Molecular Imaging and Biology

, Volume 10, Issue 4, pp 182–191 | Cite as

Genome-free Viral Capsids as Carriers for Positron Emission Tomography Radiolabels

  • Jacob M. Hooker
  • James P. O’Neil
  • Dante W. Romanini
  • Scott E. Taylor
  • Matthew B. Francis
Research Article

Abstract

Purpose

We have developed a modular synthetic strategy to append imaging agents to a viral capsid.

Procedures

The hollow protein shell of bacteriophage MS2 (mtMS2) was labeled on its inside surface with [18F]fluorobenzaldehyde through a multistep bioconjugation strategy. An aldehyde functional group was first attached to interior tyrosine residues through a diazonium coupling reaction. The aldehyde was further elaborated to an alkoxyamine functional group, which was then condensed with n.c.a. [18F]fluorobenzaldehyde. Biodistribution of the radioactive MS2 conjugates was subsequently evaluated in Sprague–Dawley rats.

Results

Relative to fluorobenzaldehyde, fluorine-18-labeled MS2 exhibited prolonged blood circulation time and a significantly altered excretion profile. It was also observed that additional small molecule cargo installed inside the capsids did not alter the biodistribution.

Conclusions

These studies provide further insight into the pharmacokinetic behavior of nanomaterials and serve as a platform for the future development of targeted imaging and therapeutic agents based on mtMS2.

