29th April 2009
Polymer Therapeutics as Nanomedicines
Converging scientific disciplines bringing huge opportunities,
but how to ensure healthcare benefits ?
Ruth Duncan
[email protected]
"Nano" medicine
2
How New ??
3
"Medicinal products containing nanoparticles have
already been authorised both in EU and the US under
the existing regulatory frameworks"
•quality
•safety
•efficacy
•risk management
4
www.esf.org
5
Evolution of Nanomedicines -- drug
drug targeting
targeting and
and controlled
controlled release
release
1970s
1980s
1990s
2008
2000s
Doxil®,Caelyx®
nanocrystals oral
Liposomes
Polymer-protein
and -drug
conjugates
SMANCS,
Oncospar®
PEG-interferon
NeulastaTM
XYOTAXTM;
OPAXIOTM
MylotargTM
Antibody
conjugates
Nanoparticles
polymer
micelles
dendrimers
SP1049C
AbraxaneTM
6
Many muticomponent systems have been
described
Duncan R (2005) Targeting and intracellular delivery of drugs.
In: Encyclopedia of Molecular Cell Biology and Molecular Medicine, R. A. Meyers (Ed); WILEY-VCH Verlag,
GmbH & Co. KGaA, Weinheim, Germany, pp 163-204
7
Nature Rev. Drug Discov. (2003)
Polymer
Therapeutics
Polymer Therapeutics Nature Rev. Cancer (2006)
- polymers as drugs
- polymer-protein
conjugates
3-20 nm
- polymer-drug
conjugates
60-200 nm
- block copolymer
micelles to which
drug is covalently
bound
- polyplexes containing
covalent linkers
Scientific
Communication
Polymeric Drug
Drug
Polymeric
Delivery Systems
Systems
Delivery
Ed. G.S.
G.S. Kwon
Kwon
Ed.
Marcel Dekker,
Dekker, Inc.,
Inc., New
New
Marcel
York
York
9
Ringsdorf Model 1975
Anticancer agents
Lab
Polymer-drug
Polymer-drugand
and
Polymer-Protein
Polymer-Proteinconjugates
conjugates
Clinic
Targeting Residues
Imaging Agent
gamma camera
Linker
Drug and Drug Combinations
6 - 20 nm
10
Dendrimers
1. Polymer-Drug Conjugates
May form a Unimolecular micelle
(or other structures) in solution
convergent
At least Two Primary
Metabolites
divergent
6 nm - 20 nm
by SANS
polymer
linker
protein
2. Polymer-Protein Conjugates
drug
Targeting
residue
Imaging
agent
3. Bioresponsive endosomolytic polymers
for cytosolic delivery
11
Preclinical evaluation of polymer-bound doxorubicin
Duncan, R., Seymour, L.W., O'Hare, K.B., Flanagan, P.A., Wedge, S., Hume, I.C., Ulbrich, K., Strohalm, J., Subr, V.,
Spreafico, F., Grandi, M., Ripamonti, M., Farao, M., Suarato, A
Journal of Controlled Release 19, 331-346 (1992)
Rationale for design
Tools
polymer
linker
drug/protein
targeting group
Pharmacokinetics
imaging agent
Methods for physico-chemical
characterisation
12
Biocompatibility
Biological
Environment
adverse or
beneficial
effect on
material
performance
Material
or Device
adverse
effect
Toxicology
Material
Or Drug
adverse
effect
OR
Biologica
l
Environme
nt
Biological
Environment
13
Ensuring sensible choice of materials suitable for human use.....
environment
accidental human
purposeful human
GLP Preclin Tox
14
About 90 % of materials being proposed are unsuitable for proposed use
…….. Reflect on safety and suitability for manufacture early
(a) DAB 10 µg/ml
(a) Control
(b) PAMAM gen 4; 10µ
10µg/mL
(c) PAMAM 10 µg/ml
(c) PAMAM gen 4; 1 mg/mL
(a) DAB 1 mg/ml
(d) PAMAM 1 mg/ml
(d) PAMAM gen 3.5; 1 mg/mL
(d) Control
15
Current Understanding of the Mechanism of Action of Polymer-Anticancer Conjugates
Duncan Nature Reviews Cancer (September 2006)
Importance of Pharmacokinetics
16
Nature
07Volume
20
umber
447
7141
N
Quantitation of Intracellular Localisation
The good, the bad
p1
38
and the ugly
Imag
ingluorescen
f
t mo
leculesinlivecell
sisrevo
lution
izing ce
ll biology.
