Multifunctional Magnetic Nanoparticles in Biomedical Applications
3.4 BioMOFs: Metal-Organic Frameworks for Biological and Medical Applications
3.4.3 MOFs as Drug Delivery Agents
One of the major challenges faced in drug delivery using MOFs is the effi cient delivery of the drug using non-toxic nano-carriers. In order to deliver the drug into the cell, the carriers should have the following fea- tures: (1) effi ciently drug trapping within the pores of MOFs; (2) controlled release; (3) controlled degradation; and (4) be detectable by imaging tech- niques (Figure 3.9). Recently Patricia Horcajada’s research group demon- strated the ibuprofen release [164], R. Morris et al.[165, 166] demonstrated delivery of NO gas for antithrombosis and vasodilatation and Lin et al. [167–169] demonstrated the imaging application using MOFs.
A series of biologically and environmentally favourable non-toxic carboxylate MOFs have been reported by Ferey and coworkers [170].
Th e MIL family, synthesized from Cr3+ centers and benzene dicar- boxylic acid have large pore sizes (25–34 Å) and outstanding surface areas (3100–5900 m2/g), and are the ideal systems for drug delivery.
Loading of drug into MOFs
Slow release of drug from MOF
Figure 3.9 Absorption and release of drug molecule through MOFs pores.
Th e storage and release of ibuprofen with chromium-based MIL-101 and MIL-100 materials showed high ibuprofen loading, with 0.347 g ibuprofen/g MOF for MIL-100 and 1.376 g ibuprofen/g MOF for MIL- 101. Th e diff erence in drug loading between the two materials is due to the pore sizes of the materials; MIL-101 has larger pore volumes of 12700 and 20600 Å3 (8200 and 12 700 Å3 for MIL-100). Th e kinetics of ibuprofen release was investigated by suspending the ibuprofen-loaded materials in simulated body fl uid (SBF) at 37 ºC.
Th ese MOFs contain toxic chromium, and thus, the use of these materi- als for drug delivery is very limited. A less-toxic analog, MIL-101(Fe) has been developed and reported by Horcajada as a biocompatible alternative, and should be a much more appropriate drug carrier [164]. Th ese MOFs have been modifi ed into nanoparticles for effi cient delivery of anti HIV and anticancer drugs (busulfan, azidothymidine triphosphate, doxorubicin or cidofovir) (Figure 3.10) [171].
Th e physical properties and the structures of the drugs are summarized in Table 3.3 and Scheme 3.3.
Recently, Zhong-Min Su and coworkers reported on chiral MOFs synthe- sized from 5,5′,5′′-(1,3,5-triazine-2,4,6-triyl)tris(azanediyl)triisophthalate and zinc nitrate [172]. Single crystal X-ray diff raction analysis revealed that enantiomers exhibit homochiral 3D structures with nanoscale porous and helical channels (Figure 3.11a). Th e large pore size of MOFs (27579.3 Å3) facilitate drug storage and subsequent drug (anticancer 5-FU D) release was observed with no burst eff ect. Th e delivery of 5-FU occurred within a week and 86.5% of the loaded drug was released (Figure 3.11b). Th e interaction between pore walls and the guest drug are mainly hydrogen bonding and π-π interaction.
Another interesting BioMOFs has been reported by Rosi and cowork- ers employing adinine, diphenyl dicarboxylate and zinc acetate [173]. Th e
MIL-53 8 Å
MIL-88 6–11 Å
MIL-100 24–29 Å
MIL-101 29–24 Å Figure 3.10 Porous iron MOFs for drug delivery applications.
Table 3.3 Th e physical properties of and the structures of the drugs.
MIL89 MIL88A MIL100 MIL53
Organic linker Muconic acid
Fumaric acid
Trimesic acid
Terphthalic acid Structure
Flexiblity Yes Yes No Yes
Pore size (Å) 11 6 25(5.6) 8.6
Particle size (nm)
50–100 150 200 350
Bu loading(%) 9.8(4.2) 8 (3.3) 25.5(31.9) 14.3(17.9) AZT-TP
loading (%)
– 0.6(6.4) 21.2(85.5) 0.24(2.8)
CDV loading (%) 14(81) 2.6(12) 16.1(46.2) –
Doxorubicin loading (%)
– – 9.1(11.2 –
Ibuprofen load- ing (%)
– – 33(11.0) 22 (7.3)
Caff eine- loading (%)
– – 24.2(16.5) 23.1(15.7)
Urea loading (%) – – 69.2(2.1) 63.5(1.9)
Benzophenone 4 loading (%)
– – 15.2(22.8) 5(7.5)
Benzophenone 3 loading (%)
– – 1.5(74.0) –
Doxorubicin loading (%)
– – 9.1(11.2) –
MOFs have a large pore volume and surface area which greatly facilitates loading of the drug (procainamide) effi ciently. Since the drug has a very short in vivo half-life, the patient is required to be dosed every 3–4 hours.
Complete loading (0.22 g/g material) was achieved aft er 15 days, and it has been estimated that ~2.5 procainamide molecules per formula unit remains in the pores while the rest adhere to the surface. Due to the ionic interactions between host and guest, cations can be used to trigger pro- cainamide release from the framework (Figure 3.12).
Lin’s research group designed and synthesized a nano-MOF (NCP- 1) from Tb3+ ions and c,c,t-(diamminedichlorodisuccinato)Pt(IV) (disuccinatocisplatin, DSCP), a cisplatin prodrug for cancer treatment [174]. Th e nanoparticles of NCP-1 (58.3-11.3 nm) were encapsulated with silica to enhance the half-life time in HEPES buff er at 37 ºC. Th ese
O O
S S
O O
O O
Busulfan (BU)
P O P
O HO
OH O OH P O O HO O O OH HO
N N N N
Azidothymidine triphosphate (AZT-TP)
N N
O NH2
OH P O HOO HO
Cidofovir (CDV) O
O OMe
OH
OH O O
OH H2N
H2N
H3C CH
3
CH3
Doxorubicin
O HO
Ibuprofen
N
N O
N N
O Caffeine
O OH
OMe SO3H Benzophenone 4
O OH
MeO
Benzophenone 3
Scheme 3.3 Structures of various anticancer drugs.
% 5-fluorouracil released
1a-L 1b-D
100 80 60 40 20 0
0 1 2 3 4
t/days
5 6 7 8
(a) (b)
Figure 3.11 (a) Th e enantiomeric nature of MOFs viewed down the [–111] direction.
Side view of left -handed and right-handed double-stranded 31 helical chains in isomeric MOFs, respectively, C grey, O red, N blue, Zn green. (b) Th e release process of 5-FU from the drug-loaded 1 (% 5-FU vs. time).
silica coated nanoparticle were further functionalized with c(RGDfk ), a cycllic peptide which targets the αnβ3 integrin, which is over expressed in many cancers. Th ese particles displayed a lower IC50 (inhibitory concentration, 50%) than that of cisplatin (9.7 mM versus 13.0 mM for cisplatin), while the untargeted particle did not exhibit signifi cant cell death. Th e improved cytotoxicity of the functionalized particles sug- gests that these particles are taken up by receptor-mediated endocytosis, followed by reduction to the active cis platinPt(II) species inside the cell (Figure 3.13).