Skip to main content

Advertisement

Log in

Molecular Imaging of Biological Gene Delivery Vehicles for Targeted Cancer Therapy: Beyond Viral Vectors

  • Review Article
  • Published:
Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Cancer persists as one of the most devastating diseases in the world. Problems including metastasis and tumor resistance to chemotherapy and radiotherapy have seriously limited the therapeutic effects of present clinical treatments. To overcome these limitations, cancer gene therapy has been developed over the last two decades for a broad spectrum of applications, from gene replacement and knockdown to vaccination, each with different requirements for gene delivery. So far, a number of genes and delivery vectors have been investigated, and significant progress has been made with several gene therapy modalities in clinical trials. Viral vectors and synthetic liposomes have emerged as the vehicles of choice for many applications. However, both have limitations and risks that restrict gene therapy applications, including the complexity of production, limited packaging capacity, and unfavorable immunological features. While continuing to improve these vectors, it is important to investigate other options, particularly nonviral biological agents such as bacteria, bacteriophages, and bacteria-like particles. Recently, many molecular imaging techniques for safe, repeated, and high-resolution in vivo imaging of gene expression have been employed to assess vector-mediated gene expression in living subjects. In this review, molecular imaging techniques for monitoring biological gene delivery vehicles are described, and the specific use of these methods at different steps is illustrated. Linking molecular imaging to gene therapy will eventually help to develop novel gene delivery vehicles for preclinical study and support the development of future human applications.

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. 1a–g
Fig. 2a–g
Fig. 3a, b

Similar content being viewed by others

References

  1. Cao S, Cripps A, Wei MQ (2009) New strategies for cancer gene therapy: progresses and opportunities. Clin Exp Pharmacol Physiol. doi:10.1111/j.1440-1681.2009.05268.x

  2. Takakura Y, Nishikawa M, Yamashita F, Hashida M (2001) Development of gene drug delivery systems based on pharmacokinetic studies. Eur J Pharm Sci 13:71–76

    Article  PubMed  CAS  Google Scholar 

  3. Soutschek J, Akinc A, Bramlage B, Charisse K, Constien R, Donoghue M et al (2004) Therapeutic silencing of an endogenous gene by systemic administration of modified siRNAs. Nature 432:173–178

    Article  PubMed  Google Scholar 

  4. Kawabata K, Takakura Y, Hashida M (1995) The fate of plasmid DNA after intravenous injection in mice: involvement of scavenger receptors in its hepatic uptake. Pharm Res 12:825–830

    Article  PubMed  CAS  Google Scholar 

  5. Lowenstein PR, Mandel RJ, Xiong WD, Kroeger K, Castro MG (2007) Immune responses to adenovirus and adeno-associated vectors used for gene therapy of brain diseases: the role of immunological synapses in understanding the cell biology of neuroimmune interactions. Curr Gene Ther 7:347–360

    Article  PubMed  CAS  Google Scholar 

  6. Daniel R, Smith JA (2008) Integration site selection by retroviral vectors: molecular mechanism and clinical consequences. Hum Gene Ther 19:557–568

    Article  PubMed  CAS  Google Scholar 

  7. Zhang JS, Liu F, Huang L (2005) Implications of pharmacokinetic behavior of lipoplex for its inflammatory toxicity. Adv Drug Deliv Rev 57:689–698

    Article  PubMed  CAS  Google Scholar 

  8. Jiang H, Couto LB, Patarroyo-White S, Liu T, Nagy D, Vargas JA et al (2006) Effects of transient immunosuppression on adenoassociated, virus-mediated, liver-directed gene transfer in rhesus macaques and implications for human gene therapy. Blood 108:3321–3328

    Article  PubMed  CAS  Google Scholar 

  9. Min JJ, Nguyen VH, Kim HJ, Hong YJ, Choy HE (2008) Quantitative bioluminescence imaging of tumor-targeting bacteria in living animals. Nat Protoc 3:629–636

    Article  PubMed  CAS  Google Scholar 

  10. Massoud TF, Gambhir SS (2003) Molecular imaging in living subjects: seeing fundamental biological processes in a new light. Genes Dev 17:545–580

