1. Metal Organic Frameworks (MOFs) Presented by: Alireza Ghane
November 2016

2. MOFs
A class of crystalline solid materials whose structure consists of a regular, two- or three-dimensional network of metal cations or metal oxide clusters (so-called nodes) connected by organic molecules (so-called linkers).
Linkers: dicarboxylic acids (i.e., oxalic acid, malonic acid, succinic acid, glutaric acid, terephthalic acid), tricarboxylic acid (i.e., citric acid, trimesic acid) or azoles (i.e., 1,2,3-triazole, pyrrodiazole), amines, nitrates, sulfates, phosphates and sulfonates.
It typically defines pores and cavities in the micropore range (<2 nm) or, less often, in the mesopore range (2–50 nm).

3. MOFs
Owing to the large surface areas and porosities, along with their amenability to be designed with adjustable surface properties and pore sizes, in the range of molecular dimensions, via either the judicious selection of the node and linker building units or post- synthesis modifications, MOFs have been long considered ideal solid adsorbents.
T. Rodenas et al. (2016); J. Mehta et al. (2016)

4. Examples of MOFs
MOF-5:
consists of tetrahedral [Zn4O]6+ units that are linked together with 1,4- benzene-dicarboxylate units.

5. Examples of MOFs
MOF-177:
consists of tetrahedral [Zn4O]6+ units are linked by large, triangular tricarboxylate ligands.

6. Examples of MOFs MIL-53- (Al)
consists linear chains of [AlO4(OH)2] octahedra that are linked together with 1,4-benzene-dicarboxylate units.
Recently, the iron, chromium and scandium analog of MIL-53 have been prepared as well.

7. Examples of MOFs

8. Synthesis of nMOFs Hydro–solvothermal synthesis
Microwave and ultrasound-assisted synthesis
Mechanochemistry
Microemulsion synthesis
Continuous flow production
Ref: nanostructured MOFs and their bio-related applications, M-Gimenez-Marques

9. MOF-5 with quantum dots of ZnO (phosphate)
Application
Gas Storage
Cu-BTC for NO
MOF-5 for CO2
Imaging
MOFs based Gadolinium
Catalysts
Biomedical
Sensors
MOF-5 with quantum dots of ZnO (phosphate)
UiO-66 as a H2O2 sensor along Pt particles within
Molecular sieve
Molecular traps
PCN-333 (HRP,Cyt c,MP-11)

10. nMOFs formulations prior to their use in biomedical applications
Control of the particle size
Design of an appropriate carrier and/or formulation
Dosage forms for the NPs
External surface modification of NPs

12. External surface modification of NPs
Coating of nMOFs with silica: MIL-101(Fe)
Advantages includes:
preventing from its rapid degradation
Its high porous character keeps accessible pores of MOFs, in order to allow encapsulation and release of drug molecule even after surface modification
Confers water dispersibility and chemical stability to nMOFs

13. External surface modification of NPs
Drawbacks includes:
Toxicity issues
Synthetic issues derived from sol-gel methods (i.e. poor yields and low reproducibility)
Its likely formation within the MOF pores, reducing and/or blocking the porosity

14. External surface modification of NPs
Coating with cylclodextrines (CD): MIL-100(Fe)
Using phosphate modified biocompatible cyclodextrines (CD) these molecules considered as smart part of drug delivery devices, strongly interact exclusively at the nMOF outer surface through selective coordination of phosphate groups with surface lewis metal sites.
Advantages includes:
Improves stability in body fluid without disruption of nMOF porosity, crystallinity, adsorption and release ability.
Can be functionalized with PEG chains to escape the immune system
Can be functionalized with targeting ligand such as mannose

15. External surface modification of NPs
PEG physically block the adhesion of proteins that normally deposit onto foreign bodies to attract macrophages
PEG hydrophilicity attracts water
Molecules to particle surface avoiding the
Adsorption of opsonins at NP surface,
Rendering them invisible to phagocyte
Cells.
Ref: V. Agostoni et al. (2015)
J. Conniot et al. (2014)
M. Gimenez-Marques et al. (2015)

16. External surface modification of NPs
Coating with heparin: MIL-100(Fe)
Advantages includes:
Reduce cell recognition (Interacting with CAMs) and therefore confer stealth properties
Preserve its ability (nMOFs) to accommodate high cargo loading
Release the cargo in simulated physiological media in a more progressive manner than their analogous uncoated NPs.

