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Recombinant elastin-based nanoparticles for targeted gene therapy

Abstract

Among viruses, lentiviral vectors have been popular vectors for gene delivery due to their efficient mode of gene delivery. However, the nonspecific delivery of genes associated with lentiviral vectors may result in undesirable side effects. Here we propose a heterogeneous nanoparticle (NP) delivery system for targeted delivery of lentiviral particles containing a therapeutic gene. The heterogeneous NPs consist of the low-density lipoprotein receptor repeat 3 (LDLR3) and the keratinocyte growth factor (KGF), each fused to elastin-like polypeptides (ELPs), LDLR3-ELP and KGF-ELP, respectively. Our results show that although homogeneous NPs comprising of LDLR3-ELP alone blocked viral transduction, heterogeneous NPs comprising of KGF-ELP and LDLR3-ELP enhanced viral transduction in cells expressing high levels of the KGF receptors compared with cells expressing low levels of KGF receptors. Overall, this novel design may help with the targeting of specific cells that overexpress growth factor receptors such as KGF receptors.

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References

  1. Nishida K, Smith Z, Rana D, Palmer J, Gallicano GI . Cystic fibrosis: a look into the future of prenatal screening and therapy. Birth Defects Res 2015; 105: 73–80.

    Article  CAS  Google Scholar 

  2. Maude SL, Frey N, Shaw PA, Aplenc R, Barrett DM, Bunin NJ et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med 2014; 371: 1507–1517.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Bartus RT, Weinberg MS, Samulski RJ . Parkinson’s disease gene therapy: success by design meets failure by efficacy. Mol Ther 2014; 22: 487–497.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Wu JX, Liu S-H, Nemunaitis JJ, Brunicardi FC . Liposomal insulin promoter–thymidine kinase gene therapy followed by ganciclovir effectively ablates human pancreatic cancer in mice. Cancer Lett 2015; 359: 206–210.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Ko NR, Cheong J, Noronha A, Wilds CJ, Oh JK . Reductively-sheddable cationic nanocarriers for dual chemotherapy and gene therapy with enhanced release. Colloids Surf B: Biointerfaces 2015; 126: 178–187.

    Article  CAS  PubMed  Google Scholar 

  6. Kraynyak K, Bodles-Brakhop A, Bagarazzi M Tapping the potential of DNA delivery with electroporation for cancer immunotherapyCurrent Topics in Microbiology and Immunology. Springer: Berlin Heidelberg, 2015, p 1–24.

    Google Scholar 

  7. Cai M, Yang Y . Targeted genome editing tools for disease modeling and gene therapy. Current Gene Ther 2014; 14: 2–9.

    Article  CAS  Google Scholar 

  8. Nasirinezhad F, Gajavelli S, Priddy B, Jergova S, Zadina J, Sagen J . Viral vectors encoding endomorphins and serine histogranin attenuate neuropathic pain symptoms after spinal cord injury in rats. Mol Pain 2015; 11: 2.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Shearer RF, Saunders DN . Experimental design for stable genetic manipulation in mammalian cell lines: lentivirus and alternatives. Genes Cells 2015; 20: 1–10.

    Article  CAS  PubMed  Google Scholar 

  10. Frimpong K, Spector SA . Cotransduction of nondividing cells using lentiviral vectors. Gene Ther 2000; 7: 1562–1569.

    Article  CAS  PubMed  Google Scholar 

  11. Beignon AS, Mollier K, Liard C, Coutant F, Munier S, Riviere J et al. Lentiviral vector-based prime/boost vaccination against AIDS: pilot study shows protection against Simian immunodeficiency virus SIVmac251 challenge in macaques. J Virol 2009; 83: 10963–10974.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Scaramuzza S, Biasco L, Ripamonti A, Castiello MC, Loperfido M, Draghici E et al. Preclinical safety and efficacy of human CD34+ cells transduced with lentiviral vector for the treatment of Wiskott-Aldrich syndrome. Mol Ther 2013; 21: 175–184.

    Article  CAS  PubMed  Google Scholar 

  13. Craigie R, Bushman FD . HIV DNA integration. Cold Spring Harb Perspect Med 2012; 2: a006890.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Cesani M, Plati T, Lorioli L, Benedicenti F, Redaelli D, Dionisio F et al. Shedding of clinical-grade lentiviral vectors is not detected in a gene therapy setting. Gene Ther 2015; 22: 496–502.

    Article  CAS  PubMed  Google Scholar 

  15. Baum C, Dullmann J, Li Z, Fehse B, Meyer J, Williams DA et al. Side effects of retroviral gene transfer into hematopoietic stem cells. Blood 2003; 101: 2099–2114.

