Amphiphile Self-Assembly Materials. Calum Drummond

Transcription

1 Amphiphile Self-Assembly Materials in anomedicine Calum Drummond Chief, CSIR Materials Science and Engineering

2 Why nano? - nanoparticles anoparticles may have a prolonged half life in systemic circulation cuato - slower so removal of foreign oeg patcesby particles reticuloendothelial system (RES) Particle size, endocytosis and Enhanced Permeability and Retention (EPR) effect Risk of vascular occlusion and embolisms may be reduced anoparticles can improve therapeutic outcomes because drugs can be delivered d directly to the tissue and in controlled doses related to the patient s personal requirement.

3 anoparticulate chemotherapy drugs EPR effect Particles > 10 nm can enter tumour tissue through imperfections of cancer vascularisation (Enhanced Permeability and Retention (EPR) effect) >300 nm - probably remain out of cells nm can potentially enter cells but not the nucleus 70 nm or smaller can potentially enter cell nuclei Duncan R. et al ature Reviews Drug Discovery, 347

4 Why nano? - nanoparticles

5 Why nano? - nanostructure anostructured materials can provide a matrix for the controlled release of drugs Diffusion out of matrix can depend on the geometry, porosity and tortuosity of the structure Possible to have different microenvironments within same material, eg hydrophobic, hydrophilic and interfacial domains, allowing different solubilising environments

6 Therapeutic window

7 Why small molecule amphiphile (lipid) self-assembly materials? Potentially very easy to manufacture Particle size and geometry controllable to some extent Potentially ti low toxicity it and good biocompatibility anostructure provides encapsulation at media and controlled release matrix amphiphile p structure

8 Amphiphile Self-Assembly: Key Questions What drives amphiphile self-assembly? What controls the amphiphile p self- assembly structures that are formed? How can we best utilize amphiphile self- assembly structures in applications?

9 anostructured anoparticles of Self-Assembled Amphiphiles Cubosome (Q 2 ) Hexosome(H 2 )

10 Cubosomes and Hexosomes Cubosome (Q 2 ) Hexosome (H 2 )

11 Amphiphile Self-Assembly: Controlling Structure Factors to consider Local constraints: t Global constraints: van der Waals effective volume fraction electrostatic steric hydrogen bonding

12 Urea H 2 H : First organic molecule synthesized in a laboratory (Frank Wohler). I iti t d f i Initiated age of organic molecular science.

13 Melting Points: n-alkyl Urea Amphiphiles Versus n-alkanes 150 Me elting point ( C) n-alkanes umber of Carbon atoms R H H R R H H R R H H R R H H R R H H R

14 Can Urea be Used as an Amphiphile Headgroup? Three approaches were tried to ameliorate the hydrogen bonding. We introduced headgroup positional isomerism along the alkyl chain; unsaturation in the alkyl chain; and iso-prenoid branching in the alkyl chain. f C. Fong et al. Chemistry of Materials 2006, 18, ; J. Phys. Chem. B 2006, 110, ; J. Phys. Chem. B 2006, 110,

15 on-linear Urea-Based Amphiphiles H 2 H leyl urea H 2 H Linoleyl urea H 2 H Phytanyl urea H 2 H H-Farnesyl urea

16 H-Farnesylurea - Water System

17 H-Farnesylurea - Water System: Inverse Hexagonal Phase SAXS HII a = 34 Å 1 I (arbitary units s) I 3 4 * * x q (1/Angstrom)

18 Drug Release from Bulk Inverse Hexagonal Phase of a Self-Assembled Amphiphile Sustained release of anti cancer agents irinotecan base/hcl (hydrophilic) and paclitaxel (lipophilic) from bulk hexagonal phase 25 IriHCl Iri Base Paclitaxel 20 % Released International PCT applications: W 2004/ A Time (h) W 2005/ A1

19 Capecitabine Xeloda

20 Capecitabine Xeloda Prodrug Intestine Liver Tumor Tissue Capecitabine H 3 C H H F H Capecitabine Carboxylesterase H 3 C H H 2F H H H 3 C H 5'-dFCyd Cytidine Deaminase H F 5'dFUrd 5'-dFCyd 5'dFUrd H H Cytidine Deaminase Thymidine Phosphorylase F 5-FU

