Metal-organic frameworks as gas delivery agents in medicine. Russell Morris University of St Andrews

Transcription

1 Metal-organic frameworks as gas delivery agents in medicine Russell Morris University of St Andrews

2 Time/minutes Intensity d-spacing Synthesis Characterisation Application

3 b c Ionothermal Synthesis Nature (2004) J. Am. Chem. Soc (2006) Synthesis New MOFs with new properties Nature Chemistry, (2009) J. Am. Chem. Soc. (2010) Nature Chemistry, (2011) New Quantum Spin Liquids Nature Chemistry (2011) Angew. Cheme (2015) Chiral Induction J. Am. Chem. Soc. (2007) Nature Chemistry (2010) ADOR Chemistry Nature Chemistry (2013) Nature Chemistry (2015 Nature Chemistry (2016)

4 Characterisation NMR ADSORPTION XRD 2 n m TEM COMPUTATION PDF

5 Zeomedix Zeolites for medical applications SASOL Energy and Chemicals MOFgen MOF Development Spin Out Company

6 Ion exchange Pigments Oil refining Zeolites Anti-microbials Adsorption Automotive Catalysis Medical Devices Space exploration

7 MOFs - Gas tanks and wine racks

8 Which gases should we store (and why)? Hydrogen Methane Other hydrocarbons Energy Energy Energy SO 2Environmental CO 2Environmental Ethylene Nitric Oxide Hydrogen Sulfide Carbon Monoxide Agriculture/Food Biology/medicine Biology/medicine Biology/medicine

9 Nitric oxide Friend or Foe? Cardiovascular System A toxic gas but vital for Central Nervous system Skin repair and wound healing The 1998 Nobel Prize for medicine awarded to Furchgott, Ignarro and Murad for discovery of NO as a signalling molecule in the cardiovascular system

10 Cleaner Cars and Greener Gases CO H 2 O CO 2 + NO x HC N 2

11 NO in the body Anti-microbial Angiogenesis Wound collagen deposition enos nnos inos Vasodilation Thrombosis Neuronal signalling Infection Delayed wound healing Smooth muscle proliferation Impaired nervous system function Hypotension Heart attack Strokes Hypertension

12 Why do we need NO delivery materials? Simple, cheap and effective means of releasing NO locally Reduction of systemic effects

13 Zeolites and MOFs Can we use Zeolites or MOFs to store and deliver NO? Issues Toxicology Chemical stability (particularly in contact with physiological solutions) Opportunities High gas storage capacities Tailorable structures with unusual properties Biocompatibility? Which structures Zeolites with high numbers of extraframework cations MOFs with accessible metal sites

14 Crystal Structure of Co-LTA NO complex XRD K. Seff, Inorg Chem 1979 Infra Red Lunsford, Inorg Chem, 1978 Theoretical Henao, J. Mol. Cat. A, 2004 O N Co Co O N Si

15 Can we use zeolites to deliver NO? From catalytic studies we know that NO makes a complex with the metal ions O N NO O Co O O Co O O O Need a simple way of releasing NO from the complex? O N Co O O H 2 O H 2 O OH 2 OH 2 + O Co NO O O O

16 MOFs Crystalline Sponges + organic linker metal ion or cluster extended framework structures flexible chemical composition many possible structures very high porosity

17 M-CPO-27: Exceptional performance over the whole adsorption-storage-release cycle M-CPO-27 Dietzel and co-workers Norway McKinlay et al, J. Am. Chem. Soc. 2008

18 % Aggregation Biology: Anti-thrombosis Materials Platelet aggregation Both zeolites and MOFs inhibit platelet aggregation Paul Wheatley HKUST-1 0 U46619 Co-LTA(A)-NO Co-LTA(A)-NO+Hb 80 Control min Co-LTA(A) Platelet Adhesion NO-Z/PTFE Z/PTFE P PA 10 µm 10 µm

19 Relaxation (%) Dermatology Studies NO dilates blood vessels Contracted vessel Relaxed vessel Zeolite Zeolite + NO Acidified Nitrite Acid Ni-MOF % 50 5 min 75 remove Acid 100 Zeolite Zeolite - NO Acidified Nitrite Time (mins) No inflammation! Unlike competitor acidified nitrite

20 Anti-Bacterial NO zeolites (a) E. coli, (b) A. baumannii, (c) S. epidermidis, (d) MRSA Neidrauer et al Journal of Medical Microbiology (2014), 63,

21 Wound Healing study Rate of wound closure ~30% faster Neidrauer et al Journal of Medical Microbiology (2014), 63, Zeomedix

22 Multifunctional antibacterial properties The anti-bacterial nature of MOFs comes from 3 different areas. Bacteriostatic or bactericidal metal ions Anti bacterial gases (e.g. NO) Anti Bacterial organic molecules (e.g. antibiotics) A combination of all three can be used from the same MOF!

