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Metals in Medicine
Prof L Cronin
NO PAPER HANDOUTS WITH THIS COURSE…
To get a PDF go to:
http://www.chem.gla.ac.uk/cronin/teaching.php
Look for the 4th year metals in medicine column and
then right click to download the pdf for lecture 1.
References
• Background
– OCP Primers:
• Inorganic Chemistry in Biology by Wilkins and Wilkins
• Biocoordination Chemistry by Fenton
• Research Papers
– Metals in Medicine, Z. Guo, P. J. Sadler, Angew. Chem.
Int. Ed. 1999, 38, 1512-1531
Introductory Comments
• Biomedical inorganic chemistry (“Elemental
Medicine”) is an important new area of chemistry.
It offers potential for the design of novel
therapeutic and diagnostic agents and hence for
the treatment and understanding of diseases
which are currently intractable.
• It is evident that many organic compounds used
in medicine do not have a purely organic mode of
action; some are activated or biotransformed by
metal ions, including metallo-enzymes, others
have a direct or indirect effect on metal ion
metabolism
Topics to be covered
1. The Biomedical Periodic Table
• Essential elements, chemotherapeutic and diagnostic elements
2. Metal Based Therapeutic Agents
• Anti-Cancer drugs
Platinum, titanium ruthenium and other metal based drugs
• Antiarthritic drugs
3. Metal Based Diagnostic Tools
• Radiopharmaceuticals
Radioisotopes for imaging and therapy
Targeting of radioactive compounds
• Contrast agents for Magnetic Resonance imaging (MRI)
• Paramagnetic relaxation agents
4. Biological Targets for Metal Based Therapies
• Metalloenzyme inhibition
• Insulin mimetics
• Nitric oxide and superoxide
• Antimicrobials
• Chelation therapy
5. The future of Bio-Inorganic Chemistry
• Polyoxometallates in medecine
• A possible inorganic Origin of Life
The biomedical periodic table
• Essential elements; metallic = red, non metallic = yellow
• Elements possibly helpful to life = cyan
• Chemotherapeutic and diagnostic elements = blue
Functions of Metal ions in Biology
Metal Function Typical Deficiency Symptoms
Na, K charge carrier, osmotic balance death
Mg Structure, hydrolase, isomerase Muscle cramps
Ca Structure, trigger, charge carrier Retarded skeletal growth
V Nitrogen fixation, oxidase N/A
Cr Glucose intolerance Diabetes symptoms
Mo N2 fixation, oxidase, oxo transfer Retardation of cell growth
Photosynthesis, oxidase,
Mn Infertility, impaired growth
structure
Co Oxidase, carbon group transfer Pernicious anaemia
O2 transport and storage, oxidase,
Fe Anaemia, disorders of the immune system
electron transfer, N2 fixation
Ni Hydrogenase, hydrolase Growth depression dermatitis
Cu E-transfer, O2 Transport, oxidase Artery weakness, liver disorders
Skin damage, stunted growth, retarded
Zn Structure, hydrolase, male fertility
sexual maturation, impaired development
Se, As Puberty (?) and growth Impaired development
Why are metal ions important in biology ?
• Catalysing reactions via:
– Hydrolytic e.g. carbonic anhydrase, carboxypeptidase
– Substrate transfer e.g. haemoglobin, myoglobin
– Electron transfer e.g. cytochrome C oxidase
• Thermodynamic and kinetic considerations
• Stabilising structure:
– Protein
– DNA
– Skeletal
• Charge balancing:
– Osmotic balance
– Nerve function
• Replication and information encoding
Chemical Considerations
• Kinetics
– Ligand Exchange Rates
• Determined by:
– Oxidation state
– Geometry
– Electron configuration (e.g. Jahn Teller)
– Ligand effects
• Theromdynamics
– Complex Stability and Formation Constant
• Determined by
– Oxidation state
– HSAB theory
– Crystal field parameters
– Ligand field parameters
– Ligand type / dentiticity
Metal based Anti-Cancer Drugs
• In 1965 Rosenberg discovered the antiproliferative effect of cisplatin whilst
conducting studies on bacteria under in an electric field produced by
platinum complexes
• He was able to show that the compound cisplatin was responsible for the
effect and this was found to be effective against treating some cancers.
• Cisplatin is now THE MOST used anti-cancer drug
BUT CONTAINS NO CARBON ATOMS!
