Metal-organic frameworks as gas delivery agents in

medicine

Russell Morris

University of St Andrews

Synthesis Characterisation

Application

7.07.5

8.08.5

9.09.5

10.010.5

11.0

20

40

60

80

100

120

140

160

180

200

d-Spacing

Tim

e/m

inute

s

-98.00

-20.00

20.00

30.00

50.00

60.00

74.00

100.0

247.0Intensity

Synthesis

New MOFs with new properties

Nature Chemistry, (2009)

J. Am. Chem. Soc. (2010)

Nature Chemistry, (2011)

Chiral Induction

J. Am. Chem. Soc. (2007)

Nature Chemistry (2010)

New Quantum Spin Liquids

Nature Chemistry (2011)

Angew. Cheme (2015)

Ionothermal Synthesis

Nature (2004)

J. Am. Chem. Soc (2006)

b

c

ADOR Chemistry

Nature Chemistry (2013)

Nature Chemistry (2015

Nature Chemistry (2016)

Characterisation

2 n m

TEM

PDF

NMR ADSORPTION XRD

COMPUTATION

ZeomedixZeolites for medical

applications

MOFgenMOF

Development

Spin Out

Company

SASOLEnergy and

Chemicals

Zeolites

Pigments

Ion exchange

Anti-microbials

Automotive CatalysisMedical Devices

Oil refining

Adsorption

Space exploration

MOFs - Gas tanks and wine racks

Which gases should we store (and why)?

• Hydrogen Energy

• Methane Energy

• Other hydrocarbons Energy

• SO2

Environmental

• CO2

Environmental

• Ethylene Agriculture/Food

• Nitric Oxide Biology/medicine

• Hydrogen Sulfide Biology/medicine

• Carbon Monoxide Biology/medicine

Nitric oxide – Friend or Foe?

A toxic gas but vital for

Cardiovascular System

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

Cleaner Cars and Greener Gases

+

CO

HC

NOx

H2O

N2

CO2

NO in the body

Vasodilation

Thrombosis

Smooth muscle

proliferation

HypotensionHeart attack

StrokesHypertension

eNOS

nNOS

iNOSNeuronal signallingAnti-microbial

Angiogenesis

Wound collagen

deposition

InfectionDelayed

wound healing

Impaired nervous

system function

Why do we need NO delivery materials?

• Simple, cheap and effective means of

releasing NO locally

– Reduction of systemic effects

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

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

Can we use zeolites to deliver NO?

• From catalytic studies we know that NO makes a

complex with the metal ions

• Need a simple way of releasing NO from the

complex?

CoO

O

O CoO

O

O

N

O

NO

CoO

O

O

N

O

CoO

O

O

H2O

OH2

OH2 + NO

H2O

MOFs – “Crystalline Sponges”

+

organic linker metal ion or

cluster

extended framework structures

• flexible chemical composition

• many possible structures

• very high porosity

M-CPO-27: Exceptional performance over the

whole adsorption-storage-release cycle

McKinlay et al, J. Am. Chem. Soc. 2008

M-CPO-27

Dietzel and co-workers Norway

Biology: Anti-thrombosis Materials

• Platelet aggregation

– Both zeolites and MOFs inhibit

platelet aggregation

• Platelet Adhesion

1-min

Control

Co-LTA(A)

Co-LTA(A)-NO+Hb

Co-LTA(A)-NO

U46619

0

20

40

60

80

100%

A

gg

reg

ati

on

HKUST-1

NO-Z/PTFE

P

10 µm

NO-Z/PTFE

P

10 µm

Z/PTFE

PA

10 µm

Z/PTFE

PA

10 µm

Paul Wheatley

Dermatology Studies

ZeoliteZeolite

+ NO

Acidified

Nitrite

Acid

No inflammation! Unlike competitor acidified nitrite

Zeolite Zeolite

- NO

Acidified

Nitrite

Acid

NO dilates

blood vessels

Contracted

vesselRelaxed

vessel

Ni-MOF

20%

5 min

remove

0

25

50

75

100

Rela

xa

tion

(%)

0 5 10 15 20 25 30

Time (mins)

Ni-MOF

20%

5 min

remove

0

25

50

75

100

Rela

xa

tion

(%)

0 5 10 15 20 25 30

Time (mins)

Ni-MOF

20%

5 min

remove

Ni-MOF

20%

5 min

remove

0

25

50

75

100

Rela

xa

tion

(%)

0 5 10 15 20 25 30

Time (mins)

Anti-Bacterial NO zeolites

(a) E. coli, (b) A. baumannii, (c) S.

epidermidis, (d) MRSA

Neidrauer et al Journal of Medical

Microbiology (2014), 63, 203–209

Wound Healing study

Rate of wound closure

~30% faster

Neidrauer et al Journal of Medical

Microbiology (2014), 63, 203–209

Zeomedix

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!

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)

23

Proven Antimicrobial Efficacy

0 6 12 18 24 30 36 42 48

0

20000

40000

60000

80000

100000

120000Ag-btc 80:20

Ag-btc 50:50

Growth Control

8 g/ml Amphotericin B

Negative Control

Teflon Control

Ag-btc 25:75

Ag-btc 10:90

Ag-btc 5:95

Incubation Time (h)

Flu

ore

scen

ce (

F530/5

90)

Meta

bo

lic G

row

th

growth control

blank

amphotericin B

MOF A. niger black mould

contaminant of food

growth control

MOF

oxacillin

vancomycinMRSA (Gram +ve)

top 5 of HAIs

skin infection pneumonia,

sepsis

Meta

bo

lic G

row

th

Multifunctional antibacterial Activity

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

0

10000

20000

30000

40000

50000

60000

70000

80000

90000

100000

S. aureus DSMZ11729

MOF1

MOF2

Teflon

Vancomycin

Growth control

Uninoculated control

MOF1-NO

MOF2-NO

Incubation Time (h)

Flu

ore

scen

ce (

A530/5

90)

MOFs are antibacterial. MOF + NO shows outstanding

antibacterial activity

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.