Buta
pretty
image
isno
t necessar
ilyagood
one,
and nma
ybiolog
istsarelear
ning
this th
e hard
way
, find
sHelen Pearson.
200
(a)
***
Doxorubicin
150
FITC-dextran
**
350
Fluorescence (AU)
**
50
Doxorubicin-equivalence ( g/mg protein)
0
N
M
L
Fractions
S
Mic
(b)
***
2
150
HPMA-Dox
0.01
0.1
1
10
Concentration (doxorubicin-equiv. mg/ml)
m
8
FITC
FITC
m
25000
***
(a) FITC-Dextran
pH 7.4
20000
1
0
200
0.0001 0.001
3
2
250
50
HPMA-DOX
**
Dox
300
100
Overlay FITC-dextran/PK1
4
Dox
Dox
400
100
NS
N
M
L
Fractions
S
Mic
Manunta et al. (2007) J. Drug Targeting, 15(1): 37–
37–50
Seib, et al. (2007) J. Controlled Release, 17, 291291-300.
Seib et al. (2006) J. Drug Targeting 14, 375375-90.
Fluorescence (AU)
Doxorubicin ( g/mg protein)
HPMA -DOX
15000
pH 6.4
10000
5000
pH 5.4
pH 4.0
0
0.1
0.2
0.3
0.4
0
1
2
3
4
mol/l
g/ml
17
In Vivo Pharmacokinetics
Passive TARGETING RELIES ON PLASMA CONCENTRATION
B16F10 tumour uptake of free DOX and the
DOX delivery systems : administered at equidose dose (5 mg/kg)
10
DOXILTM
15
Tumour accumulation
(% dose/g tumour)
Levels in blood (% dose)
Blood clearance of free DOX and the DOX
delivery systems: administered at equi-dose
100 dose (5 mg/kg)
clinical dose 60 mg/m2
DOXILTM
10
PK1
1
PAMAM (gen 3,5)
Dendrimer-DOX
.1
clinical dose 280 mg/m2
5
PK1
DOX
.01
0
20
40
60
80
PAMAM (gen 3,5)
Dendrimer-DOX
100
0
0
20
40
60
80
DOX
Time (h)
Time (h)
Duncan et al, (1986) BBA, 880,62
Seymour et al (1987) J Biomed Mater Res 21,1341
Seymour et al., (1994) Brit J Cancer; (1995) Eur J Cancer
Noguchi et al (1998) Japanese J Cancer Res
clinical dose 6060-80 mg/m2
Yee Nee Sat, et al.
Development of polymer conjugates
• Terminology for description of polymer conjugates
• Manufacture of reproducible chemistry on large scale
• Validated techniques for determination of
- product identity
- strength
- Mw and polydispersity
• Setting an appropriate specification -safety/efficacy
• Formulation development
• Preclinical toxicology - safety studies
• Clinical protocol design
19
20
Phase I clinical and pharmacokinetic study of PK1 [N-(2-hydroxypropyl)methacrylamide
copolymer doxorubicin]: first member of a new class of chemotherapeutic agents - drugpolymer conjugates. Vasey P., Kaye S.B., Morrison, R., Twelves, C., Wilson, P., Duncan R, Thomson A.H.,
Murray, L.S., Hilditch, T.E., Murray, T., Burtles, S., Fraier, D., Frigerio, E. and Cassidy, J.