• HOW DOES CISPLATIN TARGET CANCER ?
• By reaction with DNA?
cisplatin carboplatin
Mechanism of substitution of square
planar Pt(II) complexes
• Pt2+, d8 complexes are normally square planar
– Kinetically quite inert
– Ligand exchange reactions occur over an associative
mechanism with a five-coordinated intermediate under
retention of the conformation
Reactions of cisplatin under physiological conditions
Cisplatin hydrolysis
regulated by chloride
concentration
([Cl-blood] = 100 mM).
([Cl-cell] = 3 mM)[8],
Reactive COMPOUND is the aquated cisplatin
MUCH BETTER THAN transplatin
Hydrolysis of cisplatin
• The hydroxo / water ligands are much more reactive to
substitution than the chloride ligands
• The hydrolysis rate is mainly determined by the trans effect
of the ligands trans to Cl-
• Steric hindrance can also slow rates of ligand substitution
A B
A undergoes hydrolysis 6x slower than B
DNA binding
• Major adducts of platinum drugs with DNA are the 1,2-GpG
and 1,2-ApG intrastrand crosslinks – 90%
• Structural studies show that the Pt cross links induce bending
and unwinding of DNA and cause destacking of the purine
bases.
• The B-DNA backbone conformation is significantly altered to
accommodate the platinated lesion
• Spectroscopic and calorimetric studies suggest that platination
induces a conformational shift from an B-like to an A-like form
– may be important in HMG (High Mobility Group protein)
recognition.
DNA binding – GpG INTRA STRAND
• Cisplatin binds to DNA and causes a critical
structural change in the DNA – a bend of 45 degrees
Cisplatin binds to two
Adjacent G’s at N7
on the DNA in an
INTRA strand
cross-link
DNA binding cont
• It is known that platinum forms bifunctional DNA adducts with
the following order of sequence preference:
GG- > -AG- >> -GA
platination is kinetically controlled.
• Inter-strand cross links can also be generated between DNA
and cisplatin between to G’s on opposite sides of the duplex
• Monofunctional adducts can also form and can be long lived
(t1/2 = 80 hrs)
• The Stability of the Pt-N7 bond is high but can be broken by
strong nucleophiles e.g. CN-
DNA binding of trans-platin
• The adduct trans-{Pt(NH3)2}2+ d(TCTACG*CG*TTCT)
(1,3-GG cross-link) is unstable at neutral pH and
rearranges to form the linkage isomer trans-
{Pt(NH3)2}2+-d(TCTAC*GCG*TTCT) (1,4-CG cross-
link)
• Both intra- and inter-strand transplatin-DNA adducts
undergo isomerisation
• transplatin is not used in anticancer therapy
DNA recognition and repair
• DNA repair system can detect many forms of
damage
• Once detected, excision repair removes the
damaged DNA to form a gap
• This gap is then filled by DNA polymerase
– This process is complex, involving around 30 proteins
• DNA repair efficiency order 1,3-d(GTG) crosslink >
AG > GG. This implies that 1,2-d(GG) cross-links, as
form by cisplatin are toxic.
Mechanism of Cell Death
IT APPEARS THAT HMG PROTEIN DOES NOT OCCUR IN HEALTHY
CELLS IN LARGE AMOUNTS AND THEREFORE CANNOT PROTECT
AGAINST EXCISION REPAIR
Cisplatin and cellular resistance / toxicity
It appears both ACTIVE and PASSIVE mechanisms
operate to allow cisplatin to enter the cell:
– ACTIVE transport requires a channel or transport protein
– PASSIVE transport does not require chemical energy
Blood proteins rich in thiolates can deactivate
cisplatin and are responsible for the toxicity of the
drug.
Cisplatin and new drugs
From a clinical point–of-view the current challenges
in drug development include:
(i) addressing the poor solubility of cisplatin and analogues in water
(ii) cellular resistance of cancer cells to cisplatin
(iii) toxic side effects of cisplatin
(e.g. nausea, neurotoxicity, kidney damage)
(iv) use of platinum-based therapeutics to treat cisplatin resistant cell lines
Analogues under study at present
The need for new cisplatin drugs
• For understanding
• To address toxicity and cellular resistance
Non-Platinum Anti-cancer Complexes:
Other Platinum Group Metals
Ru Rh Pd
Os Ir Pt
• Palladium Complexes
Pd2+ in [Pd(en)Cl2] and Pd4+ in [Pd(NH3)2Cl4]
show some anti-cancer activity BUT: Pd2+ is much more labile
than Pt2+ (the hydrolysis rate for [Pd(en)Cl2] is 2x105 higher
than [Pt(NH3)2Cl2])
• The reactivity of palladium seems unsuitable for use in simple
cisplatin analogues
Rhodium complexes
• Bi-nuclear carboxylate complexes show some
anti-cancer activity.