21 Amphiphile Pro-Drug Homologues of Capecitabine as Controlled Release Matrices for Chemo-Therapy H 3 C H H H F Soluble H 3 C H H F H Crystalline Lamellar H F H F H 3 C H H H 3 C Cubic (Q 2 ) Hexagonal (H 2 ) H H

22 Amphiphile Pro-Drug Homologues of Capecitabine as Controlled Release Matrices for Chemo-Therapy FCPhy 5-FCPal 5-FCle Intensity Size (d nm)

23 Controlling Drug Release Rates 5 FCleyl (Cubosome) Capecitabine (o Self Assembly) FCPhytanyl (Cubosome) % Convers sion FCPalmityl (SL) Reaction Time (Hours)

24 Enzyme hydrolysis steps for 5-FC prodrugs STEP 1: Liver Carboxylesterase 5 -DFCR STEP 2: Liver Tumour Cytidine Deaminase 5 -DFUR STEP 3: Tumour Thymidine Phosphorylase 5-FU

25 In vivo 5-FC Prodrug Amphiphile Studies

26 In vivo 5-FC Prodrug Amphiphile Studies In vivo 4T1 Tumour Growth 5 FCle 5 FCPhy Cap Cont 900 (mm 3 ) Control Capecitabine 5-FC Phytanoyl 5-FC leoyl Tum mour Volume Excised Tumours 5 FCle 5 FCPhy Cap Cont Days Excised Spleens

27 In vivo 5-FC Prodrug Amphiphile Studies Xenograft Tumour Growth 90 Average Tumour size (mm 3 ) Control 1.0 mmol/day 5-FC leoyl 0.75 mmol/day 5-FC leoyl International PCT application: W 2010/ A1 Days

28 Self-Assembled Amphiphiles as Potential Magnetic Resonance Imaging (MRI) Contrast Agents MRI non-invasive diagnostic Contrast agents positive & negative relaxivity (r and r 2, mm s )

29 Gadolinium(III)-based contrast agents Limitations: Low efficacy onspecificity It is important to develop a new generation of MRI contrast agents with increased efficacy and enhanced specificity.

30 Factors controlling relaxivity Relaxivity = Inner sphere relaxivity (R 1p IS ) + uter sphere relaxivity (R 1p S ) Diffusion time of H 2 in outer sphere Mean residence time of H 2 in inner sphere Molecular rotation correlation time Electron paramagnetic relaxation time, T 1e and T 2e q Jacques, V. and Desreux, Top. Curr. Chem., 2002, 221, 123 Lowe, M.P., Aust. J. Chem., 2002, 55, 551 (q: number of bound water molecules)

31 Chelating amphiphiles used in our studies H H H H H H H H H H

32 Relaxivities of EDTA and DTPA conjugates complexed with Mn, Gd, and Eu measured at 20 MHz T1 ( msec) T2 (msec) r1(mm -1 Sec -1 ) r2(mm -1 Sec -1 ) DTPA -MP- 80.5, ; Mn (10 mm) DTPA -MP- 8.3; ; ~ Gd (10 mm) DTPA -MP- 1360; ; ~ ~0.18 EU (10 mm) DTPA -DP- 36.7; ; ~7.8 Mn (5mM) DTPA -DP- 21.1; ; ~ ~14.0 Gd (5mM) DTPA -DP- 1740; ; ~ Eu (5mM) EDTA -M Gd EDTA -Gd Magnevist DTPA -Gd ~3.5 -

33 Multifunctional nanoparticulate biomedical agents

34 Acknowledgements Celesta Fong Irena Krodkiewska Asoka Weerawardena Darrell Wells Lynne Waddington Guozhen Liu Patrick Hartley Xavier Mulet Charlotte Conn elly Gong Sharon Sagnella Minoo Moghaddam Thomas Kaasgaard Ben Boyd (Monash)

35 Thank you Calum J. Drummond CSIR Materials Science and Engineering (CMSE) Phone: calum.drummond@csiro.au Web: