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 Balegamire 1* , Salim Si-Mohamed 2,4 , Daniel Bar-Ness 2,3 , Yves Chevalier 1 , Hatem Fessi 1 , Monica Sigovan 2,4 , Marc Vandamme 5 , Emmanuel Chereul 5 , Loïc Boussel 2,4 , Philippe Douek 2,4 1 LAGEP, CNRS UMR 5007, UCB Lyon 1, 69622 Villeurbanne, France 2 CREATIS, CNRS UMR 5220, INSERM U630, UCB Lyon 1, 69621 Villeurbanne, France 3 CERMEP, 69677 Bron, France 4 Hospices Civils de Lyon, Radiology Department, 69677 Bron, France 5 VOXCAN, 69280 Marcy-l'Étoile, France This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 643694
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 2
SPECTRAL CT STANDARD CT DUAL ENERGY 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 3
SPCCT TECHNOLOGY SPECTRAL CT – Innovation: • High spatial resolution acquisition system • Photon counting detector → improved sensitivity • Material Decomposition and K-edge reconstruction – 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 4
IODINE BASED CONTRAST AGENTS Iodine Based Agents Iodine Based Agents = = small iodinated molecules Nanoparticles Prolonged blood circulation time (blood pool) - Short blood retention time Specific targeting capabilities - Renal toxicity Possible hybrid materials containing two - Non Specific in-vivo biodistribution radiopaque elements Possible loading of NP with drugs Meeting Date 5
MATERIAL DEVELOPMENT This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 643694
SYNTHESIS OF IODINATED POLYMER • 2,3,5-triiobenzoic chloride (synthtized from 2,3,5-triidobenzoic acid) • Poly(vinyl alcohol) : M w = 13 000 Da, 98% hydrolyzed • Iodine content : 71 wt% ( 1 H NMR) 1 H NMR (300 MHz, DMSO) spectra of PVAL (left) and PVAL_TIBCl (right) Meeting Date 7
FABRICATION OF THE NANOPARTICLES – Process: Nanoprecipitation ① Solution of iodinated polymer in THF is poured into H 2 O ② THF is eliminated under reduced pressure ① suspension of NPs of iodinated polymer in H 2 O – Nanoparticles properties: • Core-shell structure Iodinated polymer core PCL 65 -b-PEG 113 shell (Dispersing agent) • Size measured by TEM : 80-120 nm Meeting Date 8
PROCESS PARAMETERS AND LIMITATIONS – Parameters that control the Nanoprecipitation process: • Choice of dispersing agent • THF/H 2 O 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 9
TOWARDS INCREASING IODINE CONTENT – Solution: – Problem • Concentrate the sample without altering NP size ↑ iodine content BUT • Series of centrifugation/ redispersion X ↑ nanoparticle size Concentr ation of size Narrow 300 Redispers Iodine in average of size Ref. process ion the final 3 distribu 250 efficiency H 2 O measurem tion 200 solution ents (nm) size (nm) (mg/mL) 150 Nanoprecipitat yes JB43 7 82 ion 1 Aggregat (>95%) 100 es of NP 50 Centrifugation stuck to JB43 (10min, 50 the No 0 redispe 35 81 000 rpm) / ultracentr (<95%) 0,0 2,0 4,0 6,0 8,0 10,0 12,0 14,0 16,0 18,0 rsion [mg/mL] of Iodine redispersion ifugation tube Influence of iodine concentration on particle size (DLS) Nanoprecipitat Yes JB48 16 239 ion 2 (>95%) Possibility to ↑Iodine content without Centrifugation JB48 easy (45min, 20 Yes redispe 85 221 000 rpm) / (>95%) altering NP size rsion redispersion Meeting Date 10
Air PBS Calcium Iodine RADIOPACITY AND SENSITIVITY This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 643694
ATTENUATION EVALUATION (HU) Iodine NPs Attenuation (HU) Standard Iodine Attenuation (HU) 500 500 400 400 300 300 HU HU 200 200 100 100 0 0 0 2 4 6 8 10 12 14 16 0 5 10 15 20 -100 -100 mg (I)/mL expected mg (I)/mL expected y = 31,468x - 10,394 y = 32,09x - 9,1726 R² = 0,9998 R² = 0,9999 – Radiopacity Linear variation with Standard Gadolinium Attenuation (HU) 700 respect to concentration 600 500 400 – A Student test showed that there is no HU 300 200 statistically significant difference between 100 0 the two iodine based CA 0 5 10 15 20 -100 y = 41,493x - 8,0655 mg (Gd)/mL expected R² = 0,9997 Meeting Date 12
CONTRAST AGENT QUANTIFICATION USING SPCCT Standard iodine Material Decomposition [mg/mL Iodine NPs Material Decomposition [mg/mL element] element] 14 14 12 12 mg(I) / mL measured 10 10 mg (I) /mL measured 8 8 6 6 4 4 2 2 0 0 0 5 10 15 20 -2 0 5 10 15 20 mg (I) /mL expected -2 y = 0,8321x - 0,3038 y = 0,829x - 0,3147 mg(I)/mL expected Standard Iodine MD Iodine NPs MD R² = 0,9994 R² = 0,9991 Gadolinium K-Edge images [mg/mL element] – Good correlation between measured 16 14 mg(Gd)/mL measured 12 and expected concentrations 10 8 – 6 Measured concentration 20% error 4 2 0 0 5 10 15 20 -2 y = 0,9154x - 0,2245 mg(Gd)/mL expected Gadolinium K-Edge R² = 0,9991 Meeting Date 13
SENSITIVITY ASSESSMENT SNR of iodine atoms (Iodine Nanoparticles) SNR of iodine atoms (Standard Iodine Bracco 40 Imeron ) 35 30 30 25 25 20 20 SNR 15 15 SNR 10 10 5 5 0 0 0 2 4 6 8 10 12 14 16 -5 0 2 4 6 8 10 12 14 16 -5 mg (I)/mL mg (I)/mL y = 1,6229x - 0,4308 y = 2,0666x - 0,9007 y = 1,7573x - 0,3148 y = 1,798x + 0,0876 HU images Iodine NPs MD HU images Standard Iodine MD SNR of Gadolinium atoms (Bracco Prohance) – Detection limit on SPCCT for the 3 30 25 evaluated elements is ῀ 2 [mg/mL 20 15 element] (SNR=2) SNR 10 5 0 0 2 4 6 8 10 12 14 16 -5 mg (I)/mL y = 1,4653x + 1,8937 y = 0,5854x + 0,2307 HU images Standard Iodine MD Meeting Date 14
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 15
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 Meeting Date 16
ACKNOWLEDGEMENTS HCL Radiologist : Imaging engineers : VOXCAN team: Supervisors: ACKNOWLEDGEMENT Salim Si-Mohamed Monica Sigovan Marc Vandamme Yves Chevalier S Philippe Douek Daniel Bar-Ness Emmanuel Chereul Hatem Fessi 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 This project has received funding from the EU's H2020 research and innovation program under the grant agreement No. 633937
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
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