– e.g. R = Me, CH(OH)Me, L = H2O or lewis
base
• Recently Me2SO complexes have been of
interest following the precedent of related
ruthenium complexes
– Cytotoxicity like cisplatin
• Iridium complexes – filamentation of bacteria
reported by poorly characterised [IrCl6]2-
derivatives
Ruthenium complexes
• Anti tumour activity reported
in the mid 1970’s
• Better than cisplatin (!)
against some tumours
– Ru complexes appear to
be PRO-DRUGS
• Ru released to
transferrin
Ruthenium cont.
• Ru imidazole complexes
– Better solubility than neutral
complexes
– Active against colo-rectal
tumours
• Interstrand DNA crosslinking
agent
– Acts by intercalation followed
by crosslinking
Metallocene-based anti-cancer agents
• Metallocene Dihalides are active against a RANGE of cancers
• M = Ti, V, Nb, Mo; X = halide
– Some examples in phase I clinical trials
• M = Ge, Sn, X = nothing
• But M: M = Zr, Hf, W; X = Cl are INACTIVE
• [Ti(η5-C5RR’4)2X2] – structure activity relationships
– Keep η5-C5RR’4 as η5-C5H5
– Vary halide, N2, NCS, O2CCl3, O2CCH=CHCO2H
– Activity retained BUT TOXICITY VARIES
– Keep X as Cl, vary R, R’: R= Me, R’=H or R=R’=Me
• Activity LOST
• IMPLIES CP RING is an ESSENTIAL COMPONENT
Β-diketonate complexes
• Shows activity is some animal
models
– M = Ti, Zr, Hf; X = halide
– R1, R2 = hydrocarbyl
• Budotitane
– The most active compound
found; sent for clinical trials
– Use limited by liver toxicity and
poor solubility
Rheumatoid Arthritis: Gold Chemistry
Oxidation states Au(I), d10, and Au(III), d8, possible
Au(I) is dominant in vivo. Au(III) may form in oxidising regions but will be
reduced to Au(I) on return to other tissue zones e.g by sulphur compounds
{Au3+L4} + 2RSH {Au+L2} + RSSR + 2H+
{Au3+L4} + R2S {Au+L2} + R2S=O + 2H+
Reduction to Au(0) is also possible leading to deposition of insoluble metal
particles in tissues
Au(I) is bound by soft ligands i.e sulphur or phosphorus donors of CN-
Gold chemistry cont
• Might expect linear 2-coordination for d10 Au(I) and planar 4-
coordination for d8 Au(III)
• Peptide Au(III) complexes are known e.g. with glycyl-glycl-L-histidine
Rheumatoid Arthritis: Chrysotherapy
• Crysotherapy is the use of gold compounds in medicine
– Gold compounds are particularly effective in the treatment of Rheumatoid
Arthritis
– Injected (i.e – water soluble) drugs are more active than Oral drugs
(auranofin)
– Gold drugs show anti-inflammatory effects and inhibition of tissue
degradation
– Mechanism of action is uncertain, the compounds used are pro-drugs
undergoing ligand-exchange with serum proteins
– Trialkyl phosphine is more strongly bound to Au(I) than thiolate
– Drugs can transfer Au+ to cysteine-S- in serum albumin after a structural
rearrangement bringing the cysteine-S- to the surface of the protein
[Au(CN)2]2- can form from Au(I) thiolates which are common metabolites
Rheumatoid Arthritis: Chrysotherapy
Based on the oral drug Auranofin
(insoluble in water)
Injected (soluble in water) Drugs are gold complexes of :
Myochrisin RS Allochrisin RS
Solganol RS
AuSR oligomers
Rheumatoid arthritis
Gold and the IMMUNE response
• Rheumatoid Arthritis is a chronic autoimmune disease, which
principally causes inflammation of the joints
• In cells such as macrophages, protein fragments are passed
to cell surfaces when non-self fragments attract T cells, which
mediate an immune response
– Binding of metals to proteins or their fragments may modify the
immune response
– Metal ions may block the binding of non-self peptides to MHC
suppressing an immune response
– Complexation to, or oxidation by metal ions may interact with self
peptides causing an immune response – allergic response
– The affinity of Au(I) for thiolate, and hence protein binding to
methionine or cysteine, may be responsible for some effects on
the immune system
Magnetic Resonance Imaging
• Origin – detection of differences between 1H NMR resonances (mainly
of H2O) between normal and abnormal tissues
• Differences found my administration of external paramagnetic agents –
CONTRAST AGENTS.
