Ruth Duncanduncanr@cf.ac.uk

Polymer Therapeutics as Nanomedicines Converging scientific disciplines bringing huge opportunities,

but how to ensure healthcare benefits ?

29th April 2009

2

"Nano" medicine"Nano" medicine

3How New ??

4

"Medicinal products containing nanoparticles have already been authorised both in EU and the US under the existing regulatory frameworks"

••quality quality ••safety safety ••efficacy efficacy ••risk management risk management

5www.esf.org

6

polymer micelles

Polymer-protein and -drug conjugates

Antibodyconjugates

Liposomes

NanoparticlesNanoparticles

1970s 1980s 1990s 2000s

MylotargTM

AbraxaneTM

Evolution of Nanomedicines - drug targeting and controlled releaseEvolution of Nanomedicines - drug targeting and controlled release

NeulastaTM

PEG-interferon �

XYOTAXTM; OPAXIOTM

SP1049C

Doxil®,Caelyx®�

dendrimers

2008

nanocrystals oral

SMANCS,Oncospar®�

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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

Polymer TherapeuticsPolymer Therapeutics

3-20 nm

60-200 nm

-- polymers as drugspolymers as drugs

-- polymerpolymer--protein protein conjugatesconjugates

-- polymerpolymer--drugdrugconjugatesconjugates

-- block copolymerblock copolymermicelles to whichmicelles to whichdrug is covalentlydrug is covalentlyboundbound

-- polyplexes containingpolyplexes containingcovalent linkerscovalent linkers

Nature Rev. Drug Discov. (2003)Nature Rev. Drug Discov. (2003)Nature Rev. Cancer (2006)Nature Rev. Cancer (2006)

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Polymeric Drug Delivery Systems

Ed. G.S. Kwon

Marcel Dekker, Inc., New York

Polymeric Drug Delivery Systems

Ed. G.S. Kwon

Marcel Dekker, Inc., New York

ScientificCommunication

10

Ringsdorf Model 1975

Targeting Residues

Imaging Agentgamma camera

Drug and Drug Combinations

6 - 20 nm

Lab ClinicPolymer-drug and

Polymer-Protein conjugatesPolymer-drug and

Polymer-Protein conjugates

Anticancer agents

Linker

11

divergentconvergent

Dendrimers

polymer

linker

protein

drug

Targeting residue

2. Polymer-Protein Conjugates

6 nm - 20 nmby SANS

At least Two Primary Metabolites

May form a Unimolecular micelle(or other structures) in solution

1. Polymer-Drug Conjugates

3. Bioresponsive endosomolytic polymers for cytosolic delivery

Imaging agent

12

Rationale for design

polymer

linker

drug/protein

targeting group

imaging agent

Tools

Pharmacokinetics

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)

Methods for physico-chemicalcharacterisation

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Biocompatibility

BiologicalEnvironment

Materialor Device

Biological Environment

Toxicology

MaterialOr Drug

Biological

Environment

adverseeffect

adverse or beneficialeffect on material

performance

adverseeffect

OROR

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environment accidental human purposeful human

Ensuring sensible choice of materials suitable for human use.....

GLP Preclin Tox

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(c) PAMAM 10 (c) PAMAM 10 µµg/mlg/ml (d) PAMAM 1 mg/ml(d) PAMAM 1 mg/ml

(a) DAB 10 (a) DAB 10 µµg/mlg/ml (a) DAB 1 mg/ml(a) DAB 1 mg/ml

(d) Control(d) Control

(a) Control(a) Control (b) PAMAM gen 4; 10(b) PAMAM gen 4; 10µµg/mLg/mL

(d) PAMAM gen 3.5; 1 mg/mL(d) PAMAM gen 3.5; 1 mg/mL(c) PAMAM gen 4; 1 mg/mL(c) PAMAM gen 4; 1 mg/mL

About 90 % of materials being proposed are unsuitable for proposed use proposed use …….. Reflect on safety and suitability for manufacture early

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Duncan Nature Reviews Cancer (September 2006)

