PETMR and SPECTMR Multimodality Probes Development and Challenges
PET-MR and SPECT-MR Multimodality Probes: Development and Challenges Chang-Tong YANG, Ph. D 1. Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 2. Ningbo Institute of Material Technology and Engineering, Chinese Academy of Sciences, China
Types of PET/SPECT-MR Probes Yang C-T, Ghosh KK, Padmanabhan P, Langer O, Liu J, Halldin C and Gulyás B. Theranostics, Accepted. All references were adapted with permission.
Content 1. Small molecular bimodal and trimodal probes 2. Nano-sized bimodal probes 3. Nano-sized trimodal probes 4. Challenges of designing PET/SPECT-MR probes 5. Conclusion and Acknowledgments
1. Small molecular bimodal probes Bimodal probes [Gd-L][166 Ho-L] Gd-DOTA-4 AMP-18/19 F Caravan P, et al. Angew. Chem. Int. Ed. 2010, 49, 2382. Application: Quantitative p. H imaging or p. H mapping Relaxivity p. H dependence (7. 1 T and 298 K) Aime S, et al. Chem Commun. 2011; 47: 1539 -41.
1. Small molecular trimodal probe Trimodal probe Gd(DO 3 A-AM)-64 Cu(Porphyrin) • Only one small molecular trimodality probe • Higher relaxivity due to bigger molecular weight compared to commercial CAs Gros CP, et al. Med. Chem. Comm. 2011; 2: 119
2. Nano-sized bimodal probes 64 Cu-DOTA-m. SPIO (coated with PEGylated phospholipid micelles) (A) T 2 -weighted MR image of 25 µg Fe/m. L (top) and 10 µg Fe/m. L (bottom) (B) Decay-corrected micro. PET image of 25 µg Fe/m. L (top) and 10 µg Fe/m. L (bottom) • Strong MR and PET signals and stable in serum • Optimal blood retention with a circulation lifetime (143 min) • Disease detection and treatment in cancer models. Glaus C, et al. Bioconjugate Chem. 2010; 21: 715
2. Nano-sized bimodal probes 64 Cu-DOTA-IO-RGD PET images of nude mouse bearing human U 87 MG tumor at 1, 4, and 21 h (injection of 3. 7 MBq)
2. Nano-sized bimodal probes 64 Cu-DOTA-IO-RGD T 2 -weighted MR images of nude mice bearing U 87 MG tumor before injection of IO nanoparticles (A and E) and at 4 h after tail-vein injection • Nanoprobe for dual PET-MR of tumor integrin αγβ 3 expression • Potential application for early clinical tumor detection with a high degree of sensitivity Chen X, et al. J Nucl Med. 2008, 49: 1371
2. Nano-sized bimodal probes PEG-BP-99 m. Tc-USPIOs High stability, long blood half life, high r 1 relaxivity. • Bisphonate anchors allow strong and stable binding of PEG polymers and radionuclides on the surface of the USPIOs; • The bimodal nanoparticles circulate in the bloodstream, as indicated by the strong imaging signal in the heart and vessels. de Rosales RTM, et al. ACS Nano. 2013; 7: 500
2. Nano-sized bimodal probes Radiolabeling Methodology -- Radiolabeling of 89 Zr with chelator and chelator-free approaches 89 Zr-DFO(Desferrioxoamine)-Ferumoxytol mapping of deep-tissue lymph nodes for Thorek DL, et al. Nat Commun. 2014; 5: 3097 Heat-induced chelator free radiolabeling SPIONs Boros E, et al, Chem Sci. 2015; 6: 225
Radiolabeling Methodology -Pros and cons of two approaches Pros Chelator (1) A specific coordination is needed for radiometal based on its physicochemical properties such as oxidation state, coordination number, kinetic inertness etc. (2) Bifunctional characteristics-second function to covalently bind to the targeting moiety Chelator- (1) improved stability which is critical free or for diagnostic accuracy, core(2) increased radiolabeling yield by coped attachment of radionuclides to the nanoparticles surface or incorporation into the particle core, (3) better in vivo performance due to no transchelation of radiometal for misinterpretation of PET images and non-necessary radiation burden Cons (1) Unfavorable radiolabeling conditions; (2) Transchelation of radiometal to proteins leading to high uptake in nontargeted organs and further misinterpretation of PET images (1) lack general labeling procedures. (2) Radiolabeling usually occurs before nanoparticle fabrication is another drawback. So incorporation of the radiometals during nanoparticle fabrication is not feasible for many shortlived radionuclides such as 68 Ga. (3) needs full preparation and characterization of the entire nanoparticle for each radiosynthesis.