• Most contrast agents contain GdIII, MnII, or FeIII ions which have a large
number of unpaired electrons and long electron spin relaxation times.
Gd3+ Fe3+ Mn2+ Cr3+
f7 d5 d5 d3
S=7/2 S=5/2 S=5/2 S=3/2
labile labile labile inert
MRI Contrast Agents
• Effectiveness in relaxation is a function of several parameters
– Ri = f(T1e, M, R, D)
– where Ri is the relaxivity (R1 = 1/T1, R2 = 1/T2), T1e is the
longitudinal electron spin relaxation time, M is the residence
lifetime of bound H2O, R is the rotational tumbling time of the
complex, and D is the relative translational diffusion time (outer
sphere relaxation).
• Operate through effect of paramagnetic ions on the relaxation
times of T1 and T2 of protons in water
MRI Contrast agents
• T1 = spin-lattice relaxation time for energy transfer to surroundings –
depends on μ2
• μ is the magnetic moment of the
metal ion
• T2 = spin-spin relaxation time for energy transfer from excited to ground
state nuclei ( IN BRAIN TISSUE T1 = 750 ms, T2 = 70 ms – approx)
• Relaxivity, r1, for a metal ion: r1 = (q / 55,5)(T1p+ M)-1
– q = number of water molecules bound to the metal ion
– T1p = T1 for metal bound water protons
– M = lifetime for water molecule binding
Criteria for good contrast agents
• For Large r1 and so good MRI contrast need:
• a large μ2 value
• At least one water molecule binding to the metal ion
• M << T1p so labile complexation of water
i.e large rate of exchange with, kex with water
• Also need a very stable complex to allow control of
biodistribution and, toxicity and excretion
Example Complexes
• Four complexes have been approved for clinical use
DTPA DOTA
BMA-DTPA HP-DOTA
Examples of Structures
- Take home message: One water site is left unprotected for fast exchange
Relaxation Data etc
298
Agent kex R1 [mM-1s-1] lg K
[Gd(dtpa)]2- 3.3 4.5 22.5
[Gd(dota)]- 4.8 3.4 25.8
[Gd(bma-dtpa)] 0.45 4.4 16.9
[Gd(hp-dota)] 3.6 23.8
[Gd(bopta)]2- 4.4 22.5
[Mn(dpdp)]4- 2.8 15.1
Movie of BRAIN MRI
MRI Contrast Complexes
• Complexes containing DTPA and DOTA ligands are ionic
whereas those of BMA-DTPA and HP-DOTA are neutral;
• Their low osmolarity decreases the pain of the injections
• All the reagents are extracellular, and diffuse rapidly into the
interstitial space.
• GdIII ion is nine coordinate and contains one bound H2O
• Water exchange here is dissociative and steric crowding
increases this rate
Experimental Contrast Agents
• Mn complex for liver scans
• Polyethers increase solubility
• Superparamagnetic nano-particles
containing iron oxide coated with
dextran are also being used as MRI
contrast agents.
– For liver and gastrointestinal tract
Magnetic Resonance Imaging
• Origin – detection of differences between 1H NMR resonances (mainly
of H2O) between normal and abnormal tissues
• Differences found my administration of external paramagnetic agents –
CONTRAST AGENTS.
• Most contrast agents contain GdIII, MnII, or FeIII ions which have a large
number of unpaired electrons and long electron spin relaxation times.
Gd3+ Fe3+ Mn2+ Cr3+
f7 d5 d5 d3
S=7/2 S=5/2 S=5/2 S=3/2
labile labile labile inert
MRI Contrast Agents
• Effectiveness in relaxation is a function of several parameters
– Ri = f(T1e, M, R, D)
– where Ri is the relaxivity (R1 = 1/T1, R2 = 1/T2), T1e is the
longitudinal electron spin relaxation time, M is the residence
lifetime of bound H2O, R is the rotational tumbling time of the
complex, and D is the relative translational diffusion time (outer
sphere relaxation).
