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Pharmacokinetics, Biodistribution and Contrast Enhanced MR Blood Pool Imaging of Gd-DTPA Cystine Copolymers and Gd-DTPA Cystine Diethyl Ester Copolymers in a Rat Model

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Purpose

To investigate plasma pharmacokinetics and biodistribution of biodegradable polydisulfide Gd(III) complexes, Gd-DTPA cystine copolymers (GDCP) and Gd-DTPA cystine diethyl ester copolymers (GDCEP) and their efficacy as blood pool MRI contrast agents in comparison with a nondegradable macromolecular agent, Gd-DTPA 1,6-hexanediamine copolymers (GDHC).

Methods

The pharmacokinetics and biodistribution of GDCP and GDCEP with molecular weight of 35 KDa were investigated in Sprague‐Dawley rats after intravenous administration at a dose of 0.1 mmol Gd/kg. GDHC with the same molecular weight was used as a control. The Gd content in the plasma and various tissues and organs were determined by the ICP-OES. Plasma pharmacokinetic parameters were calculated by using a two-compartment model. The contrast enhanced blood pool MR imaging of the agents was evaluated in Sprague‐Dawley rats on a Siemens Trio 3T MR scanner.

Results

The biodegradable macromolecular agents, GDCP and GDCEP, had faster blood pool clearance than the nondegradable GDHC. The long-term Gd(III) tissue retention of the biodegradable polydisulfide agents was substantially lower than the nondegradable macromolecular agent. Both GDCP and GDCEP resulted in significant blood pool enhancement for the first 2 min post-injection and more rapid disappearance of the enhancement over time than GDHC. The negatively charged GDCP had prolonged enhancement duration as compared to GDCEP. The structure and biodegradability of the macromolecular contrast agents significantly affected their pharmacokinetics and blood pool contrast enhancement.

Conclusion

Both GDCP and GDCEP provided effective contrast enhancement for MR imaging of the blood pool. The accumulation of toxic Gd(III) ions in the body was greatly reduced with GDCP and GDCEP as compared to the nondegradable control.

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References

  1. P. Caravan, J. J. Ellison, T. J. McMurry, and R. B. Lauffer. Gadolinium(III) chelates as MRI contrast agents: structure, dynamics, and applications. Chem. Rev. 99:2293–2352 (1999).

    Article  PubMed  CAS  Google Scholar 

  2. X. Wang, Y. Feng, T. Ke, M. Schabel, and Z.-R. Lu. Pharmacokinetics and tissue retention of (Gd-DTPA)-cystamine copolymers, a biodegradable macromolecular magnetic resonance imaging contrast agent. Pharm. Res. 22:596–602 (2005).

    Article  PubMed  CAS  Google Scholar 

  3. Y. Zong, X. Wang, K. C. Goodrich, A. M. Mohs, D. L. Parker, and Z.-R. Lu. Contrast-enhanced MRI with new biodegradable macromolecular Gd(III) complexes in tumor-bearing mice. Magn. Reson. Med. 53:835–842 (2005).

    Article  PubMed  CAS  Google Scholar 

  4. R. Laufferand, and T. J. Brady. Preparation and water relaxation properties of proteins labeled with paramagnetic metal chelates. Magn. Reson. Imaging 3:11–16 (1985).

    Article  Google Scholar 

  5. A. A. J. Bogdanov, R. Weissleder, H. W. Frank, A. V. Bogdanova, N. Nossif, B. K. Schaffer, E. Tsai, M. I. Papisov, and T. J. Brady. A new macromolecule as a contrast agent for MR angiography: preparation, properties, and animal studies. Radiology 187:701–706 (1993).

    PubMed  CAS  Google Scholar 

  6. V. P. Torchilin. Polymeric contrast agents for medical imaging. Curr. Pharm. Biotechnol. 1:183–215 (2000).

    Article  PubMed  CAS  Google Scholar 

  7. H. Kobayashiand, and M. W. Brechbiel. Dendrimer-based macromolecular MRI contrast agents: characteristics and application. Mol. Imaging 2:1–10 (2003).

    Article  PubMed  CAS  Google Scholar 

  8. C. Fink, S. Ley, M. Puderbach, C. Plathow, M. Bock, and H. U. Kauczor. 3D pulmonary perfusion MRI and MR angiography of pulmonary embolism in pigs after a single injection of a blood pool MR contrast agent. Eur. Radiol. 14:1291–1296 (2004).

    Article  PubMed  Google Scholar 

  9. L. E. Gerlowskiand, and R. K. Jain. Microvascular permeability of normal and neoplastic tissues. Microvasc. Res. 31:288–305 (1986).

    Article  PubMed  CAS  Google Scholar 

  10. A. Gossmann, Y. Okuhata, D. M. Shames, T. H. Helbich, T. P. Roberts, M. F. Wendland, S. Huber, and R. C. Brasch. Prostate cancer tumor grade differentiation with dynamic contrast-enhanced MR imaging in the rat: comparison of macromolecular and small-molecular contrast media-preliminary experience. Radiology 213:265–272 (1999).

    PubMed  CAS  Google Scholar 

  11. R. Weissleder, A. J. Bogdanov, C. H. Tung, and H. J. Weinmann. Size optimization of synthetic graft copolymers for in vivo angiogenesis imaging. Bioconjug. Chem. 12:213–219 (2001).

