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Synthesis and Evaluation of a Targeted Nanoglobular Dual-Modal Imaging Agent for MR Imaging and Image-Guided Surgery of Prostate Cancer

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Abstract

Purpose

To synthesize and evaluate a peptide targeted nanoglobular dual modal imaging agent specific to a cancer biomarker in tumor stroma for MRI and fluorescence visualization of prostate tumor in image-guided surgery.

Methods

A peptide (CGLIIQKNEC, CLT1) targeted generation 2 nanoglobular (polylysine dendrimer with a silsesquioxane core) dual modal imaging agent, CLT1-G2-(Gd-DOTA-MA)-Cy5, was synthesized by stepwise conjugation of Gd-DOTA-MA, Cy5 and peptide to the dendrimer. Contrast enhanced MR imaging of the targeted dual imaging agent was evaluated on a Bruker 7T animal scanner with male athymic nude mice bearing orthotopic PC3-GFP prostate tumor. Fluorescence tumor imaging of the agent was carried out on a Maestro fluorescence imaging system.

Results

The targeted agent CLT1-G2-(Gd-DOTA-MA)-Cy5 produced greater contrast enhancement in the tumor tissue than the control agent KAREC-G2-(Gd-DOTA-MA)-Cy5 at a dose of 30 μmol-Gd/kg in the MR images of the tumor bearing mice. Signal-to-noise ratio (SNR) of CLT1-G2-(Gd-DOTA-MA)-Cy5 in the tumor tissue was approximately 2 fold of that of the control agent in the first 15 min post-injection. The targeted agent also resulted in bright fluorescence signals in the tumor tissue.

Conclusion

The CLT1 peptide targeted nanoglobular dual-imaging agent CLT1-G2-(Gd-DOTA-MA)-Cy5 has a potential for MRI and fluorescence visualization of prostate tumor.

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References

  1. Gioux S, Choi HS, Frangioni JV. Image-guided surgery using invisible near-infrared light: fundamentals of clinical translation. Mol Imaging. 2010;9:237–55.

    CAS  PubMed Central  PubMed  Google Scholar 

  2. Mieog JS, Vahrmeijer AL, Hutteman M, van der Vorst JR, Drijfhout van Hooff M, Dijkstra J, et al. Novel intraoperative near-infrared fluorescence camera system for optical image-guided cancer surgery. Mol Imaging. 2010;9:223–31.

    PubMed  Google Scholar 

  3. Ukimura O. Image-guided surgery in minimally invasive urology. Curr Opin Urol. 2010;20:136–40.

    Article  PubMed  Google Scholar 

  4. Bogaards A, Sterenborg HJ, Trachtenberg J, Wilson BC, Lilge L. In vivo quantification of fluorescent molecular markers in real-time by ratio imaging for diagnostic screening and image-guided surgery. Lasers Surg Med. 2007;39:605–13.

    Article  CAS  PubMed  Google Scholar 

  5. Gotoh K, Yamada T, Ishikawa O, Takahashi H, Eguchi H, Yano M, et al. A novel image-guided surgery of hepatocellular carcinoma by indocyanine green fluorescence imaging navigation. J Surg Oncol. 2009;100:75–9.

    Article  PubMed  Google Scholar 

  6. Keramidas M, Josserand V, Righini CA, Wenk C, Faure C, Coll JL. Intraoperative near-infrared image-guided surgery for peritoneal carcinomatosis in a preclinical experimental model. Br J Surg. 2010;97:737–43.

    Article  CAS  PubMed  Google Scholar 

  7. Frullano L, Meade TJ. Multimodal MRI contrast agents. J Biol Inorg Chem. 2007;12:939–49.

    Article  CAS  PubMed  Google Scholar 

  8. Olson ES, Jiang T, Aguilera TA, Nguyen QT, Ellies LG, Scadeng M, et al. Activatable cell penetrating peptides linked to nanoparticles as dual probes for in vivo fluorescence and MR imaging of proteases. Proc Natl Acad Sci U S A. 2010;107:4311–6.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Koyama Y, Talanov VS, Bernardo M, Hama Y, Regino CAS, Brechbiel MW, et al. A dendrimer-based nanosized contrast agent, dual-labeled for magnetic resonance and optical fluorescence imaging to localize the sentinel lymph node in mice. J Magn Reson Imaging. 2007;25:866–71.

    Article  PubMed  Google Scholar 

  10. Yiu HH, Pickard MR, Olariu CI, Williams SR, Chari DM, Rosseinsky MJ. Fe3O4-PEI-RITC magnetic nanoparticles with imaging and gene transfer capability: development of a tool for neural cell transplantation therapies. Pharm Res. 2012;29:1328–43.

    Article  CAS  PubMed  Google Scholar 

  11. Mishra A, Pfeuffer J, Mishra R, Engelmann J, Mishra AK, Ugurbil K, et al. A new class of Gd-based DO3A-ethylamine-derived targeted contrast agents for MR and optical imaging. Bioconjugate Chem. 2006;17:773–80.

    Article  CAS  Google Scholar 

  12. Mulder WJM, Koole R, Brandwijk RJ, Storm G, Chin PTK, Strijkers GJ, et al. Quantum dots with a paramagnetic coating as a bimodal molecular imaging probe. Nano Lett. 2006;6:1–6.