17. External surface modification of NPs
Coating with polysaccharide chitosan (CS) polymer: MIL-100(Fe)
Enhancing permeability of the NPs across the intestinal barrier
Supplementary:
Chitosan (COS) is an alkaline glucosamine polymer derived from hydrolysed chitosan.
The mechanisms behind the enhanced absorption are thought to relate to mucoadhesion and relaxing intercellular tight junctions.The mucus membrane bears negatively charged sialic acid groups with interacting with chitosan’s positively charged amino groups.
Ref: G. Guan et al. (2016)
M. Gimenez-Marques et al. (2015)

18. Biomedical applications
Drug carriers:
The MOFs with hydrophobic pores such as the MIL family are ideal for encapsulating drug molecules that have poor aqueous solubility. MOFs can also be designed to have hydrophilic pores that can carry either positive or negative charges, and such MOFs can be used to encapsulate drugs that contain opposite charges to the MOFs.
Exp:MIL-100 and MIL-101 for loading ibuprofen that both of them showed high loading, g IBU/g MOF and g IBU/ g MOF respectively. kinetic of ibuprofen release investigated in SBF at 37oC. weakly bound drug release was observed within the first 2hrs and entire release within 3days for MIL-100 and for MIL-101 was observed respectively 8hrs-6days.

19. Biomedical applications
MIL-53(Cr) and less toxic MIL-53(Fe) achieved loading of .220 g IBU/g MOF and .210 g IBU/g MOF respectively. The delivery kinetics was investigated in SBF at 37oC and complete drug release occurred in 3 weeks, the long release of this drug attributed to strong drug-framework interaction.
Bio-MOF1 is anionic and then carry procainamide (cationic drug) that is used for arrhythmia and can exchange with cations in biological fluids.

21. Biomedical applications
Anti-virals:
cidofovir and the anti-HIV (human immunodeficiency virus) azidothymidine triphosphate (AZT-TP) strongly limits their cell penetration and then, their efficacy. So both drugs were successfully encapsulated in their active forms in different nanoMOFs, reaching exceptionally high loading rates of around 20 wt% in MIL-100(Fe) NPs, and 42 wt% in MIL-101(Fe) NH2 NPs. The important affinity of these phosphorylated drugs with the nanoMOF, displaying efficiencies of encapsulation close to 100%, was explained by the strong interaction of the phosphate groups with the iron metal sites of the nanoMOFs, which was also related with a slow progressive release.

22. Biomedical applications
Antibacterials:
A porous cobalt carboxylate nanoMOF, Co-TDM, showed a relevant bactericidal activity due to the presence of Co2+ metal sites at the outer surface of the NPs with a resulting enhanced interaction with the bacteria cell wall. This solid was thus proposed as a viable and potent disinfectant toward inactivation of the Gram-negative bacteria (E. coli), reducing the population to zero or near-zero in short times (1 h).

23. Biomedical applications
Antitumorals:
reached exceptional Doxo loading capacities also using the ZIF-8 NPs covered with polyacrylic acid (PAA) (1.9 g g-1; with an encapsulation efficiency of ∼95%) with pH-sensitive release properties: 36.5% of Doxo was released after 60 hrs at pH 7.4 while a faster drug release rate was found under acidic conditions (∼76% delivered after 60 h at pH 5.5), Considering the characteristic acidic pH of the extracellular tumoral microenvironment, NPs seem a very promising anticancer drug nanocarrier. The outer surface of these Doxo-containing core–shell NPs was engineered with an anticancer aptamer (AS1411, 26-mer guaninerich oligonucleotide) with the aim to target cancer cells.

24. Biomedical applications
Supplementary:
Aptamers:
small single-stranded nucleic acids that fold into a well-defined three-dimensional structure. They show a high affinity and specificity for their target molecules and inhibit their biological functions.
AS1411:
functions as an aptamer to nucleolin, a multifunctional protein that is highly expressed by cancer cells, both intracellularly and on the cell surface.
Ref: P. Bates et al. (2010)

25. Mixed ligand MOFs as transport vehicles for drugs
Four MOFs designed:
MOF-1 and MOF-4: single ligand
MOF-2 and MOF-3: mixed ligand (BTC, IPA)
Drugs includes: IBU, DOX
loading capability is dominated by both the pore size and the interaction of carboxyl group of IBU and MOFs.
Loading of DOX is pore size dependent.
Ref: K. sun et al. (2016)
IPA= Isophthalic acid BTC=1,3,5-benzene tricarboxylate

29. MOFs in enzyme encapsulation
series of stable metal-organic frameworks with rationally designed ultra- large mesoporous cages can be used as single-molecule traps (SMTs) for enzyme encapsulation.
Primarily, the MOFs with sufficiently large pore diameters (e.g., Cu-MOF (1.78 nm), Tb-TATB (3.9 and 4.7 nm), Mn-MOF (3.4 nm), and PCN-333 (4.2 and 5.5 nm)) have been investigated as potential candidates for the enzyme immobilization.
Immobilized enzymes that most likely undergo single-enzyme encapsulation (SEE) show smaller Km than free enzymes while maintaining comparable catalytic efficiency.

30. MOFs in enzyme encapsulation
Under harsh conditions, the enzyme in SEE exhibits better performance than free enzyme, showing the effectiveness of SEE in preventing enzyme aggregation or denaturation.
NOTE: difference between PCN-332 (M) and PCN-333 (M)
Linker in PCN-332 (M) is BTTC and in PCN-333 (M) is TATB
PCN-332 exhibits a similar structure as PCN-333, but with smaller cages due to smaller linker.

35. THE END