    Article  PubMed  CAS  Google Scholar 

  11. Gambhir SS (2002) Molecular imaging of cancer with positron emission tomography. Nat Rev Cancer 2:683–693

    Article  PubMed  CAS  Google Scholar 

  12. Min JJ, Gambhir SS (2004) Gene therapy progress and prospects: noninvasive imaging of gene therapy in living subjects. Gene Ther 11:115–125

    PubMed  CAS  Google Scholar 

  13. Weissleder R, Mahmood U (2001) Molecular imaging. Radiology 219:316–333

    PubMed  CAS  Google Scholar 

  14. Gambhir SS, Herschman HR, Cherry SR, Barrio JR, Satyamurthy N, Toyokuni T et al (2000) Imaging transgene expression with radionuclide imaging technologies. Neoplasia 2:118–138

    Article  PubMed  CAS  Google Scholar 

  15. Yang M, Baranov E, Moossa AR, Penman S, Hoffman M (2000) Visualizing gene expression by whole-body fluorescence imaging. Proc Natl Acad Sci USA 97:12278–12282

    Article  PubMed  CAS  Google Scholar 

  16. Ntziachristos V, Ripoll J, Wang LV, Weissleder R (2005) Looking and listening to light: the evolution of whole-body photonic imaging. Nat Biotech 23:313–320

    Article  CAS  Google Scholar 

  17. Shaner NC, Steinbach PA, Tsien RY (2005) A guide to choosing fluorescent proteins. Nat Meth 2:905–909

    Article  CAS  Google Scholar 

  18. Ntziachristos V, Tung CH, Bremer C, Weissleder R (2002) Fluorescence molecular tomography resolves protease activity in vivo. Nat Med 8:757–761

    Article  PubMed  CAS  Google Scholar 

  19. Bhaumik S, Gambhir SS (2002) Optical imaging of Renilla luciferase reporter gene expression in living mice. Proc Natl Acad Sci USA 99:377–382

    Article  PubMed  CAS  Google Scholar 

  20. Contag CH, Bachmann MH (2002) Advances in in vivo bioluminescence imaging of gene expression. Annu Rev Biomed Eng 4:235–260

    Article  PubMed  CAS  Google Scholar 

  21. Edinger M, Hoffmann P, Contag CH, Negrin RS (2003) Evaluation of effector cell fate and function by in vivo bioluminescence imaging. Methods 31:172–179

    Article  PubMed  CAS  Google Scholar 

  22. Matthews JC, Hori K, Cormier MJ (1977) Purification and properties of Renilla reniformis luciferase. Biochemistry 16:85–91

    Article  PubMed  CAS  Google Scholar 

  23. Tannous BA, Kim DE, Fernandez JL, Weissleder R, Breakefield XO (2005) Codon-optimized Gaussia luciferase cdna for mammalian gene expression in culture and in vivo. Mol Ther 11:435–443

    Article  PubMed  CAS  Google Scholar 

  24. Min JJ, Kim HJ, Park JH, Moon SM, Jeong J, Hong YJ et al (2008) Noninvasive real-time imaging of tumors and metastases using tumor-targeting light-emitting Escherichia coli. Mol Imaging Biol 10:54–61

    Article  PubMed  Google Scholar 

  25. Allport JR, Weissleder R (2001) In vivo imaging of gene and cell therapies. Exp Hematol 29:1237–1246

    Article  PubMed  CAS  Google Scholar 

  26. Wu JC, Sundaresan G, Iyer M, Gambhir SS (2001) Noninvasive optical imaging of firefly luciferase reporter gene expression in skeletal muscles of living mice. Mol Ther 4:297–306

    Article  PubMed  CAS  Google Scholar 

  27. Nichol C, Kim EE (2001) Molecular imaging and gene therapy. J Nucl Med 42:1368–1374

    PubMed  CAS  Google Scholar 

  28. Weissleder R (2002) Scaling down imaging: molecular mapping of cancer in mice. Nat Rev Cancer 2:11–18

    Article  PubMed  CAS  Google Scholar 

  29. Ryan RM, Green J, Lewis CE (2006) Use of bacteria in anti-cancer therapies. BioEssays 28:84–94

    Article  PubMed  CAS  Google Scholar 

  30. Palffy R, Gardlik R, Hodosy J, Behuliak M, Resko P, Radvansky J et al (2006) Bacteria in gene therapy: bactofection versus alternative gene therapy. Gene Ther 13:101–105