• Operate through effect of paramagnetic ions on the relaxation
times of T1 and T2 of protons in water
MRI Contrast agents
• T1 = spin-lattice relaxation time for energy transfer to surroundings –
depends on μ2
• μ is the magnetic moment of the
metal ion
• T2 = spin-spin relaxation time for energy transfer from excited to ground
state nuclei ( IN BRAIN TISSUE T1 = 750 ms, T2 = 70 ms – approx)
• Relaxivity, r1, for a metal ion: r1 = (q / 55,5)(T1p+ M)-1
– q = number of water molecules bound to the metal ion
– T1p = T1 for metal bound water protons
– M = lifetime for water molecule binding
Criteria for good contrast agents
• For Large r1 and so good MRI contrast need:
• a large μ2 value
• At least one water molecule binding to the metal ion
• M << T1p so labile complexation of water
i.e large rate of exchange with, kex with water
• Also need a very stable complex to allow control of
biodistribution and, toxicity and excretion
Example Complexes
• Four complexes have been approved for clinical use
DTPA DOTA
BMA-DTPA HP-DOTA
Examples of Structures
- Take home message: One water site is left unprotected for fast exchange
Relaxation Data etc
298
Agent kex R1 [mM-1s-1] lg K
[Gd(dtpa)]2- 3.3 4.5 22.5
[Gd(dota)]- 4.8 3.4 25.8
[Gd(bma-dtpa)] 0.45 4.4 16.9
[Gd(hp-dota)] 3.6 23.8
[Gd(bopta)]2- 4.4 22.5
[Mn(dpdp)]4- 2.8 15.1
Movie of BRAIN MRI
MRI Contrast Complexes
• Complexes containing DTPA and DOTA ligands are ionic
whereas those of BMA-DTPA and HP-DOTA are neutral;
• Their low osmolarity decreases the pain of the injections
• All the reagents are extracellular, and diffuse rapidly into the
interstitial space.
• GdIII ion is nine coordinate and contains one bound H2O
• Water exchange here is dissociative and steric crowding
increases this rate
Experimental Contrast Agents
• Mn complex for liver scans
• Polyethers increase solubility
• Superparamagnetic nano-particles
containing iron oxide coated with
dextran are also being used as MRI
contrast agents.
– For liver and gastrointestinal tract
Nuclear Medicine – What is it?
• The use of radioactive isotopes in medicine as agents to allow
the diagnosis or treatment of conditions like cancer
• Radioactivity was discovered at the start of the 1900s
• Frederick Soddy (Glasgow) was awarded the Nobel Prize for
Chemistry in 1921 for contributions to the chemistry of
radioactive substances and the nature of isotopes.
• Radioactivity is given off as the result of nuclear decay of
unstable nucleii
– Radioactivity can take several forms which vary in energy
Nuclear Medicine
• Types of Ionising Radiation
Radiation Type Energy Wavelength Use in Medicine
Alpha – α (He2+) 2-10 MeV μm Therapy
Beta – β 1-3 MeV mm Therapy
(511 keV γ) (γ m)
Beta+ - β+ (γ) Imaging (PET)
0.05 - 2
Gamma – γ M Imaging (SPEC)
MeV
X-ray – X 0.1 130 keV dm Imaging (CAT)
Some examples of radioisotopes used in nuclear medicine
Radio- Half Decay Principal Energy Production Applications
nuclide life mode radiations (MeV) method
51Cr Red blood cell and protein labelling, glomerular filtration
27.8d EC γ 0.322 50Cr(n,γ) 51Cr
rate.