23 23 Multifunctionality of Antimicrobial MOFs Store / Release antimicrobial metals from framework antibacterial gases (e.g. nitric oxide) from pores antimicrobial molecules from pores or framework (e.g. antibiotics, biocides, therapeutics)

24 Metabolic Growth Fluorescence (F530/590) Metabolic Growth Proven Antimicrobial Efficacy growth control oxacillin vancomycin MOF MRSA (Gram +ve) top 5 of HAIs skin infection pneumonia, sepsis growth control Incubation Time (h) Ag-btc 80:20 Ag-btc 50:50 Ag-btc 25:75 Ag-btc 10:90 blank Ag-btc 5:95 Teflon Control amphotericin B 8 g/ml Amphotericin B Growth Control Negative MOF Control A. niger black mould contaminant of food

25 Fluorescence (A530/590) Multifunctional antibacterial Activity S. aureus DSMZ MOF1-NO MOF2-NO MOF MOF2 Teflon Vancomycin Growth control Uninoculated control Incubation Time (h) MOFs are antibacterial. MOF + NO shows outstanding antibacterial activity

26 Anti-biofilm studies using MOFs Pseudomonas Aeruginosa and Staphylococcus aureus MOFs (blue), NO-loaded MOFs (green) compared with 100 x dose of preferred antibiotic (ciprofloxacin and vancomycin, brown) Red line is the biofilm control.

27 Multirate delivery of multiple therapeutic agents Why is the rate of delivery important?

28 Amount released from HKUST-1 (%) Multirate delivery of therapeutic agents Amount of Cu released (%) Amount of Metro released (%) Amount of NO released (%) Time (hours) Fast delivery of NO leads to sterilisation of media Slow delivery of other agents (e.g. metals) prevents recolonisation over much longer timescale Relies on fundamental instability of the MOF

29 Toxicity Cytotoxicity against dermal fibroblasts and red blood cells.

30 Simple synthesis developed and demonstrated scalable, low temperature manufacturing process Scaling up 1L lab scale 20L development scale 100L pilot scale

31 Formulating products demonstrated compatibility with wide range of polymers using various techniques solvent cast polyurethane film silicone extruded tubing coated non woven polyester

32 Commercial Partnering

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34 funding partnering scale up formulation unmet need solution performance

35 The international journal for inorganic, organometallic and bioinorganic chemistry Impact Factor of 4.2* 48 issues a year Fast publication times *2013 Journal Citation Reports The only major weekly journal for inorganic

36 Thanks

37 Should the data behind this research be open for everyone? Arguments for Data (especially in certain fields) belongs to the human race Public money was used to develop the research, therefore making the data available is for the common good Sponsors of the research do not get full value for their funding Better access to data means better science

38 Should the data behind this research be open for everyone? Arguments against Privacy concerns: this may be data about me! Collecting, managing and disseminating data are typically labour- and/or cost-intensive processes: This should be fairly protected/renumerated. if anyone has access to the data, none may have an incentive to invest in the processing required to make data useful Sponsors do not get full value unless their data is used appropriately.

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40 MOF Synthesis Targets Bigger is better Super porous materials for high capacity gas storage Flexibility is key Soft porous crystals give unusual properties

41 Designing New Hemilabile MOFs Metal Organic Linker Weak Bond Strong Bond 5-sulfoisophthalate

42 Cu-SIP-3 Metal Organic framework with structural flexibility Cu-tetramers linked into layers by the sulfoisophthalate linker groups Layers connected into 3-dimensional structure by coordination of sulfonate group to a Cu-cluster in another layer b Two of the three sulfonate oxygens are used in framework bonding Three water molecules in unit cell one coordinated to metal centre Xiao et. al. Nature Chemistry, 2009, 1, 298 c

43 Dehydration driven phase transformation -H 2 O +H 2 O

44 VT Single crystal studies Increasing temperature Good Bragg diffraction Low temperature structure No Bragg diffraction between 370 K and 405K Structure unable to be solved by single crystal diffraction? Bragg diffraction returns High temperature structure