    Article  CAS  PubMed  Google Scholar 

  13. Pfaff A, Schallon A, Ruhland TM, Majewski AP, Schmalz H, Freitag R, et al. Magnetic and fluorescent glycopolymer hybrid nanoparticles for intranuclear optical imaging. Biomacromolecules. 2011;12:3805–11.

    Article  CAS  PubMed  Google Scholar 

  14. Tan MQ, Wu XM, Jeong EK, Chen QJ, Lu ZR. Peptide-targeted nanoglobular Gd-DOTA monoamide conjugates for magnetic resonance cancer molecular imaging. Biomacromolecules. 2010;11:754–61.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Tan MQ, Wu XM, Jeong EK, Chen QJ, Parker DL, Lu ZR. An effective targeted nanoglobular manganese(II) chelate conjugate for magnetic resonance molecular imaging of tumor extracellular matrix. Mol Pharmaceut. 2010;7:936–43.

    Article  CAS  Google Scholar 

  16. Pilch J, Brown DM, Komatsu M, Jarvinen TAH, Yang M, Peters D, et al. Peptides selected for binding to clotted plasma accumulate in tumor stroma and wounds. Proc Natl Acad Sci U S A. 2006;103:2800–4.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. Kaneshiro TL, Jeong EK, Morrell G, Parker DL, Lu ZR. Synthesis and evaluation of globular Gd-DOTA-monoamide conjugates with precisely controlled nanosizes for magnetic resonance angiography. Biomacromolecules. 2008;9:2742–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Tan MQ, Burden-Gulley SM, Li W, Wu XM, Lindner D, Brady-Kalnay SM, et al. MR molecular imaging of prostate cancer with a peptide-targeted contrast agent in a mouse orthotopic prostate cancer model. Pharm Res-Dordr. 2012;29:953–60.

    Article  CAS  Google Scholar 

  19. Louie AY. Multimodality imaging probes: design and challenges. Chem Rev. 2010;110:3146–95.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Kobayashi H, Koyama Y, Barrett T, Hama Y, Regino CAS, Shin IS, et al. Multimodal nanoprobes for radionuclide and five-color near-infrared optical lymphatic imaging. ACS Nano. 2007;1:258–64.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Kaneshiro TL, Wang X, Lu ZR. Synthesis, characterization, and gene delivery of poly-L-lySine octa(3-aminopropyl)silsesquioxane dendrimers: nanoglobular drug carriers with precisely defined molecular architectures. Mol Pharmaceut. 2007;4:759–68.

    Article  CAS  Google Scholar 

  22. Kaneshiro TL, Lu ZR. Targeted intracellular codelivery of chemotherapeutics and nucleic acid with a well-defined dendrimer-based nanoglobular carrier. Biomaterials. 2009;30:5660–6.

    Article  CAS  PubMed  Google Scholar 

  23. Sonmez H, Suer S, Karaarslan I, Baloglu H, Kokoglu E. Tissue fibronectin levels of human prostatic cancer, as a tumor marker. Cancer Biochem Bioph. 1995;15:107–10.

    CAS  Google Scholar 

  24. Ye F, Wu X, Jeong EK, Jia Z, Yang T, Parker D, et al. A peptide targeted contrast agent specific to fibrin-fibronectin complexes for cancer molecular imaging with MRI. Bioconjug Chem. 2008;19:2300–3.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Yeeprae W, Kawakami S, Suzuki S, Yamashita F, Hashida M. Physicochemical and pharmacokinetic characteristics of cationic liposomes. Pharmazie. 2006;61:102–5.

    CAS  PubMed  Google Scholar 

  26. Kurmi BD, Gajbhiye V, Kayat J, Jain NK. Lactoferrin-conjugated dendritic nanoconstructs for lung targeting of methotrexate. J Pharm Sci. 2011;100:2311–20.

    Article  CAS  PubMed  Google Scholar 

  27. Yu T, Hubbard D, Ray A, Ghandehari H. In vivo biodistribution and pharmacokinetics of silica nanoparticles as a function of geometry, porosity and surface characteristics. J Control Release. 2012;163:46–54.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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Acknowledgments and Disclosures

This work is supported in part by the NIH R01 CA097465. We greatly appreciate Drs. Ya Chen, Yong Chen and Wen Li for their technical assistance in MRI data acquisition.

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Authors and Affiliations

  1. Department of Biomedical Engineering, Case Western Reserve University, Wickenden Building, Room 427, 10900 Euclid Avenue, Cleveland, Ohio, 44106-7207, USA

    Mingqian Tan, Zhen Ye & Zheng-Rong Lu

  2. Laboratory of Biomedical Material Engineering Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, 116023, People’s Republic of China

    Mingqian Tan

  3. Department of Translational Hematology & Oncology Research, Cleveland Clinic, Cleveland, Ohio, 44195, USA

    Daniel Lindner

  4. Department of Molecular Biology and Microbiology School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA

    Susann M. Brady-Kalnay

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  1. Mingqian Tan
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  2. Zhen Ye
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  3. Daniel Lindner
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  4. Susann M. Brady-Kalnay
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  5. Zheng-Rong Lu
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Correspondence to Zheng-Rong Lu.

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Tan, M., Ye, Z., Lindner, D. et al. Synthesis and Evaluation of a Targeted Nanoglobular Dual-Modal Imaging Agent for MR Imaging and Image-Guided Surgery of Prostate Cancer. Pharm Res 31, 1469–1476 (2014). https://doi.org/10.1007/s11095-013-1008-5

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  • DOI: https://doi.org/10.1007/s11095-013-1008-5

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