52Fe β+ e+ 0.81 Cyclotron
8.3h Bone marrow imaging
EC γ 0.51 52Cr(α,4n)52Fe
59Fe e- 0.27,0.46
45d β 58Fe(n,γ)59Fe Iron absorption kinetics
γ 1.29,1.10
57Co Cyclotron
267d EC γ 0.12 60Ni(p,α)57Co Vitamin B12 absorption studies and pernicious anemia
58Co β+ e+ 0.49
71d 58Ni(n,p)58Co Diagnosis
EC γ 0.81,0.51
64Cu β e- 0.6
12.7h 63Cu(n,γ)64Cu Wilson’s disease and copper metabolism studies
β+ e+ 0.7
67Cu e- 0.4,0.6 cyclotron
61.9h β Gastrointestinal protein loss
γ 0.18,0.09 64Ni(α,p)67Cu
65Zn β+ e+ 0.33
245d 64Zn(n,γ)65Zn Zinc absorption studies
EC γ 0.11,0.51
67Ga cyclotron
78h EC γ 0.30,0.18 65Cu(α,2n)67Cu Imaging of abscesses and neoplasms
Cyclotron
68Ga 1.9
1.13h β+ e+ 69Ga(p,2n)68Ge Tumour imaging, available from a generator
0.08,0.51 68Ge(EC)68Ga
cyclotron
85mSr Bone scanning and bone cancer detection, available
2.83h EC γ 0.39 87Sr(p.n)87Y
87Y(EC)85mSr from a generator
EC=electron capture, IT=internal transition
Radio- Half Decay Principal Energy Production Applications
nuclide life mode radiations (MeV) method
85Sr Cyclotron
64d EC γ 0.51,0.013 85Rb(p,n)85Sr Bone scanning
90Y 64.4h β e- 2.27 89Y(n,γ)90Y Treatment of arthritic joints
98Mo(n,γ)99Mo Many uses in diagnostic imaging, available from
99mTc 6h IT γ 0.14 99Mo(β,γ)99mTc generator
111In Cyclotron
2.8d EC γ 0.25,0.17 109Ag(α,2n)111In White cell and protein labelling
112Sn(n,γ)113Sn
113mIn 1.73h IT γ 0.39 Brain scanning, cardiac output, liver scanning
113Sn(EC)113mIn
188Re e- 2.1 188W(β)188mRe
17h β
γ 0.155 188mRe(γ)188Re
195mPt 4.02d IT 0.13,0.099 194Pt(n,γ)195Pt Pharmacy research
197Hg Cyclotron
64h EC γ 0.19,0.077 197Au(p,n)197Hg Brain scanning
203Hg e- 0.2
46.6d β 202Hg(n,γ)203Hg Kidney scanning
γ 0.28
198Au 65h β e- 0.96 197Au(n,γ)198Au Liver scanning, treatment of interperitoneal neoplasms
Cyclotron
201Tl 74h EC γ 0.07 203Tl(p,3n)201Pb Myocardial imaging
201Pb(EC)201Tl
EC=electron capture, IT=internal transition
Isotope Production
• Cyclotron
– e.g. 65Cu (α, Zn) 67Ga
– E.g 69Ga(p, Zn)68Ge(EC)68Ga
– Expensive and VERY LOW YIELD
• Nuclear reactor
Fission Neutron Capture
235U to 99Mo + other FP’s 98Mo (n,γ)99 Mo
99Mo precursor to Tc 89Y(n, γ) 90Y
Chemical Separation free
99m Technetium Radiopharmaceuticals
• Technetium is an ‘Artificial Element’ NOT available from
natural sources
n, γ β-
98Mo 99Mo 99mTc
Nuclear 2.8 d
Reactor (m refers to a
metastable excited
state of the nucleus)
• Why Technetium ?
– Due to availability from ‘Technetium Generators’
•Absorb 99MoO42- on alumina
•Elute 99mTcO4- produced
Nuclear Properties of Tc
γ β-
99Tc 99Ru
99mTc
t½ = 6h t½ = 2.1 x 105 y
Energy 140 KeV ideal Soft β- (0.3MeV) weak
for imaging t1/2 a bit radioactivity stable
short decay product
100-200 KeV good for imaging
• Chemical properties:
– Wide range of oxidation states for Tc (-1 to +7 known – large
variety of stable complexes)
Shake ‘n Shoot Drugs / Diagnostics
Nuclear reaction 99mTcO -
4
LIGAND REDUCTANT
Obtain Picture
of 99mTc images INJECT 99mTc complex
99mTc Radiophamaceuticals
99mTc Radiophamaceuticals
99mTc Radiophamaceuticals
R = (Me)2(MeO)CCH2
Cardiolite
Ceretec Heart
Brain
DMSA MAG3
Kidney
99mTc Radiophamaceuticals
MDP R’ = CH2C(O)NHAr
Bone Mebrofenin
Liver
99mTc Radiophamaceuticals
A Cautionary Tale
Heart Imaging for beagles but not humans
99mTc Radiophamaceuticals
But Amersham-Nycomed now sell:
Myoview
For heart imaging
Cardiotec
A neutral heart imaging agent
Structure/Activity Relationships
Not well developed for ‘metallodrugs’
An example from 99mTc imaging agents:
Imido-diacetic acid complexes
RN(CH2CO2H)2 (R = hydrocarbyl)
More hydrophobic compounds excreted via kidney
More lipophilic compounds excreted via liver
Nanotechnology in medicine – Quantum Dots
Quantum Dots (QDs) are crystals of semiconductor materials which range from
molecular to protein sizes;
•Typically contain 100 – 100,000 atoms
•Range from ~ 1nm to ~20nm in size
•Have properties different from both bulk semiconductors and molecular
materials
•Exhibit strong fluorescence
•Fluorescence properties can be tuned by the size of QD rather than
composition
•QDs can be functionalised to have affinities to biological systems
Quantum Dots are mostly used for biodetection and bioimaging applications
What are Quantum Dots?