Key words

Virus PET Oxime Bioconjugation F-18 

References

  1. 1.
    Tsien RY (2003) Imagining imaging’s future. Nat Cell Biol 4:Ss16–Ss21Google Scholar
  2. 2.
    Séve P, Billotey C, Broussolle C, Dumontet C, Mackey JR (2007) The role of 2-deoxy-2-[F-18]fluoro-D-glucose positron emission tomography in disseminated carcinoma of unknown primary site. Cancer 109:292–299PubMedCrossRefGoogle Scholar
  3. 3.
    Okarvi SM (2001) Recent progress in fluorine-18 labelled peptide radiopharmaceuticals. Eur J Nucl Med 28:929–938PubMedCrossRefGoogle Scholar
  4. 4.
    Lang LX, Eckelman WC (1994) One-step synthesis of F-18 labeled [F-18] N-succinimidyl 4-(Fluoromethyl)benzoate for protein labeling. Appl Radiat Isotopes 45:1155–1163CrossRefGoogle Scholar
  5. 5.
    Cai WB, Zhang XZ, Wu Y, Chen X (2006) A thiol-reactive F-18-labeling agent, N-[2-(4-F-18-fluorobenzamido)ethyl]maleimide, and synthesis of RGD peptide-based tracer for PET imaging of alpha(v)beta(3) integrin expression. J Nucl Med 47:1172–1180PubMedGoogle Scholar
  6. 6.
    Mammen M, Choi SK, Whitesides GM (1998) Polyvalent interactions in biological systems: implications for design and use of multivalent ligands and inhibitors. Angew Chem (Int Ed) 37:2755–2794Google Scholar
  7. 7.
    Gordon EJ, Kiessling LL (1997) The role of multivalency in the shedding of L-selectin. FASEB J 11:A832–A832Google Scholar
  8. 8.
    Huskens J (2006) Multivalent interactions at interfaces. Curr Opin Chem Biol 10:537–543PubMedCrossRefGoogle Scholar
  9. 9.
    Haag R, Kratz F (2006) Polymer therapeutics: concepts and applications. Angew Chem (Int Ed) 45:1198–1215CrossRefGoogle Scholar
  10. 10.
    Dufes C, Uchegbu IF, Schaetzlein AG (2005) Dendrimers in gene delivery. Adv Drug Deliv Rev 57:2177–2202PubMedCrossRefGoogle Scholar
  11. 11.
    Douglas T, Young M (2006) Viruses: making friends with old foes. Science 312:873–875PubMedCrossRefGoogle Scholar
  12. 12.
    Lee LA, Wang Q (2006) Adaptations of nanoscale viruses and other protein cages for medical applications. Nanomedicine 2:137–149PubMedGoogle Scholar
  13. 13.
    Ren Y, Wong SM, Lim LY (2007) Folic acid-conjugated protein cages of a plant virus: a novel delivery platform for doxorubicin. Bioconjugate Chem 18:836–843CrossRefGoogle Scholar
  14. 14.
    Serwinski PR, Esat B, Lahti PM et al (2004) Photolysis and oxidation of azidophenyl-substituted radicals: delocalization in heteroatom-based radicals. J Org Chem 69:5247–5260PubMedCrossRefGoogle Scholar
  15. 15.
    Valegard K, Liljas L, Fridborg K, Unge T (1990) The 3-dimensional structure of the bacterial-virus Ms2. Nature 345:36–41PubMedCrossRefGoogle Scholar
  16. 16.
    Golmohammadi R, Valegard K, Fridborg K, Liljas L (1993) The refined structure of bacteriophage-Ms2 at 2.8-Angstrom resolution. J Mol Biol 234:620–639PubMedCrossRefGoogle Scholar
  17. 17.
    Hooker JM, Kovacs EW, Francis MB (2004) Interior surface modification of bacteriophage MS2. J Am Chem Soc 126:3718–3719PubMedCrossRefGoogle Scholar
  18. 18.
    Johnson HR, Hooker JM, Francis MB, Clark DS (2007) Solubilization and stabilization of bacteriophage MS2 in organic solvents. Biotechnol Bioeng 97:224–234PubMedCrossRefGoogle Scholar
  19. 19.
    Kovacs EW, Hooker JM, Romanini DW et al (2007) Dual-surface-modified bacteriophage MS2 as an ideal scaffold for a viral capsid-based drug delivery system. Bioconjugate Chem 18:1140–1147CrossRefGoogle Scholar
  20. 20.
    Hooker JM, Datta A, Botta M, Raymond KN, Francis MB (2007) Magnetic resonance contrast agents from viral capsid shells: a comparison of exterior and interior cargo strategies. Nano Lett 7:2207–2210PubMedCrossRefGoogle Scholar
  21. 21.
    Schottelius M, Poethko T, Herz M et al (2004) First 18F-labeled tracer suitable for routine clinical imaging of sst receptor-expressing tumors using positron emission tomography. Clin Cancer Res 10:3593–3606PubMedCrossRefGoogle Scholar
  22. 22.
    Poethko T, Schottelius M, Thumshirn G et al (2004) Chemoselective pre-conjugate radiohalogenation of unprotected mono- and multimeric peptides via oxime formation. Radiochim Acta 92:317–327CrossRefGoogle Scholar
  23. 23.
