SYNTHESIS AND CHARACTERIZATION OF IODINATED POLYMER NANOPARTICLES - - PowerPoint PPT Presentation

This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 643694

SYNTHESIS AND CHARACTERIZATION OF IODINATED POLYMER NANOPARTICLES AND USE AS A CONTRAST AGENT FOR TOMOGRAPHY USING A SPECTRAL SCANNER

NANOHYBRIDES 14 –CORSICA 31/05/2017

Joëlle Balegamire1*, Salim Si-Mohamed2,4, Daniel Bar-Ness2,3, Yves Chevalier1, Hatem Fessi1, Monica Sigovan2,4, Marc Vandamme5, Emmanuel Chereul5, Loïc Boussel2,4, Philippe Douek2,4

1LAGEP, CNRS UMR 5007, UCB Lyon 1, 69622 Villeurbanne, France 2CREATIS, CNRS UMR 5220, INSERM U630, UCB Lyon 1, 69621 Villeurbanne, France 3CERMEP, 69677 Bron, France 4Hospices Civils de Lyon, Radiology Department, 69677 Bron, France 5VOXCAN, 69280 Marcy-l'Étoile, France

Meeting Date 2

SPCCT PROJECT OBJECTIF :

Develop and validate a new in-vivo imaging technology combining:

• Spectral Photon Counting Computed Tomography (SPCCT)
• Specific Contrast Agents based on iodinated polymer materials as

nanoparticles

For an improved detection and monitoring of cardiovascular and neurovascular diseases

Meeting Date 3

STANDARD CT DUAL ENERGY CT SPECTRAL CT

• S. Si-Mohamed et al.,

Nuclear Inst. and Methods in Physics Research,A, http://dx.doi.org/10.1016/j. nima.2017.04.014

Meeting Date 4

SPECTRAL CT – Innovation:

• High spatial resolution acquisition system
• Photon counting detector → improved sensitivity
• Material Decomposition and K-edge reconstruction

SPCCT TECHNOLOGY

– Applications:

• Differentiation and classification of different

tissue types and CA (i.e Calcium in bones)

• Simultaneous discrimination between different

attenuation profiles > multiple-contrast agents imaging possible

• Contrast Agent quantification
• S. Si-Mohamed et al.,

Nuclear Inst. and Methods in Physics Research,A, http://dx.doi.org/10.1016/j. nima.2017.04.014

Meeting Date 5

IODINE BASED CONTRAST AGENTS

Iodine Based Agents = small iodinated molecules

• Short blood retention time
• Renal toxicity
• Non Specific in-vivo biodistribution

Iodine Based Agents = Nanoparticles  Prolonged blood circulation time (blood pool)  Specific targeting capabilities  Possible hybrid materials containing two radiopaque elements  Possible loading of NP with drugs

This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 643694

MATERIAL DEVELOPMENT

Meeting Date 7

SYNTHESIS OF IODINATED POLYMER

• 2,3,5-triiobenzoic chloride (synthtized from

2,3,5-triidobenzoic acid)

• Poly(vinyl alcohol) : Mw = 13 000 Da, 98%

hydrolyzed

• Iodine content : 71 wt% (1H NMR)

1H NMR (300 MHz, DMSO) spectra of PVAL (left) and PVAL_TIBCl (right)

Meeting Date 8

FABRICATION OF THE NANOPARTICLES

– Process: Nanoprecipitation ① Solution of iodinated polymer in THF is poured into H2O ② THF is eliminated under reduced pressure ① suspension of NPs of iodinated polymer in H2O – Nanoparticles properties:

• Core-shell structure
• Size measured by TEM : 80-120 nm

Iodinated polymer core PCL65-b-PEG113 shell (Dispersing agent)

Meeting Date 9

PROCESS PARAMETERS AND LIMITATIONS

– Parameters that control the Nanoprecipitation process:

• Choice of dispersing agent
• THF/H2O ratio
• Iodinated polymer/Dispersing Agent ratio
• Iodinated polymer content in THF

– Limitations :

• Highest iodine content: 15,6 mg(I)/mL
• Concentration must be ↑ for in-vivo biodistribution

studies

Meeting Date 10

TOWARDS INCREASING IODINE CONTENT

– Problem  ↑ iodine content BUT X ↑ nanoparticle size

50 100 150 200 250 300

0,0 2,0 4,0 6,0 8,0 10,0 12,0 14,0 16,0 18,0 size (nm) [mg/mL] of Iodine

Influence of iodine concentration on particle size (DLS)

Ref. process Redispers ion efficiency Concentr ation of Iodine in the final H2O solution (mg/mL) size average of 3 measurem ents (nm) Narrow size distribu tion JB43 Nanoprecipitat ion 1 Aggregat es of NP stuck to the ultracentr ifugation tube 7 82 yes (>95%) JB43 redispe rsion Centrifugation (10min, 50 000 rpm) / redispersion 35 81 No (<95%) JB48 Nanoprecipitat ion 2 easy 16 239 Yes (>95%) JB48 redispe rsion Centrifugation (45min, 20 000 rpm) / redispersion 85 221 Yes (>95%)