    Article  PubMed  CAS  Google Scholar 

  31. McCarthy EF (2006) The toxins of William B. Coley and the treatment of bone and soft-tissue sarcomas. Iowa Orthop J 26:154–158

    PubMed  Google Scholar 

  32. Zhao M, Yang M, Ma H, Li XM, Tan X, Li S et al (2006) Targeted therapy with a Salmonella typhimurium leucine-arginine auxotroph cures orthotopic human breast tumors in nude mice. Cancer Res 66:7647–7652

    Article  PubMed  CAS  Google Scholar 

  33. Pawelek JM, Low KB, Bermudes D (1997) Tumor-targeted Salmonella as a novel anticancer vector. Cancer Res 57:4537–4544

    PubMed  CAS  Google Scholar 

  34. Toso JF, Gill VJ, Hwu P, Marincola FM, Restifo NP, Schwartzentruber DJ et al (2002) Phase I study of the intravenous administration of attenuated Salmonella typhimurium to patients with metastatic melanoma. J Clin Oncol 20:142–152

    Article  PubMed  Google Scholar 

  35. Zhao M, Yang M, Li XM, Jiang P, Baranov E, Li S et al (2005) Tumor-targeting bacterial therapy with amino acid auxotrophs of GFP-expressing Salmonella typhimurium. Proc Natl Acad Sci USA 102:755–760

    Article  PubMed  CAS  Google Scholar 

  36. Zhao M, Geller J, Ma H, Yang M, Penman S, Hoffman RM (2007) Monotherapy with a tumor-targeting mutant of Salmonella typhimurium cures orthotopic metastatic mouse models of human prostate cancer. Proc Natl Acad Sci USA 104:10170–10174

    Article  PubMed  CAS  Google Scholar 

  37. Brader P, Stritzker J, Riedl CC, Zanzonico P, Cai S, Burnazi EM et al (2008) Escherichia coli Nissle 1917 facilitates tumor detection by positron emission tomography and optical imaging. Clin Cancer Res 14:2295–2302

    Article  PubMed  CAS  Google Scholar 

  38. Lemmon MJ, van Zijl P, Fox ME, Mauchline ML, Giaccia AJ, Minton NP et al (1997) Anaerobic bacteria as a gene delivery system that is controlled by the tumor microenvironment. Gene Ther 4:791–796

    Article  PubMed  CAS  Google Scholar 

  39. Kimura NT, Taniguchi SI, Aoki K, Baba T (1980) Selective localization and growth of Bifidobacterium bifidum in mouse tumors following intravenous administration. Cancer Res 40:2061–2068

    PubMed  CAS  Google Scholar 

  40. Craft N, Bruhn KW, Nguyen BD, Prins R, Liau LM, Collisson EA et al (2005) Bioluminescent imaging of melanoma in live mice. J Invest Dermatol 125:159–165

    Article  PubMed  CAS  Google Scholar 

  41. Shahabi V, Reyes-Reyes M, Wallecha A, Rivera S, Paterson Y, Maciag P (2008) Development of a Listeria monocytogenes based vaccine against prostate cancer. Cancer Immunol Immunother 57:1301–1313

    Article  PubMed  CAS  Google Scholar 

  42. Shen H, Kanoh M, Maruyama S, Matsumoto A, Zhang W, Asano Y (2008) Attenuated Listeria infection activates natural killer cell cytotoxicity to regress melanoma growth in vivo. Microbiol Immunol 52:107–117

    Article  PubMed  CAS  Google Scholar 

  43. Wood L, Guirnalda P, Seavey M, Paterson Y (2008) Cancer immunotherapy using Listeria monocytogenes and listerial virulence factors. Immunol Res 42:233–245