• Quantum Dots are made from semiconductors such as CdSe and ZnS
Bulk Semi conductors Quantum Dots
•In bulk materials electronic •Because QDs contain relatively
orbitals combine to form energy few atoms the conductance
bands rather than discrete and valence bands retain
energy levels discrete energy levels
•Conduction occurs when •Addition or subtraction of just a
electrons are promoted from the few atoms can alter the
valence (occupied) band to the boundaries of the band gap
conductance (unoccupied)
band •Emission of light can therefore
be tuned by size of QD
•Recombination of excited
electrons with the positive •The Larger the QD the longer
‘holes’ in the valence band the wavelength of light emitted
leads to emission of light
(LEDs) with a wavelength
characteristic of the band gap
Quantum Dots in medicine
Most quantum dots are synthesised in organic solvents and require
functionalisation for biological applications:
1. Solubilisation: Usually surface ligands are exchanged for thiol groups such as
mercapto acetic acid
2. Bioconjugation: Attachment of biomolecules (such as antibodies, proteins
etc...) to the surface of the quantum dots enable the QDs to interact with
biological systems
In Vitro or
In Vivo
1. 2.
Semi-
conductor
Hydrophilic
core attached
hydrophobic shell
shell biomolecules
biological
receptors
Quantum Dots in medicine
Various different biomolecules can be attached to label different biological systems and
fluorescence used to monitor the biological system. Quantum dots have several
advantages over traditional fluorescent probes (organic molecules):
•Tunable light emission
•Improved signal brightness
•Resistance to photobleaching
•Not pH dependant
However the physical size of QDs (roughly comparable to proteins) can limit their
applications.
Nanotechnology in medicine – Gold Nanoparticles
•Gold nano particles (colloidal gold) are submicrometer particles of elemental gold,
usually <100nm which have properties significantly different from bulk gold or gold
complexes.
•Similar to quantum dots Au-nanoparticles have size and
shape dependant optical and electronic properties and
high surface to volume ratios
•functional groups such as thiols, phosphines and amines have affinity for gold
surfaces and can be used to modify the Au-nps by anchoring biomolecules such
as oligonucleotides, proteins and antibodies (similar to QDs)
Gold Nanoparticle Bioconjugates
Synthesis of Gold nanoparticles.
Au nanoparticles are generally formed in solution by the controlled reduction of
Chloroauric acid, H(AuCl4), generally in the presence of a stabilising ligand which
prevents aggregation of the nanoparticles.
Varying the synthetic conditions can control the size, shape and size distribution of
the resulting nanoparticles.
Reducing Ligand
agent Exchange
H(AuCl4) Capping
ligand
Biomolecule
Or
Au NPs Linking molecule
Bioconjugated Au nanoparticles are playing an increasing role in biological and
medical research, and various different ligands are used for different applications
Gold Nanoparticle Bioconjugates
Surface Functionality Application
citrate cell uptake
transferrin cell uptake
CTAB
cell uptake
(Cetyl trimethylammonium bromide)
gene transfection
antiviral activity
amine
drug delivery
oligonucleotide transfection
antisense gene regulation
mRNA detection
oligonucleotide small-molecule detection
RNA interference
cancer cell detection
nuclear translocation
peptide
antisense gene regulation
imaging
antibody
photothermal therapy
imaging
lipid
cholesterol binding
Gold Nanoparticle Bioconjugates
Example: Amine functionalised Au NPs as potential drug delivery agents:
Using thiol-modified alkyl amines containing photo-cleavable o-nitrobenzyl
ester linkages, Au NPs can be used to effectively deliver negatively charged
payloads, such as oligonucleotides into cells.