– Solution:

• Concentrate the sample without altering NP size
• Series of centrifugation/ redispersion

 Possibility to ↑Iodine content without altering NP size

This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 643694

RADIOPACITY AND SENSITIVITY

Calcium PBS Air Iodine

Meeting Date 12

ATTENUATION EVALUATION (HU)

– Radiopacity  Linear variation with respect to concentration – A Student test showed that there is no statistically significant difference between the two iodine based CA

y = 31,468x - 10,394 R² = 0,9998

• 100

100 200 300 400 500 2 4 6 8 10 12 14 16

HU mg (I)/mL expected

Iodine NPs Attenuation (HU)

y = 32,09x - 9,1726 R² = 0,9999

• 100

100 200 300 400 500 5 10 15 20

HU mg (I)/mL expected

Standard Iodine Attenuation (HU)

y = 41,493x - 8,0655 R² = 0,9997

• 100

100 200 300 400 500 600 700 5 10 15 20

HU mg (Gd)/mL expected

Standard Gadolinium Attenuation (HU)

Meeting Date 13

CONTRAST AGENT QUANTIFICATION USING SPCCT

– Good correlation between measured and expected concentrations – Measured concentration 20% error

y = 0,829x - 0,3147 R² = 0,9991

• 2

2 4 6 8 10 12 14 5 10 15 20 mg(I) / mL measured mg (I) /mL expected

Iodine NPs Material Decomposition [mg/mL element]

Iodine NPs MD y = 0,8321x - 0,3038 R² = 0,9994

• 2

2 4 6 8 10 12 14 5 10 15 20 mg (I) /mL measured mg(I)/mL expected

Standard iodine Material Decomposition [mg/mL element]

Standard Iodine MD y = 0,9154x - 0,2245 R² = 0,9991

• 2

2 4 6 8 10 12 14 16 5 10 15 20 mg(Gd)/mL measured mg(Gd)/mL expected

Gadolinium K-Edge images [mg/mL element]

Gadolinium K-Edge

Meeting Date 14

SENSITIVITY ASSESSMENT

– Detection limit on SPCCT for the 3 evaluated elements is ῀2 [mg/mL element] (SNR=2)

y = 1,6229x - 0,4308 y = 2,0666x - 0,9007

• 5

5 10 15 20 25 30 35 40 2 4 6 8 10 12 14 16

SNR mg (I)/mL

SNR of iodine atoms (Iodine Nanoparticles)

HU images Iodine NPs MD y = 1,7573x - 0,3148 y = 1,798x + 0,0876

• 5

5 10 15 20 25 30 2 4 6 8 10 12 14 16

SNR mg (I)/mL

SNR of iodine atoms (Standard Iodine Bracco Imeron )

HU images Standard Iodine MD y = 1,4653x + 1,8937 y = 0,5854x + 0,2307

• 5

5 10 15 20 25 30 2 4 6 8 10 12 14 16

SNR mg (I)/mL

SNR of Gadolinium atoms (Bracco Prohance)

HU images Standard Iodine MD

Meeting Date 15

MULTI-CONTRAST AGENT QUANTITATIVE SEPARATION VIA K-EDGE IMAGING USING SPCCT

– Spectral photon-counting images of a phantom containing :

• 2 mixed contrast agents: Iodine and Gadolinium
• 11 test tubes of different dilutions in water  all solutions had an attenuation of ~280HU

– Specific detection of the element  possibility of the specific labelling of ≠ parts of the body

Meeting Date 16

FUTURE STUDIES:

– Assessement of biodistribution In-Vivo – Grafting of targeting biomarkers on the surface of the nanoparticles (fibrin, elastin  atherosclerosis plaque) – Development of hybrid materials with two radiopaque elements – Incorporation of active ingredients into the nanoparticles of iodinated polymers : theranostic

ACKNOWLEDGEMENT S

This project has received funding from the EU's H2020 research and innovation program under the grant agreement No. 633937

ACKNOWLEDGEMENTS

Supervisors: Yves Chevalier Hatem Fessi Imaging engineers : Monica Sigovan Daniel Bar-Ness VOXCAN team: Marc Vandamme Emmanuel Chereul HCL Radiologist : Salim Si-Mohamed Philippe Douek Loic Boussel

• S. Si-Mohamed et al., Review of an initial experience with an

experimental spectral photon-counting computed tomography system, Nuclear Inst. and Methods in Physics Research,A, http://dx.doi.org/10.1016/j.nima.2017.04.014

ACKNOWLEDGEMENT S

THANKS FOR YOUR ATTENTION !

This project has received funding from the EU's H2020 research and innovation program under the grant agreement No. 633937