Current Understanding of the Mechanism of Action of Polymer-Anticancer Conjugates

Importance of PharmacokineticsImportance of Pharmacokinetics

17

N M L S MicFractions

Dox

orub

icin

-equ

ival

ence

(�g/

mg

prot

ein)

***

*****

NS

0

1

2

3

4

N M L S MicFractions

Dox

orub

icin

(�g/

mg

prot

ein)

***

** **

0

50

100

150

200(a)

(b)

Doxorubicin

HPMA-DOX

FITC-dextran

Overlay FITC-dextran/PK1

HPMA -DOX

8 �m

2 �m

Quantitation of Intracellular Localisation

Manunta et al. (2007) J. Drug Targeting, Manunta et al. (2007) J. Drug Targeting, 15(1): 3715(1): 37––5050Seib, et al. (2007) J. Controlled Release, 17, 291Seib, et al. (2007) J. Controlled Release, 17, 291--300.300.Seib et al. (2006) J. Drug Targeting 14, 375Seib et al. (2006) J. Drug Targeting 14, 375--90. 90.

Nature 2007 Volume 447 Number 7141 The good, the bad and the ugly p138 Imaging fluorescent molecules in live cells is revolutionizing cell biology. But a pretty image is not necessarily a good one, and many biologists are learning this the hard way, finds Helen Pearson.

1010.10.010.0010.0001

50

100

150

200

250

300

350

400

Concentration (doxorubicin-equiv. mg/ml)

Fluo

resc

ence

(AU

) Dox

HPMA-Dox

0.4 �mol/l0.30.20.10

5000

10000

15000

20000

25000

Fluo

resc

ence

(AU

)

FITC-Dextran

4 �g/ml3210

pH 7.4

pH 6.4

pH 5.4

pH 4.0

(a)

DoxDox

FITCFITC

Blood clearance of free DOX and the DOX delivery systems: administered at equi-dose dose (5 mg/kg)

Time (h)

Leve

ls in

blo

od (%

dos

e)

100806040200

DOX

DOXILTM

PK1

PAMAM (gen 3,5) Dendrimer-DOX

.01

.1

1

10

100

B16F10 tumour uptake of free DOX and the DOX delivery systems : administered at equi-dose dose (5 mg/kg)

Time (h)

Tum

our a

ccum

ulat

ion

(% d

ose/

g tu

mou

r)

8060402000

5

10

15

PK1

DOXILTM

PAMAM (gen 3,5) Dendrimer-DOX

DOX

clinical dose 60 mg/mclinical dose 60 mg/m22

clinical dose 280 mg/mclinical dose 280 mg/m22

Yee Nee Sat, et al.Yee Nee Sat, et al.

In Vivo PharmacokineticsIn Vivo PharmacokineticsPassive TARGETING RELIES ON PLASMA CONCENTRATIONPassive TARGETING RELIES ON PLASMA CONCENTRATION

Duncan et al, (1986) BBA, 880,62Seymour et al (1987) J Biomed Mater Res 21,1341Seymour et al., (1994) Brit J Cancer; (1995) Eur J CancerNoguchi et al (1998) Japanese J Cancer Res

clinical dose 60clinical dose 60--80 mg/m80 mg/m22

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Development of polymer conjugatesDevelopment 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

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21

Mw ~30,000 g/molMw ~30,000 g/mol

GLY

GLY

-- PH

EP

HE

-- LEU

LEU

-- GLY

GLY

8 wt%8 wt%

FCE28068 FCE28068 HPMA Copolymer-doxorubicin

Phase I clinical and pharmacokinetic study of PK1 [N-(2-hydroxypropyl)methacrylamide copolymer doxorubicin]: first member of a new class of chemotherapeutic agents - drug-polymer 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.