Gold Nanoparticle Bioconjugates
Example: Photothermal therapy:
•Gold nanorods (i.e. Rod shaped nanoparticles) can absorb light in the Near
Infrared (NIR) region very efficiently.
•Irradiation of cells containing these nanorods in the NIR region can cause
localised heating leading to cell death.
•This process is being investigated as a possible therapy for use against cancer
cells.
Chelation Therapy
• Use of Ligands to remove metal ions from the body
The ligands used MUST:
• Be able to discriminate between metals
• Be excretable
Chelation theraputics include:
Drugs to treat iron overload (Thallassaemia)
Drugs to remove excess copper (Wilson’s Disease)
Can Chelation therapy be used to prevent cancer and other
diseases caused by oxidative damage?
Chelation Therapy
Ligands for chelation therapy:
Ligands must be SPECIFIC
Ligands must form very STABLE complexes
We must know what oxidation states will be present
This is achieved through careful LIGAND DESIGN, taking
into account such factors as:
•HSAB factors
•The irving Williams series
In order to design kinetically inert complexes, it is necessary to
have a broad understanding of metal ion properties
Chelation Therapy
Iron Chelation therapeutics - Thallasaemia
logβ3{Fe(III)} = 37
logβ3{Cu(II)} = 17
logβ3{Zn(II)} = 12.5
R1 = Et, R2 = Me
logβ3{Fe(III)} ≈ 37
R = alkyl
Chelation Therapy
Copper Chelation therapeutics – Wilson’s Disease
TETRA
d-penicillamine
EDTAH4 as the Ca2+ salt
Chelation Therapy with EDTA – a
breakthrough?
• EDTA is fast being adopted as a
potential treatment for
Cardiovascular Disease.
• This probably is linked with the
extraction of Fe from the blood
stream
• EDTA is a hexadentate ligand and is
preorganised for binding octahedral
metal ions
Molecular Targets for Metal-based drugs
• Targets include:
– Metalloenzyme inhibition
– insulin mimetics
– nitric oxide and superoxide,
carbon monoxide
– antimicrobials
• Vanadium(IV) complex as an
insulin mimic
Molecular Targets for Metal-based drugs
• Targets include:
– Metalloenzyme inhibition
– insulin mimetics
– nitric oxide and superoxide, carbon
monoxide
– antimicrobials
• Vanadium(IV) complex as an insulin
mimic
Metals and Depression
• Manic depression affects up to 1% of the world population and
is currently treated using lithium ion therapy
• Lithium is VERY toxic Binding Binding
-thought to be an
inhibitor in inositol
monophosphatase
• Strong need to
replace it with a
Binding
safer alternative Catalytic
Enzyme
Interactions of inositol monophosphate at the enzyme active site
Polyoxomolybdate Drugs
• Polyoxomolybdates are synthesised by acidification of
molybdate [MoO4]2- :
7[MoO4]2- + 8H+ [Mo7O24]6- + 4H2O
8[MoO4]2- + 12H+ [Mo8O26]4- + 6H2O >H+
36[MoO4]2- + 64H+ [Mo36O112]8- + 32H2O
MoO6 Octahedra Corner sharing Edge sharing
Species are formed with shared polyhedra; basic units include {MoO6} octahedra
joined by shared corners and edges and some {MoO4} tetrahedra; the {Mo36}
species also contains pentagonal bipyramids.
Hetero-polyanions e.g keggin ion
• 12[MoO4]2- + 8HPO42-+ 23H+ [PMo12O40]3- +12H2O
• Here the P acts as a tetrahedral template
• Keggin ion Chemistry is also very diverse and
interesting.
POMs have many Structural Types
{Mo6} {Mo6} {Mo12} {Mo18}
{Mo8}
Lindqvist Anderson Keggin Dawson
{Mo150} {Mo186}
POMs are excellent potential drugs
• Some Keggin-like ions show activity against many viruses
including HIV
– POMS appear to have be extremely good anti-virals
– Can penetrate cell membranes!
– Mechanism appears to relate to redox behaviour of Mo-POMS
– Drawback – early studies showed a great deal of side effects..
