Radioiodinated choline analogues as theranostics for cancer
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1 Radioiodinated choline analogues as theranostics for cancer Milos Petrik, Pavel Svec, Martin Hruby, Jan Kucka, Ondrej Sedlacek, Zbynek Novy, Marian Hajduch
2 Cancer cancer is the second leading cause of death globally, and was responsible for 8.8 million deaths in 2015 globally, nearly 1 in 6 deaths is due to cancer the number of new cases is expected to rise by about 70% over the next 2 decades the economic impact of cancer is significant and is increasing the total annual economic cost of cancer in 2010 was estimated at approximately US$ 1.16 trillion cancer mortality can be reduced if cases are detected and treated early according to WHO
3 Choline amine (quarternary ammonium salt) physiological role of choline: substrate for acetylcholine (neurotransmitter) synthesis X = Cl -, OH - substrate for phosphatidylcholine (lecithin) synthesis important component of cell membranes (induced in cancer cells) betaine (trimethylglycine) synthesis donor of methyl groups in cell metabolism pathophysiology: accumulation in tumor tissue (overexpression of choline transporter like proteins)
4 Tumor imaging using radiolabelled choline FCH= 18 F-fluorocholine, FECH= 18 F-fluoroethylcholine a CH= 11 C-choline PET/CT imaging = diagnostics (positron emission tomography) (computed tomography) prostate cancer gliomas hepatocellular carcinoma lung cancer colorectal cancer Pacient (63 years old) with prostate tumor: (A) 18 F-FCH PET increased accumulation in pelvis area and in peritoneum (blue arrows). (B) Transversal plane 18 F-FCH PET/CT imaging - up: 18 F-FCH PET; middle: CT; down: PET/CT, metastases in lymph nodes (yellow arrows); CT (middle) shows only small unsuspected lymph nodes (red arrows)
5 Novel choline analogues labelled with radioactive iodine Use: nuclear imaging and targeted radionuclide therapy diagnostics - SPECT imaging ( 123 I, 125 I, 131 I) - PET imaging ( 124 I) therapy I, 125 I theranostics (therapy+diagnostics) I (β - and γ emitter)
6 nuclear imaging visualize organ functions/dysfunctions at the cellular and molecular level allows early identification of disease highly senstive (pmol) and non-invasive targeted radionuclide therapy offers possibilities for personalized treatment of cancer typically has milder side effects compared with chemotherapy currently used to treat certain cancers (e.g. neuroendocrine carcinomas, prostate and pancreatic tumors) non-invasive and very safe - the benefits very far outweigh the risks
7 Preclinical data tested > 50 choline analogues R = aryl, heterocycle, ethynyl IC 50 determination of studied choline analogues ADME testing - plasma and microsomal stabilities - plasma protein binding - membrane permeability (PAMPA) Toxicity testing Animal experiments
8 2 compounds similar or better in vitro and in vivo characteristics than 18 F-FCH F-choline in SCID tumor (PC 3) mice (male) % Injected dose per gram organ (%ID/g) blood spleen 125 I-PS152 in SCID tumor (PC 3) mice (male) pancreas stomach intestine kidneys 1h 1h p.i. (n=3) 3h p.i. (n=3) liver heart lung muscle femur tumor 3h % Injected dose per gram organ (%ID/g) blood spleen 1h p.i. (n=3) 3h p.i. (n=3) pancreas stomach intestine kidneys liver heart lung muscle femur tumor 1h 3h tumor/blood tumor/muscle tumor/bone IC 50 = 3.0 x 10-6 mol/l % Injected dose per gram organ (%ID/g) blood spleen 125 I-PS229 in SCID tumor (PC 3) mice (male) pancreas stomach intestine kidneys 1h 1h p.i. (n=3) 3h p.i. (n=3) liver heart lung muscle femur tumor 3h tumor/blood tumor/muscle tumor/bone IC 50 = 1.3 x 10-5 mol/l tumor/blood tumor/muscle tumor/bone IC 50 = 4.4 x 10-8 mol/l
9 Development of novel radiopharmaceuticals radiopharmaceuticals have an excellent safety profile due to extremely small quantity of applied dose (in the range of µg) microdosing concept of a clinical trial, which shorten time-lines and cut costs, can be used diagnostic investigational radiopharmaceuticals - simplification in terms of qualified persons, specific authorizations, etc. budget needed compared to conventional drug development
10 the EU patent application is filed co-development partner for clinical study comercialization partner welcomed
11 Acknowledgements
12 See you at the poster session I2 Milos Petrik
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