Skip to main content
Log in

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

  • Research Article
  • Published:
Molecular Imaging and Biology Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Scheme 1
Fig. 3
Scheme 2
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

References

  1. Tsien RY (2003) Imagining imaging’s future. Nat Cell Biol 4:Ss16–Ss21

    Google Scholar 

  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 109:292–299

    Article  PubMed  Google Scholar 

  3. Okarvi SM (2001) Recent progress in fluorine-18 labelled peptide radiopharmaceuticals. Eur J Nucl Med 28:929–938

    Article  PubMed  CAS  Google Scholar 

  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 45:1155–1163

    Article  CAS  Google Scholar 

  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 47:1172–1180

    PubMed  CAS  Google Scholar 

  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) 37:2755–2794

    CAS  Google Scholar 

  7. Gordon EJ, Kiessling LL (1997) The role of multivalency in the shedding of L-selectin. FASEB J 11:A832–A832

    Google Scholar 

  8. Huskens J (2006) Multivalent interactions at interfaces. Curr Opin Chem Biol 10:537–543

    Article  PubMed  CAS  Google Scholar 

  9. Haag R, Kratz F (2006) Polymer therapeutics: concepts and applications. Angew Chem (Int Ed) 45:1198–1215

    Article  CAS  Google Scholar 

  10. Dufes C, Uchegbu IF, Schaetzlein AG (2005) Dendrimers in gene delivery. Adv Drug Deliv Rev 57:2177–2202

    Article  PubMed  CAS  Google Scholar 

  11. Douglas T, Young M (2006) Viruses: making friends with old foes. Science 312:873–875

    Article  PubMed  CAS  Google Scholar 

  12. Lee LA, Wang Q (2006) Adaptations of nanoscale viruses and other protein cages for medical applications. Nanomedicine 2:137–149

    PubMed  CAS  Google Scholar 

  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 18:836–843

    Article  CAS  Google Scholar 

  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 69:5247–5260

    Article  PubMed  CAS  Google Scholar 

  15. Valegard K, Liljas L, Fridborg K, Unge T (1990) The 3-dimensional structure of the bacterial-virus Ms2. Nature 345:36–41

    Article  PubMed  CAS  Google Scholar 

  16. Golmohammadi R, Valegard K, Fridborg K, Liljas L (1993) The refined structure of bacteriophage-Ms2 at 2.8-Angstrom resolution. J Mol Biol 234:620–639

    Article  PubMed  CAS  Google Scholar 

  17. Hooker JM, Kovacs EW, Francis MB (2004) Interior surface modification of bacteriophage MS2. J Am Chem Soc 126:3718–3719

    Article  PubMed  CAS  Google Scholar 

  18. Johnson HR, Hooker JM, Francis MB, Clark DS (2007) Solubilization and stabilization of bacteriophage MS2 in organic solvents. Biotechnol Bioeng 97:224–234

    Article  PubMed  CAS  Google Scholar 

  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 18:1140–1147

    Article  CAS  Google Scholar 

  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 7:2207–2210

    Article  PubMed  CAS  Google Scholar 

  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 10:3593–3606

    Article  PubMed  CAS  Google Scholar 

  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 92:317–327

    Article  CAS  Google Scholar 

  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 16:1329–1333

    Article  CAS  Google Scholar 

  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 33:677–683

    Article  PubMed  CAS  Google Scholar 

  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 46:766

    CAS  Google Scholar 

  26. Rae CS, Khor IW, Wang Q et al (2005) Systemic trafficking of plant virus nanoparticles in mice via the oral route. Virology 343:224–235

    Article  PubMed  CAS  Google Scholar 

  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 17:31–45

    Article  PubMed  CAS  Google Scholar 

  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 2:43–51

    CAS  Google Scholar 

  29. Moghimi SM, Hunter AC, Murray JC (2001) Long-circulating and target-specific nanoparticles: theory to practice. Pharmacol Rev 53:283–318

    PubMed  CAS  Google Scholar 

  30. Monfardini C, Veronese FM (1998) Stabilization of substances in circulation. Bioconjugate Chem 9:418–450

    Article  CAS  Google Scholar 

  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 3:614–627

    Article  CAS  Google Scholar 

  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 114:69–77

    Article  PubMed  CAS  Google Scholar 

  33. Kamei S, Kopecek J (1995) Prolonged blood-circulation in rats of nanospheres surface-modified with semitelechelic poly[N-(2-Hydroxypropyl)Methacrylamide]. Pharm Res 12:663–668

    Article  PubMed  CAS  Google Scholar 

  34. Thordarson P, Droumaguet B, Velonia K (2006) Well-defined protein-polymer conjugates-synthesis and potential applications. Appl Microbiol Biotechnol 73:243–254

    Article  PubMed  CAS  Google Scholar 

  35. Wen X, Cao X, Pasuelo MJ, Wendt R, Li C (2004) Polymeric radiotracers in nuclear imaging. Curr Drug Deliv 1:377–384

    Article  PubMed  CAS  Google Scholar 

  36. Torchilin VP, Trubetskoy VS (1995) Which polymers can make nanoparticulate drug carriers long-circulating? Adv Drug Deliv Rev 16:141–155

    Article  CAS  Google Scholar 

  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 6:2541–2554

    Article  PubMed  CAS  Google Scholar 

  38. Owens DE, Peppas NA (2006) Opsonization, biodistribution, and pharmacokinetics of polymeric nanoparticles. Int J Pharm 307:93–102

    Article  PubMed  CAS  Google Scholar 

  39. Hillyer JF, Albrecht RM (2001) Gastrointestinal persorption and tissue distribution of differently sized colloidal gold nanoparticles. J Pharm Sci 90:1927–1936

    Article  PubMed  CAS  Google Scholar 

  40. Bohrer MP, Baylis C, Humes HD et al (1978) Permselectivity of glomerular capillary wall-facilitated filtration of circulating polycations. J Clin Invest 61:72–78

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Matthew B. Francis.

Rights and permissions

Reprints and permissions

About this article

Cite this article

M. Hooker, J., P. O’Neil, J., W. Romanini, D. et al. Genome-free Viral Capsids as Carriers for Positron Emission Tomography Radiolabels. Mol Imaging Biol 10, 182–191 (2008). https://doi.org/10.1007/s11307-008-0136-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11307-008-0136-5

Key words

Navigation