    Chang YS, Jeong JM, Lee YS et al (2005) Preparation of F-18-human serum albumin: a simple and efficient protein labeling method with F-18 using a hydrazone-formation method. Bioconjugate Chem 16:1329–1333CrossRefGoogle Scholar
  24. 24.
    Lee YS, Jeong JM, Kim HW et al (2006) An improved method of F-18 peptide labeling: hydrazone formation with HYNIC-conjugated c(RGDyK). Nucl Med Biol 33:677–683PubMedCrossRefGoogle Scholar
  25. 25.
    Testa E, Pagani G, Nicolaus BJ, Mariani L (1963) O,N-substituierte hydroxylamine.5. Uber synthese und eigenschaften der alpha-aminoxy-carbonsauren, analoga naturlicher alpha-aminocarbonsauren. Helv Chim Acta 46:766Google Scholar
  26. 26.
    Rae CS, Khor IW, Wang Q et al (2005) Systemic trafficking of plant virus nanoparticles in mice via the oral route. Virology 343:224–235PubMedCrossRefGoogle Scholar
  27. 27.
    Naik AM, Chalikonda S, McCart JA et al (2006) Intravenous and isolated limb perfusion delivery of wild type and a tumor-selective replicating mutant vaccinia virus in nonhuman primates. Hum Gene Ther 17:31–45PubMedCrossRefGoogle Scholar
  28. 28.
    Poirier A, Campbell-Thompson M, Tang Q et al (2004) Toxicology and biodistribution studies of a recombinant adeno-associated virus 2-a-1 antitrypsin vector. Preclinica 2:43–51Google Scholar
  29. 29.
    Moghimi SM, Hunter AC, Murray JC (2001) Long-circulating and target-specific nanoparticles: theory to practice. Pharmacol Rev 53:283–318PubMedGoogle Scholar
  30. 30.
    Monfardini C, Veronese FM (1998) Stabilization of substances in circulation. Bioconjugate Chem 9:418–450CrossRefGoogle Scholar
  31. 31.
    Boyd BJ, Kaminskas LM, Karellas P et al (2006) Cationic poly-L-lysine dendrimers: pharmacokinetics, biodistribution, and evidence for metabolism and bioresorption after intravenous administration to rats. Mol Pharmacol 3:614–627CrossRefGoogle Scholar
  32. 32.
    Okuda T, Kawakami S, Maeie T et al (2006) Biodistribution characteristics of amino acid dendrimers and their pegylated derivatives after intravenous administration. J Control Release 114:69–77PubMedCrossRefGoogle Scholar
  33. 33.
    Kamei S, Kopecek J (1995) Prolonged blood-circulation in rats of nanospheres surface-modified with semitelechelic poly[N-(2-Hydroxypropyl)Methacrylamide]. Pharm Res 12:663–668PubMedCrossRefGoogle Scholar
  34. 34.
    Thordarson P, Droumaguet B, Velonia K (2006) Well-defined protein-polymer conjugates-synthesis and potential applications. Appl Microbiol Biotechnol 73:243–254PubMedCrossRefGoogle Scholar
  35. 35.
    Wen X, Cao X, Pasuelo MJ, Wendt R, Li C (2004) Polymeric radiotracers in nuclear imaging. Curr Drug Deliv 1:377–384PubMedCrossRefGoogle Scholar
  36. 36.
    Torchilin VP, Trubetskoy VS (1995) Which polymers can make nanoparticulate drug carriers long-circulating? Adv Drug Deliv Rev 16:141–155CrossRefGoogle Scholar
  37. 37.
    Sun XK, Rossin R, Turner JL et al (2005) An assessment of the effects of shell cross-linked nanoparticle size, core composition, and surface PEGylation on in vivo biodistribution. Biomacromolecules 6:2541–2554PubMedCrossRefGoogle Scholar
  38. 38.
    Owens DE, Peppas NA (2006) Opsonization, biodistribution, and pharmacokinetics of polymeric nanoparticles. Int J Pharm 307:93–102PubMedCrossRefGoogle Scholar
  39. 39.
    Hillyer JF, Albrecht RM (2001) Gastrointestinal persorption and tissue distribution of differently sized colloidal gold nanoparticles. J Pharm Sci 90:1927–1936PubMedCrossRefGoogle Scholar
  40. 40.
    Bohrer MP, Baylis C, Humes HD et al (1978) Permselectivity of glomerular capillary wall-facilitated filtration of circulating polycations. J Clin Invest 61:72–78PubMedCrossRefGoogle Scholar

Copyright information

© Academy of Molecular Imaging 2008

Authors and Affiliations

  • Jacob M. Hooker
    • 1
  • James P. O’Neil
    • 2
  • Dante W. Romanini
    • 1
  • Scott E. Taylor
    • 2
  • Matthew B. Francis
    • 1
    • 3
  1. 1.Department of ChemistryUniversity of CaliforniaBerkeleyUSA
  2. 2.Department of Molecular Imaging and NeuroscienceLawrence Berkeley National LaboratoryBerkeleyUSA
  3. 3.Materials Sciences DivisionLawrence Berkeley National LabsBerkeleyUSA

Personalised recommendations