    Article  PubMed  Google Scholar 

  44. Maciag PC, Radulovic S, Rothman J (2009) The first clinical use of a live-attenuated Listeria monocytogenes vaccine: a phase I safety study of Lm-LLO-E7 in patients with advanced carcinoma of the cervix. Vaccine 27:3975–3983

    Article  PubMed  CAS  Google Scholar 

  45. Pawelek JM, Low KB, Bermudes D (2003) Bacteria as tumour-targeting vectors. Lancet Oncol 4:548–556

    Article  PubMed  Google Scholar 

  46. Platt J, Sodi S, Kelley M, Rockwell S, Bermudes D, Low KB et al (2000) Antitumour effects of genetically engineered Salmonella in combination with radiation. Eur J Cancer 36:2397–2402

    Article  PubMed  CAS  Google Scholar 

  47. Seow Y, Wood MJ (2009) Biological gene delivery vehicles: beyond viral vectors. Mol Ther 17:767–777

    Article  PubMed  CAS  Google Scholar 

  48. Yu YA, Shabahang S, Timiryasova TM, Zhang Q, Beltz R, Gentschev I et al (2004) Visualization of tumors and metastases in live animals with bacteria and vaccinia virus encoding light-emitting proteins. Nat Biotechnol 22:313–320

    Article  PubMed  CAS  Google Scholar 

  49. Hoffman RM, Zhao M (2007) Whole-body imaging of bacterial infection and antibiotic response. Nat Protoc 1:2988–2994

    Article  CAS  Google Scholar 

  50. Hoffman RM, Yang M (2006) Whole-body imaging with fluorescent proteins. Nat Protoc 1:1429–438

    Article  PubMed  CAS  Google Scholar 

  51. Arrach N, Zhao M, Porwollik S, Hoffman RM, McClelland M (2008) Salmonella promoters preferentially activated inside tumors. Cancer Res 68:4827–4832

    Article  PubMed  CAS  Google Scholar 

  52. Curtiss R, Kelly SM, Gulig PA, Nakayama K (1989) Stable recombinant avirulent Salmonella vaccine strains. Adv Exp Med Biol 251:33–47

    PubMed  CAS  Google Scholar 

  53. Datsenko KA, Wanner BL (2000) One-step inactivation of chromosomal genes in Escherichia coli K-12 using PCR products. Proc Natl Acad Sci USA 97:6640–6645

    Article  PubMed  CAS  Google Scholar 

  54. Riedel CU, Monk IR, Casey PG, Morrissey D, O'Sullivan GC, Tangney M et al (2007) Improved luciferase tagging system for listeria monocytogenes allows real-time monitoring in vivo and in vitro. Appl Environ Microbiol 73:3091–3094

    Article  PubMed  CAS  Google Scholar 

  55. Soghomonyan SA, Doubrovin M, Pike J, Luo X, Ittensohn M, Runyan JD et al (2004) Positron emission tomography (PET) imaging of tumor-localized Salmonella expressing HSV1-TK. Cancer Gene Ther 12:101–108

    Article  CAS  Google Scholar 

  56. Tjuvajev J, Blasberg R, Luo X, Zheng LM, King I, Bermudes D (2001) Salmonella-based tumor-targeted cancer therapy: tumor amplified protein expression therapy (TAPET) for diagnostic imaging. J Control Release 74:313–315

    Article  PubMed  CAS  Google Scholar 

  57. Benoit MR, Mayer D, Barak Y, Chen IY, Hu W, Cheng Z et al (2009) Visualizing implanted tumors in mice with magnetic resonance imaging using magnetotactic bacteria. Clin Cancer Res 15:5170–5177

    Article  PubMed  CAS  Google Scholar 

  58. Bermudes D, Low B, Pawelek J (2000) Tumor-targeted salmonella. Highly selective delivery vectors. Adv Exp Med Biol 465:57–63

    Article  PubMed  CAS  Google Scholar 

  59. Ryan RM, Green J, Williams PJ, Tazzyman S, Hunt S, Harmey JH et al (2009) Bacterial delivery of a novel cytolysin to hypoxic areas of solid tumors. Gene Ther 16:329–339