45 Pair Distribution Function (PDF) Analysis C C bonds in sulfoisophthalate Cu Cu distances Cu O bonds Cu C, some C C distances Function, G(r), with peaks at distances corresponding to atom-atom distances

46 Results - PDF Partial PDFs - give contributions to the total PDF from one set of atoms e.g. Cu O bonds allows assignment of some of the peaks to specific distances Differential PDFs - show the changes in structure e.g. subtract the low T structure Cu-S Cu-Cu

47 Cu-S distances change before the Cu-Cu distances

48 PDF derived mechanism

49 NO loading P NO = 230 mbar P NO = 338 mbar NO ads NO des NO adsorbed/mmolg Pressure/mbar N 2 CO 2 H 2

50 Force of contraction to U46619 (mn) Myography : Relaxation to H 2 S-loaded MOFs or NaHS Porcine coronary arteries ± EC: 1)Incubated for 30 min with or without channel inhibitors 150 MOF-H 2 S 2) H 2 S-loaded MOF introduced for 30 min, or cumulative ½ log concentrations of NaHS for 2 min per concentration, or time required to reach plateau Time (min) Relaxation response of PCA to an H 2 S-loaded MOF of Mg(dhtp) 10% Teflon

51 % Relaxation % Relaxation % Relaxation % Relaxation Comparison of relaxation responses to NaHS and H 2 S gas H 2 S MOF NaHS 50% Teflon MOF 10% Teflon MOF NaHS 300 M NaHS 1 mm 0 20 Control XE-991 Control XE-991 Control XE-991 Control XE endothelium -endothelium 20 +endothelium -endothelium H2 S NS NS * NS Hy poxia * Hy poxia+h2 S HC H2S * * # # * HC hypoxia HC hypoxia+H2S 40 NS endothelium 0 -endothelium 20 * * NaHS Hypoxia Hypoxia+NaHS HC NaHS HC hypoxia HC hypoxia+NaHS +endothelium -endothelium 100s of papers using NaHS to deliver H 2 S But MOF-H2S is more potent and has a different mechanism

52 Biological applications of MOFs Some instability (wrt MOFs) is actually an advantage Functionality Biodegradeability Controlling the rate of degrading is key Hemilabile MOFs MOFs Engineering weakness into a MOF can lead to unusual properties that can be exploited e.g. Ultraselective NO adsorption

53 Acknowledgments Phoebe Allan, Catherine Renouf, Alistair McKinlay, Damiano Cattaneo, Daniel Firth, Sam Morris, Matthew MacPherson, Yuyang Tian, Mazlina Musa, Jurgen Kahr, Giulia Bignami, Katrazyna Mocniak, Pavla Chlubna- Eliasova, Katharina Peikert, Sara Rojas, Paul Wheatley, Morven Duncan, Stewart Warrender, Farida Aidoudi, Laura McCormick, Marta Navarro-Rojas, Valerie Seymour, Fengjiao Yu, Daniel Dawson, Ana Belen Pinar, Lucy Clark, He Xiang, Maksym Opanasenko Katie Ridley, Sarah Morgan, Emily Pearson, Lily Hayes, Stephen Moggach, Ian Megson, Richard Weller, Mark Thomas, Barbara Gil, Tina Dueren, Jiri Cejka, Petr Nachtigall, Wiesiek Roth, Sharon Ashbrook, Wuzong Zhou, Heather Greer, Joe Hriljac, Karena Chapman, Paul Attfield, Andrew Harrison, Anthony Cheetham, Simon Teat, Michael Froba, Mark de Vries

54 Thanks

55 The international journal for inorganic, organometallic and bioinorganic chemistry Impact Factor of 4.2* 48 issues a year Fast publication times *2013 Journal Citation Reports The only major weekly journal for inorganic

56 STAM-1 Switchable adsorption H 2 O Room Temp Room Temp 393 K 393 K

57 MOFs First example of pressure-induced ligand exchange STAM-1 versus HKUST-1 Ultrasound transformation of STAM-1 into STAM-2 Significant for increasing throughput in scaled-up synthesis

58 Where are the weaknesses here? PSM of open metal sites

59 Pressure Induced PSM of STAM-1

60 STAM-1 v HKUST-1

61 Ultrasound synthesis of STAM-2 from STAM-1 10 mm 1 mm

62 What is STAM-2?

63 The structure?