Multirate delivery of multiple therapeutic agents

Why is the rate of delivery important?

Multirate delivery of therapeutic agents

0 24 48 72 96 120 144 168 192 2160

10

20

30

40

50

60

70

80

90

100

Am

ou

nt

rele

ase

d f

rom

HK

US

T-1

(%

)

Time (hours)

Amount of Cu released (%)

Amount of Metro released (%)

Amount of NO released (%)

• 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

Toxicity

• Cytotoxicity against dermal fibroblasts and

red blood cells.

Scaling upSimple synthesis

• developed and demonstrated scalable, low

temperature manufacturing process

1L lab scale

20L development

scale

100L pilot scale

Formulating products

solvent cast polyurethane film

silicone extruded

tubing coated non woven polyester

• demonstrated compatibility with wide range of

polymers using various techniques

Commercial Partnering

formulation

scale up

partnering

funding

unmet need

solution

performance

• Impact Factor of 4.2*

• 48 issues a year

• Fast publication times

www.rsc.org/dalton

@DaltonTrans

The international journal for inorganic, organometallic and bioinorganic chemistry

The only major weekly journal

for inorganic chemistry

*2013 Journal Citation Reports®

Thanks

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

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.

MOF Synthesis Targets

•Bigger is better

–Super porous materials for high capacity gas storage

•Flexibility is key

–Soft porous crystals give unusual properties

Designing New Hemilabile MOFs

Organic LinkerMetal

Strong Bond

5-sulfoisophthalate

Weak Bond

• 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

• Two of the three sulfonate oxygens are used in framework bonding

• Three water molecules in unit cell – one coordinated to metal centre

Cu-SIP-3

Xiao et. al. Nature Chemistry, 2009, 1, 298

b

c

Dehydration driven phase transformation

-H2O

+H2O

VT Single crystal studies

Increasing temperature

?

Good Bragg diffraction

Low temperature structure

Bragg diffraction returns

High temperature structure

No Bragg diffraction between 370 K and 405K

Structure unable to be solved by single crystal diffraction

• Function, G(r), with peaks at distances corresponding to atom-atom distances

Pair Distribution Function (PDF) Analysis

C – C bonds in sulfoisophthalate

Cu – O bonds

Cu – Cu distances

Cu – C, some C – C distances

Results - PDFPartial 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 distancesDifferential PDFs - show the changes in structure e.g. subtract the low T structure

Cu-S

Cu-Cu

Cu-S distances change before the Cu-Cu distances

PDF derived mechanism

NO loading

PNO = 230 mbar PNO = 338 mbar

0 200 400 600 800 1000

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

N2

CO2

H2

NO ads

NO des

NO

ad

so

rbe

d/m

mo

lg-1

Pressure/mbar

Myography : Relaxation to H2S-loaded MOFs or NaHS

Relaxation response of PCA to an

H2S-loaded MOF of Mg(dhtp) 10%

Teflon

Porcine coronary arteries ± EC:

1)Incubated for 30 min with or without channel

inhibitors

2) H2S-loaded MOF introduced for 30 min, or

cumulative ½ log concentrations of NaHS for 2

min per concentration, or time required to reach

plateau

0

50

100

150

MOF-H2S

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

Time (min)

Fo

rce o

f co

ntr

acti

on

to U

46619 (

mN

)

Comparison of relaxation responses to

NaHS and H2S gas

Control XE-991 Control XE-9910

20

40

60

80

100

+endothelium

-endothelium

NaHS 300 M NaHS 1 mM

% R

ela

xati

on

NaH

S

Hyp

oxia

Hyp

oxia+

NaH

S

HC-0

3003

1+NaH

S

HC-0

3003

1+hyp

oxia

HC-0

3003

1+hyp

oxia+

NaH

S

-20

0

20

40

60

80

100

+endothelium

-endothelium

*

*

% R

ela

xati

on

H2S

Hypoxi

a

Hypoxi

a+H2

S

HC-0

3003

1+H2S

HC-0

3003

1+hyp

oxia

HC-0

3003

1+hyp

oxia+

H2S

-20

0

20

40

60

80

100

+endothelium

-endothelium

NS

* NS

NS

#

*

*

*

*

#

NS

% R

ela

xati

on

Control XE-991 Control XE-9910

20

40

60

80

100

+endothelium

-endothelium

50% Teflon MOF 10% Teflon MOF

% R

ela

xati

on

H2S MOF ‘NaHS’

100s of papers using

NaHS to deliver H2S

But MOF-H2S is

more potent and has

a different

mechanism

MOFs

• Biological applications of MOFs

– Some instability (wrt MOFs) is actually an

advantage

• Functionality

• Biodegradeability

– Controlling the rate of degrading is key

• Hemilabile MOFs

– Engineering weakness into a MOF can lead to

unusual properties that can be exploited

• e.g. Ultraselective NO adsorption

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

Thanks

• Impact Factor of 4.2*

• 48 issues a year

• Fast publication times

www.rsc.org/dalton

@DaltonTrans

The international journal for inorganic, organometallic and bioinorganic chemistry

The only major weekly journal

for inorganic chemistry

*2013 Journal Citation Reports®

STAM-1 Switchable adsorption

Room Temp

393 K

Room Temp

393 K

H2O

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

Where are the weaknesses here?

PSM of open metal sites

Pressure Induced PSM of STAM-1

STAM-1 v HKUST-1

Ultrasound synthesis of STAM-2 from STAM-1

10mm

1mm

What is STAM-2?

The structure?