Mw ~30,000
g/mol
Clinical
Cancer Research 5, 83-94 (1999)
doxorubicin
MTD 80 mg/m2
HPMA copolymer-doxorubicin
MTD 320 mg/m2
Mean Grade of toxicity
GLY-PHEPHE-LEULEU-GLY
GLY-
or Mean number of Cycles
6
5
4
Neutopenia
3
2
Thrombocytopenia
1
8 wt%
0
0
20 40 60 80 100 120 140 160 180 200 220 240 260 280 300 320
Dox Dose mg/m2
•• Polymer
Polymer conjugate
conjugate was
was 4-5
4-5 fold
fold fold
fold
less
toxic
than
doxorubicin
less toxic than doxorubicin
•• Activity
Activity seen
seen in
in Breast
Breast and
and NSCLC
NSCLC
FCE28068
HPMA Copolymer-doxorubicin
•• HPMA
HPMA was
was shown
shown ‘safe’
‘safe’ as
as aa new
new
carrier
carrier
21
22
FCE28069 Phase I/II Trials
Seymour
Seymouret
etal.
al.J.
J.Clin.
Clin.Oncol.
Oncol.20,
20,1668
1668(2002)
(2002)
HPMA copolymer -Gly-Phe-Leu-Gly
-doxorubicin-galactose
MTD
280 mg/m2
MTD
160 mg/m2 Dox-Equiv
galactose
• Polymer conjugate was 2 fold less toxic than
doxorubicin
• Liver targeting confirmed – via asialoglycoprotein
receptor on hepatocytes
• Activity seen in hepatocellular carcinoma
• HPMA was shown ‘safe’ as a new carrier
23
STATE OF ART IS (i) drug combinations
Vicent et al. (2005) Angew.
Angew. Chem. Int. Ed. 44, 2 –6.
Duncan et al. (2005) Endocrine
Endocrine--Related Cancer, 12, S189S189-S199.
Greco et al. (2005) J. Drug Targeting 13, 459459-470.
Greco et al. (2007) J. Controlled Release 117, 2828-39.
MCF-7Ca
MCF-7Ca
II HPMA-R-DOX
III HPMA-AGM-DOX
Cell Viability (%)
I HPMA-R-AGM
120
z
O
NH
O
R
R
x
O
y
O
NH
NH
OH
NH
O
HN
x
O
O
R
R
HN
NH
O
HN
OH O
O
OH O
80
60
40
O
HO
NH
20
O
O
O
aminoglutethimide
OH
HN
O
HO
HO
O
O
O
HN
100
NH
R
R
NH
O
HO
NH
O
OH
R
R
y
O
NH
O
O
z
O
NH
x
O
OH O
O
00.000
HO
HO
HN
O
OH O
0.050
0.100
Dox concentration (mg/mL)
MCF7
O
MCF7 ca
doxorubicin
50 KD
75 KD
R :Peptidyl linkers (Gly-Gly or Gly-Phe-Leu-Gly)
24
• Bioresponsive polymer therapeutics for – wound repair
arthritis, cancer, infectious diseases
• Need for interdisciplinary teams with early input from medical colleagues
"Medicinal products containing nanoparticles have
already been authorised both in EU and the US
under the existing regulatory frameworks"
• Although nanosizing does not necessarily imply novelty, it is expected that
nanotechnology will yield innovative products.
• Such products could span the regulatory boundaries between medicinal products
and medical devices, challenging current criteria for classification and evaluation.
• Appropriate expertise will need to be mobilised for the evaluation of the
quality,
safety,
efficacy and risk management
of nanomedicinal products and the need for new or updated guidelines will be
reviewed in the light of accumulated experience.
27
ISSUES
General
• Terminology – what is nano ? – what is a product ?
• Boundaries ….. Drug delivery…device…diagnostic
Specific
-Specification
-justification in respect of toxicity/efficacy
- Reproducible Manufacture of Complex Systems
- Validated techniques – quality of validation
- assessment of key parameters
28