    Article  PubMed  CAS  Google Scholar 

  60. Loessner H, Endmann A, Leschner S, Westphal K, Rohde M, Miloud T et al (2007) Remote control of tumour-targeted Salmonella enterica serovar Typhimurium by the use of L-arabinose as inducer of bacterial gene expression in vivo. Cell Microbiol 9:1529–1537

    Article  PubMed  CAS  Google Scholar 

  61. Nguyen VH, Kim HS, Ha JM, Hong YJ, Choy HE, Min JJ (2010) Genetically engineered Salmonella typhimurium as an imageable therapeutic probe for cancer. Cancer Res 70:18–23

    Google Scholar 

  62. Akin D, Sturgis J, Ragheb K, Sherman D, Burkholder K, Robinson JP et al (2007) Bacteria-mediated delivery of nanoparticles and cargo into cells. Nat Nanotechnol 2:441–449

    Article  PubMed  CAS  Google Scholar 

  63. de Boer PA, Crossley RE, Rothfield LI (1989) A division inhibitor and a topological specificity factor coded for by the minicell locus determine proper placement of the division septum in E. coli. Cell 56:641–649

    PubMed  Google Scholar 

  64. MacDiarmid JA, Madrid-Weiss J, Amaro-Mugridge NB, Phillips L, Brahmbhatt H (2007) Bacterially-derived nanocells for tumor-targeted delivery of chemotherapeutics and cell cycle inhibitors. Cell Cycle 6:2099–2105

    PubMed  CAS  Google Scholar 

  65. MacDiarmid JA, Mugridge NB, Weiss JC, Phillips L, Burn AL, Paulin RP et al (2007) Bacterially derived 400 nm particles for encapsulation and cancer cell targeting of chemotherapeutics. Cancer Cell 11:431–445

    Article  PubMed  CAS  Google Scholar 

  66. MacDiarmid JA, Amaro-Mugridge NB, Madrid-Weiss J, Sedliarou I, Wetzel S, Kochar K et al (2009) Sequential treatment of drug-resistant tumors with targeted minicells containing siRNA or a cytotoxic drug. Nat Biotechnol 27:643–651

    Article  PubMed  CAS  Google Scholar 

  67. Larocca D, Jensen-Pergakes K, Burg MA, Baird A (2001) Receptor-targeted gene delivery using multivalent phagemid particles. Mol Ther 3:476–484

    Article  PubMed  CAS  Google Scholar 

  68. Chatel JM, Pothelune L, Ah-Leung S, Corthier G, Wal JM, Langella P (2008) In vivo transfer of plasmid from food-grade transiting lactococci to murine epithelial cells. Gene Ther 15:1184–1190

    Article  PubMed  CAS  Google Scholar 

  69. Newton JR, Kelly KA, Mahmood U, Weissleder R, Deutscher SL (2006) In vivo selection of phage for the optical imaging of PC-3 human prostate carcinoma in mice. Neoplasia 8:772–780

    Article  PubMed  CAS  Google Scholar 

  70. Newton JR, Miao Y, Deutscher SL, Quinn TP (2007) Melanoma imaging with pretargeted bivalent bacteriophage. J Nucl Med 48:429–436

    PubMed  CAS  Google Scholar 

  71. Woo Y, Adusumilli PS, Fong Y (2006) Advances in oncolytic viral therapy. Curr Opin Investig Drugs 7:549–559

    PubMed  CAS  Google Scholar 

  72. Nettelbeck DM, Jérôme V, Müller R (2000) Gene therapy: designer promoters for tumour targeting. Trends Genet 16:174–181

    Article  PubMed  CAS  Google Scholar 

  73. Dachs GU, Dougherty GJ, Stratford IJ, Chaplin DJ (1997) Targeting gene therapy to cancer: a review. Oncol Res 9:313–325

    PubMed  CAS  Google Scholar 

  74. Kashentseva EA, Douglas J, Zinn KR, Curiel DT, Dmitriev IP (2009) Targeting of adenovirus serotype 5 pseudotyped with short fiber from serotype 41 to c-erbB2-positive cells using bispecific single-chain diabody. J Mol Biol 388:443–461