2. Nano-sized bimodal probes Carbon nanotubes • CNTs characteristics: high surface area, nanoscale tube with hollow cavity, capability of further engineering, etc. • Incorporating of imaging probe into make multimodal probes for diagnostic and therapeutic applications. • Their potential cytotoxicity remain the major challenges. Wang JT-W, et al. Adv Funct Mater, 2014; 24: 1880
3. Nano-sized trimodal probes Melanin nanoparticles for tumor targeting • Water soluble MNP, PEG surface-modification, RGD was further attached to the MNP for tumor targeting. • Fe 3+ and/or 64 Cu 2+ were chelated for PAI/MRI/PET multimodal imaging. • Nanoplatforms for molecular theranostics and clinical translation Foster N, et al. J Am Chem Soc. 2014; 136: 15185
3. Nano-sized trimodal probes Multi-functional HSA-IONPs • Dopamine modified IONPs encapsulated into human serum albumin (HSA) matrices • 64 Cu-DOTA and Cy 5. 5, for NIRF and PET for imaging U 87 MG xenograft tumor mouse Xie J, et al. Biomaterials. 2010; 31: 3016 NIRF, PET and MR images HSA-IONPs. dopamine incubated , doped into HSA matrices
3. Nano-sized trimodal probes Hetero-nanostructure Dumbbell Au-IONP Affibody binding IONPs and dumbbell Au-IONP, functionalized with Affibody. • Gold-Iron oxide hetero-nanostructures for tumor PET, optical and MR imaging • Surface specific modification of anti- epidermal growth factor receptor Affibody protein for imaging EGFR positive tumors Yang M, et al. Biomaterials. 2013; 34: 2796
3. Nano-sized trimodal probes Na. Gd. F 4: Yb 3+/Er 3+ Upconversion Nanophosphors • Polymer-coated UCNP (pc. UCNP) was Functionalized both with (c. RGDyk)2 peptide and with Me. O-PEGNH 2. • 124 I ion from Iodo-Beads will be oxidized to form a reactive 124 ICl which reacts with the ortho position of Tyrosine. Lee J, et al. J Nucl Med. 2013; 54: 96
Our probes 64 Cu-labeled triphenylphosphonium cations • TPP+ could increase mitochondrial transmenbrane potential ( m). • m in carcinoma cell is significantly higher than that in normal cell (60 m. V). • High selectivity and high uptake for tumor cell.
Our probes 64 Cu-labeled triphenylphosphonium cations Effects of targeting moiety, linker, bifunctional chelator and molecular charge Bioconjugated Chem. J Med Chem, Inorg Chem, etc. DO 3 A-xy-TPEP stands out as the best candidate
tumor-bearing mice administered with ~250 μCi of 64 Cu(DO 3 A-xy-TPP)+. Arrows indicate the presence of glioma tumors. Yang C-T, et al. Boimaterials. 2012, 33, 9225
4. Challenges of designing PET/SPECT-MR probes Concentration of probes • Significant difference----PET tracers in pico-nano-molar , whilst MR CAs in millimolar. • Individual PET tracer and MR CAs could be injected simultaneously, but validation and registration problems could arise unless they have identical pharmacodynamics properties.
4. Challenges of designing PET/SPECT-MR probes Nano-structure vs Small molecule Nano-structure probes : • large surface area for conjugation sites, targeting and therapy biomolecules functionalizations • advantages for diagnosis of tumors, inflammatory disease, etc Small molecules probes: • limited loading capacity, unlikely to be designed as a multimodal imaging probe • certain biological events such as p. H-responsive
Size of nano-sized probes • Size: one of the most important factors for biodistribution. • The smaller size, higher uptakes in target or interest, higher tumor uptake. • larger nanoparticles transported more slowly to the target.
Targeting ability • Through the molecular design, surface modifications or conjugation with targeting biomolecules, radiolabeled SPIOs can be developed as : targeting hepatocytes with lactobionic acid, targeting macrophages with maleic anhydride , targeting HT-29 cancer cells with oleanilic acid, targeting MUC-1 -positive breast cancer cells with monoclonal antibody C 595 m. Ab, etc.
Conclusions • The first comprehensive overview of all PET-MR and SPECT-MR multimodal imaging probes. • Theranostic bimodal probes will be developed.
Acknowledgements • A/Prof Oliver Langer, Biomedical Systems, AIT Austrian Institute of Technology and Medical University of Vienna, Austria • Christer Halldin, Director of PET center, Karolinska Institutet, Stockholm, Sweden • Balázs Gulyás, Professor at Lee Kong Chian School of Medicine, Nanyang Technological University 1. Lee Kong Chian School of Medicine, Nanyang Technological University (NTU) Start-Up Grant, . 2. NTU and Austrian Institute of Technology & Medical University of Vienna grant (NAM/15005), Singapore.
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