Clinical Cancer Research 5, 83-94 (1999)

• Polymer conjugate was 4-5 fold fold less toxic than doxorubicin

• Activity seen in Breast and NSCLC

• HPMA was shown ‘safe’ as a new carrier

• Polymer conjugate was 4-5 fold fold less toxic than doxorubicin

• Activity seen in Breast and NSCLC

• HPMA was shown ‘safe’ as a new carrier

32030028026024022020018016014012010080604020000

1

2

3

4

5

6

Neutopenia

Thrombocytopenia M

ean

Gra

de o

f tox

icity

or M

ean

num

ber o

f Cyc

les

Dox Dose mg/m2

doxorubicin MTD 80 mg/m2 HPMA copolymer-doxorubicin

MTD 320 mg/m2

22

23

HPMA copolymer HPMA copolymer -Gly-Phe-Leu-Gly-doxorubicin-galactose

MTD280 mg/m2

MTD160 mg/m2 Dox-Equiv

Seymour et al. J. Clin. Oncol. 20, 1668 (2002)Seymour et al. J. Clin. Oncol. 20, 1668 (2002)Seymour et al. J. Clin. Oncol. 20, 1668 (2002)FCE28069 Phase I/II Trials

• 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

galactosegalactose

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I HPMA-R-AGM

aminoglutethimide

:Peptidyl linkers (Gly-Gly or Gly-Phe-Leu-Gly)R

O

NH

OH

HN

ONH

RO

HNO

z

NH

O

O

R

x

II HPMA-R-DOX

doxorubicin

ONH

RO

O

NH

OH

y

HO

O

OOHO

OH

OH

O

OHO

O

NH

HN

O

R

x

III HPMA-AGM-DOX

ONH

RO

O

NH

OH

y

HNHO

O

OOHO

OH

OH

O

OHO

O

NH

ONH

RO

HNO

z

NH HN

O

O

O

RR

x

50 KD75 KD

MCF7 caMCF7

MCF-7CaMCF-7Ca

0.1000.0500.0000

20

40

60

80

100

120

Dox concentration (mg/mL)

Cel

l Via

bilit

y (%

)

STATE OF ART IS STATE OF ART IS (i) drug combinations

VicentVicent et al. (2005) et al. (2005) AngewAngew. Chem. Int. Ed. 44, 2 . Chem. Int. Ed. 44, 2 ––6.6.Duncan et al. (2005) EDuncan et al. (2005) Endocrinendocrine--Related Cancer, 12, S189Related Cancer, 12, S189--S199. S199. Greco et al. (2005) Greco et al. (2005) J. Drug Targeting 13, 459J. Drug Targeting 13, 459--470.470.Greco et al. (2007) J. Controlled Release 117, 28Greco et al. (2007) J. Controlled Release 117, 28--39.39.

• Bioresponsive polymer therapeutics for – wound repairarthritis, cancer, infectious diseases

• Need for interdisciplinary teams with early input from medical colleagues

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"Medicinal products containing nanoparticles have already been authorised both in EU and the USunder the existing regulatory frameworks"

•• Although Although nanosizingnanosizing does not necessarily imply novelty, it is expected that does not necessarily imply novelty, it is expected that nanotechnology will yield innovative products. nanotechnology will yield innovative products.

•• Such products could span the regulatory boundaries between mediSuch products could span the regulatory boundaries between medicinal products cinal products and medical devices, challenging current criteria for classificaand medical devices, challenging current criteria for classification and evaluation. tion and evaluation.

•• Appropriate expertise will need to be Appropriate expertise will need to be mobilisedmobilised for the evaluation of the for the evaluation of the quality, quality, safety, safety, efficacy and risk management efficacy and risk management

of of nanomedicinalnanomedicinal products and the need for products and the need for new or updated guidelines new or updated guidelines will be will be reviewed in the light of accumulated experience.reviewed in the light of accumulated experience.

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SpecificSpecific-Specification

-justification in respect of toxicity/efficacy

- Reproducible Manufacture of Complex Systems- Validated techniques – quality of validation

- assessment of key parameters

ISSUESISSUES

GeneralGeneral

• Terminology – what is nano ? – what is a product ?• Boundaries ….. Drug delivery…device…diagnostic