoparticles as drug delivery vehicles have also been reported by Cheng and coworkers (Figure 27).245,246 The trialkoxysilane-containing drugs were synthesized by forming a degradable ester linker between drug and trialkoxysilane group and then condensed with tetraalkoxysilane to incorporate the drug into the resulting nanoparticles. Anticancer drugs including campothecin, paclitaxel, and docetaxel were loaded into the nanoparticles with precisely controlled sizes (ranging from 20 to

further coated with PEG and conjugated with RGD peptide or anisamide to allow the active targeting to cancer cells.108 The PSQ-oxali nanoparticles carried exceptionally high drug loading of 35−47 wt % and showed a particle size of ∼90− 100 nm with a narrow size distribution. The PSQ-oxali nanoparticles exhibited favorable stability under normal physiological conditions, but can be readily reduced to release their cargoes in highly reducing tumor microenvironments and intracellular environment. Superior cytotoxicity of PSQoxali nanoparticles to free oxaliplatin was observed in four human cancer cell lines including colon cancer cells HT-29 and DLD-1 and pancreatic cancer cells BxPC-3 and AsPC-1, and the RGD and anisamide targeting further enhanced the cytotoxicity. The enhanced anticancer efficacy of PSQ-oxali nanoparticles with RGD and PEGylation by intravenous injection was confirmed in a pancreatic cancer xenograft mouse model AsPC-1. Recently, Lin and co-workers reported a PSQ-cis nanoparticle carrying a cisplatin prodrug, c,c,t-Pt(NH3)2Cl2(OH)2, and its applications in chemoradiotherapy (Figure 26).73 The PSQ-cis nanoparticles carried 42 wt % of cisplatin and were 11100


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Figure 28. Efficient MR and optical imaging of PSQ nanoparticles. (a) TEM image of Gd-PSQ. (2) Particle size distribution of Gd-PSQ by DLS measurements. T1- (c) and T2-weighted (d) MR phantom images of Gd-PSQ, PEG- Gd-PSQ, and AA-PEG-Gd-PSQ at various Gd(III) concentrations at 3 T. Reprinted with permission from ref 109. Copyright 2013 Wiley.

imaging agents or therapies for chronic indications such as AIDS, bowel inflammation, etc. We believe that synthetic tunability of NMOFs and NCPs can be further leveraged to fine-tune their properties for biomedical applications as well as to combine multiple therapeutic/imaging modalities into one platform to synergistically enhance therapeutic efficacy or to obtain theranostic nanomaterials. Although still in their infancy, NMOFs and NCPs have already shown significant promise in drug delivery and biomedical imaging, and are expected to have a bright future in nanomedicine.

200 nm). The investigation on the correlation between the particle size and tumor accumulation/penetration revealed that particles with diameter of 20−50 nm exhibited enhanced anticancer efficacy, which resulted from the faster cellular internalization and more efficient tumor accumulation/ penetration.245,246 The applications of PSQ nanoparticles as T1-weighted MRI contrast agents in cancer imaging have been demonstrated by the Lin group (Figure 28).109 Gd(III) chelates were covalently conjugated to PSQ nanoparticles via a labile disulfide bond, and the Gd-PSQ nanoparticles were further coated with PEG and anisamide to enhance biocompatibility, stability, and cellular uptake in cancer cells. The Gd-PSQ nanoparticles carry ∼50 wt % of Gd chelates and are readily degradable to release Gd(III) in the presence of endogenous reducing agents intracellullarly. The MR relaxivities of Gd-PSQ nanoparticles were determined by a 3T MR scanner, with r1 values ranging from 5.9 to 17.8 mM−1 s−1 per Gd(III). These results suggested that Gd-PSQ nanoparticles could be T1weighted MR contrast agents with high sensitivity, which was further confirmed by in vitro MR imaging studies of human lung and pancreatic cancer cells including H460 and AsPC-1 cells.

AUTHOR INFORMATION Corresponding Author

*Tel.: (773) 834-7163. Fax: (773) 702-0805. E-mail: [email protected]. Author Contributions †

C.H. and D.L. contributed equally.

Notes

The authors declare no competing financial interest. Biographies

9. CONCLUSIONS AND OUTLOOK As outlined in this Review, NMOFs and NCPs have emerged as a promising platform for developing novel nanomedicines. Their synthetic tunability has allowed the design of a large number of hybrid nanomaterials for cancer therapy, drug delivery, biomedical imaging, and biological sensing. However, relatively little in vivo data are available to date, making it difficult to assess the clinical relevance of many of the reported NMOFs/NCPs. Key issues that need to be addressed include: (1) more rigorous in vivo testing is needed for the most promising NMOFs/NCPs to establish their therapeutic and imaging efficacy; (2) optimized surface functionalization of NMOFs/NCPs is needed to achieve prolonged blood circulation and selective tumor targeting after systemic administration; and (3) evaluation of “ADME” (“absorption-distribution-metabolism-excretion”) of NMOFs/ NCPs is needed to understand their in vivo toxicity profiles. On the basis of the trends observed for other classes of nanomedicines, we can expect that safety and regulatory hurdles will likely be lower for anticancer therapeutics than for

Chunbai He received her B.S. (2007) and Ph.D (2012) in Biology from Fudan University, China. She is currently a postdoctoral researcher with Dr. Wenbin Lin in the Department of Chemistry and Comprehensive Cancer Center at the University of Chicago. Her research interest mainly focuses on designing hybrid nanomaterials for cancer therapy and drug delivery. 11101


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Demin Liu obtained his B.S. degree in Chemistry from Xiamen University in 2009 and graduated from the University of Chicago with a Ph.D. in Chemistry in 2014 under the supervision of Prof. Wenbin Lin. His Ph.D. work focused on using nanoscale coordination polymers (NCPs) to deliver imaging contrast agents and chemotherapeutics to cancer cells.

Wenbin Lin is the James Franck Professor of Chemistry and Comprehensive Cancer Center at the University of Chicago. His research efforts focus on designing novel supramolecular systems and hybrid nanomaterials for applications in chemical and life sciences. He has published >250 papers and is among the 2014 list of highly cited chemists (group website: http://linlab.uchicago.edu/).

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