    Article  PubMed  CAS  Google Scholar 

  75. Bachtarzi H, Stevenson M, Fisher K (2008) Cancer gene therapy with targeted adenoviruses. Exp Opin Drug Deliv 5:1231–1240

    Article  CAS  Google Scholar 

  76. Douglas JT, Rogers BE, Rosenfeld ME, Michael SI, Feng M, Curiel DT (1996) Targeted gene delivery by tropism-modified adenoviral vectors. Nat Biotechnol 14:1574–1578

    Article  PubMed  CAS  Google Scholar 

  77. Watkins SJ, Mesyanzhinov VV, Kurochkina LP, Hawkins RE (1997) The 'adenobody' approach to viral targeting: specific and enhanced adenoviral gene delivery. Gene Ther 4:1004–1012

    Article  PubMed  CAS  Google Scholar 

  78. Greco O, Scott S (2007) Tumor hypoxia and targeted gene therapy. Int Rev Cytol 257:181–212

    Article  PubMed  CAS  Google Scholar 

  79. Jounaidi Y, Doloff JC, Waxman DJ (2007) Conditionally replicating adenoviruses for cancer treatment. Curr Cancer Drug Targets 7:285–301

    Article  PubMed  CAS  Google Scholar 

  80. Chang E, Chalikonda S, Friedl J, Xu H, Phan GQ, Marincola FM et al (2005) Targeting vaccinia to solid tumors with local hyperthermia. Hum Gene Ther 16:435–444

    Article  PubMed  CAS  Google Scholar 

  81. Foloppe J, Kintz J, Futin N, Findeli A, Cordier P, Schlesinger Y et al (2008) Targeted delivery of a suicide gene to human colorectal tumors by a conditionally replicating vaccinia virus. Gene Ther 15:1361–1371

    Article  PubMed  CAS  Google Scholar 

  82. Brader P, Kelly KJ, Chen N, Yu YA, Zhang Q, Zanzonico P et al (2009) Imaging a genetically engineered oncolytic vaccinia virus (GLV-1h99) using a human norepinephrine transporter reporter gene. Clin Cancer Res 15:3791–3801

    Article  PubMed  CAS  Google Scholar 

  83. Peerlinck I, Merron A, Baril P, Conchon S, Martin-Duque P, Hindorf C et al (2009) Targeted radionuclide therapy using a Wnt-targeted replicating adenovirus encoding the Na/I symporter. Clin Cancer Res 15:6595–6601

    Article  PubMed  CAS  Google Scholar 

  84. Msaouel P, Iankov ID, Allen C, Aderca I, Federspiel MJ, Tindall DJ et al (2009) Noninvasive imaging and radiovirotherapy of prostate cancer using an oncolytic measles virus expressing the sodium iodide symporter. Mol Ther 17:2041–2048

    Google Scholar 

  85. Adams JY, Johnson M, Sato M, Berger F, Gambhir SS, Carey M et al (2002) Visualization of advanced human prostate cancer lesions in living mice by a targeted gene transfer vector and optical imaging. Nat Med 8:891–896

    PubMed  CAS  Google Scholar 

  86. Rubinchik S, Wang D, Yu H, Fan F, Luo M, Norris JS et al (2001) A complex adenovirus vector that delivers FASL-GFP with combined prostate-specific and tetracycline-regulated expression. Mol Ther 4:416–426

    Article  PubMed  CAS  Google Scholar 

  87. Sato M, Johnson M, Zhang L, Gambhir SS, Carey M, Wu L (2005) Functionality of androgen receptor-based gene expression imaging in hormone refractory prostate cancer. Clin Cancer Res 11:3743–3749

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This research was supported by the the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (No. 2009-0091729).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Jung-Joon Min.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Min, JJ., Nguyen, V.H. & Gambhir, S.S. Molecular Imaging of Biological Gene Delivery Vehicles for Targeted Cancer Therapy: Beyond Viral Vectors. Nucl Med Mol Imaging 44, 15–24 (2010). https://doi.org/10.1007/s13139-009-0006-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13139-009-0006-3

Keywords

Navigation