    Article  PubMed  CAS  Google Scholar 

  12. Q. G. de Lussanet, S. Langereis, R. G. Beets-Tan, M. H. van Genderen, A. W. Griffioen, J. M. van Engelshoven, and W. H. Backes. Dynamic contrast-enhanced MR imaging kinetic parameters and molecular weight of dendritic contrast agents in tumor angiogenesis in mice. Radiology 235:65–72 (2005).

    Article  PubMed  Google Scholar 

  13. B. F. Jordan, M. Runquist, N. Raghunand, R. J. Gillies, W. R. Tate, G. Powis, and A. F. Baker. The thioredoxin-1 inhibitor 1-methylpropyl 2-imidazolyl disulfide (PX-12) decreases vascular permeability in tumor xenografts monitored by dynamic contrast enhanced magnetic resonance imaging. Clin. Cancer Res. 11:529–536 (2005).

    PubMed  CAS  Google Scholar 

  14. P. Marzola, A. Degrassi, L. Calderan, P. Farace, E. Nicolato, C. Crescimanno, M. Sandri, A. Giusti, E. Pesenti, A. Terron, A. Sbarbati, and F. Osculati. Early antiangiogenic activity of SU11248 evaluated in vivo by dynamic contrast-enhanced magnetic resonance imaging in an experimental model of colon carcinoma. Clin. Cancer Res. 11:5827–5832 (2005).

    Article  PubMed  CAS  Google Scholar 

  15. D. Wang, S. C. Miller, M. Sima, D. Parker, H. Buswell, K. C. Goodrich, P. Kopeckova, and J. Kopecek. The arthrotropism of macromolecules in adjuvant-induced arthritis rat model: a preliminary study. Pharm. Res. 21:1741–1749 (2004).

    Article  PubMed  CAS  Google Scholar 

  16. B. Misselwitz, H. Schmitt-Willich, W. Ebert, T. Frenzel, and H. J. Weinmann. Pharmacokinetics of Gadomer-17, a new dendritic magnetic resonance contrast agent. Magma 12:128–134 (2001).

    Article  PubMed  CAS  Google Scholar 

  17. M. S. Dirksen, H. J. Lamb, P. Kunz, P. Robert, C. Corot, and A. de Roos. Improved MR coronary angiography with use of a new rapid clearance blood pool contrast agent in pigs. Radiology 227:802–808 (2003).

    Article  PubMed  Google Scholar 

  18. H. Kobayashi, and M. W. Brechbiel. Nano-sized MRI contrast agents with dendrimer cores. Adv. Drug Deliv. Rev. 57:2271–2286 (2005).

    Article  PubMed  CAS  Google Scholar 

  19. Z.-R. Lu, A. M. Mohs, Y. Zong, and Y. Feng. Polydisulfide Gd(III) chelates as biodegradable macromolecular magnetic resonance imaging contrast agents. Intl. J. Nanomed. 31–40 (2006).

  20. Z.-R. Lu, D. L. Parker, K. C. Goodrich, X. Wang, J. G. Dalle, and H. R. Buswell. Extracellular biodegradable macromolecular gadolinium(III) complexes for MRI. Magn. Reson. Med. 51:27–34 (2004).

    Article  PubMed  CAS  Google Scholar 

  21. Z.-R. Lu, X. Wang, D. L. Parker, K. C. Goodrich, and H. R. Buswell. Poly(l-glutamic acid) Gd(III)-DOTA conjugate with a degradable spacer for magnetic resonance imaging. Bioconjug. Chem. 14:715–719 (2003).

    Article  PubMed  CAS  Google Scholar 

  22. T. Kaneshiro, T. Ke, E.-K. Jeong, D. L. Parker and Z.-R. Lu. Synthesis and characterization of (Gd-DTPA)-(l-cystine bisalkylamide) copolymers as novel biodegradable macromolecular MRI contrast agents. Pharm. Res. In press: (2006).

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Acknowledgments

The research work is supported in part by the NIH grants R33 CA095873 and R01 EB00489. The authors thank Sheryl Dutson and Melody Johnson for technical support and valuable discussion.

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Authors and Affiliations

  1. Department of Materials Science and Engineering, University of Utah, Salt Lake City, Utah, USA

    Yi Feng

  2. Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, Utah, USA

    Yuda Zong, Tianyi Ke & Zheng-Rong Lu

  3. Department of Radiology, University of Utah, Salt Lake City, Utah, USA

    Eun-Kee Jeong & Dennis L. Parker

  4. 421 Wakara Way, Suite 318, Salt Lake City, Utah, 84108, USA

    Zheng-Rong Lu

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  1. Yi Feng
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  2. Yuda Zong
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  3. Tianyi Ke
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  6. Zheng-Rong Lu
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Correspondence to Zheng-Rong Lu.

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Feng, Y., Zong, Y., Ke, T. et al. Pharmacokinetics, Biodistribution and Contrast Enhanced MR Blood Pool Imaging of Gd-DTPA Cystine Copolymers and Gd-DTPA Cystine Diethyl Ester Copolymers in a Rat Model. Pharm Res 23, 1736–1742 (2006). https://doi.org/10.1007/s11095-006-9028-z

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  • DOI: https://doi.org/10.1007/s11095-006-9028-z

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