    Article  CAS  PubMed  Google Scholar 

  16. Das SK, Menezes ME, Bhatia S, Wang X-Y, Emdad L, Sarkar D et al. Gene therapies for cancer: strategies, challenges and successes. J Cell Physiol 2015; 230: 259–271.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Lichty BD, Power AT, Stojdl DF, Bell JC . Vesicular stomatitis virus: re-inventing the bullet. Trends Mol Med 2004; 10: 210–216.

    Article  CAS  PubMed  Google Scholar 

  18. Ge P, Tsao J, Schein S, Green TJ, Luo M, Zhou ZH . Cryo-EM model of the bullet-shaped vesicular stomatitis virus. Science 2010; 327: 689–693.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Cronin J, Zhang XY, Reiser J . Altering the tropism of lentiviral vectors through pseudotyping. Cuee Gene Ther 2005; 5: 387–398.

    Article  CAS  Google Scholar 

  20. Finkelshtein D, Werman A, Novick D, Barak S, Rubinstein M . LDL receptor and its family members serve as the cellular receptors for vesicular stomatitis virus. Proc Natl Acad Sci USA 2013; 110: 7306–7311.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Han S, Mahato RI, Sung YK, Kim SW . Development of biomaterials for gene therapy. Mol Ther 2000; 2: 302–317.

    Article  CAS  PubMed  Google Scholar 

  22. Kowalczyk T, Hnatuszko-Konka K, Gerszberg A, Kononowicz AK . Elastin-like polypeptides as a promising family of genetically-engineered protein based polymers. World J Microbiol Biotechnol 2014; 30: 2141–2152.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Rodriguez-Cabello JC, Arias FJ, Rodrigo MA, Girotti A . Elastin-like polypeptides in drug delivery. Adv Drug Deliv Rev 2016; 97: 85–100.

    Article  CAS  PubMed  Google Scholar 

  24. Kim JS, Chu HS, Park KI, Won JI, Jang JH . Elastin-like polypeptide matrices for enhancing adeno-associated virus-mediated gene delivery to human neural stem cells. Gene Ther 2012; 19: 329–337.

    Article  CAS  PubMed  Google Scholar 

  25. Dreher MR, Raucher D, Balu N, Michael Colvin O, Ludeman SM, Chilkoti A . Evaluation of an elastin-like polypeptide-doxorubicin conjugate for cancer therapy. J Control Release 2003; 91: 31–43.

    Article  CAS  PubMed  Google Scholar 

  26. Bidwell GL 3rd, Fokt I, Priebe W, Raucher D . Development of elastin-like polypeptide for thermally targeted delivery of doxorubicin. Biochem Pharmacol 2007; 73: 620–631.

    Article  CAS  PubMed  Google Scholar 

  27. Koria P, Yagi H, Kitagawa Y, Megeed Z, Nahmias Y, Sheridan R et al. Self-assembling elastin-like peptides growth factor chimeric nanoparticles for the treatment of chronic wounds. Proc Natl Acad Sci USA 2011; 108: 1034–1039.

    Article  CAS  PubMed  Google Scholar 

  28. Trabbic-Carlson K, Meyer DE, Liu L, Piervincenzi R, Nath N, LaBean T et al. Effect of protein fusion on the transition temperature of an environmentally responsive elastin-like polypeptide: a role for surface hydrophobicity? Protein Eng Design Select 2004; 17: 57–66.

    Article  CAS  Google Scholar 

  29. Urry DW . Physical chemistry of biological free energy transduction as demonstrated by elastic protein-based polymers. J Phys Chem B 1997; 101: 11007–11028.

    Article  CAS  Google Scholar 

  30. Meyer DE, Chilkoti A . Purification of recombinant proteins by fusion with thermally-responsive polypeptides. Nat Biotechnol 1999; 17: 1112–1115.

    Article  CAS  PubMed  Google Scholar 

  31. McCarthy B, Yuan Y, Koria P . Elastin-like-polypeptide based fusion proteins for osteogenic factor delivery in bone healing. Biotechnol Progr 2016; 32: 1029–1037.

    Article  CAS  Google Scholar 

  32. Johnson T, Koria P . Expression and purification of neurotrophin-elastin-like peptide fusion proteins for neural regeneration. BioDrugs 2016; 30: 117–127.

    Article  CAS  PubMed  Google Scholar 

  33. Iglesias R, Koria P . Leveraging growth factor induced macropinocytosis for targeted treatment of lung cancer. Med Oncol (Northwood, Lond, Engl) 2015; 32: 259.

    Article  Google Scholar 

  34. Lopes CD, Goncalves NP, Gomes CP, Saraiva MJ, Pego AP . BDNF gene delivery mediated by neuron-targeted nanoparticles is neuroprotective in peripheral nerve injury. Biomaterials 2017; 121: 83–96.

    Article  CAS  PubMed  Google Scholar 

  35. Chen Y, Xu M, Guo Y, Tu K, Wu W, Wang J et al. Targeted chimera delivery to ovarian cancer cells by heterogeneous gold magnetic nanoparticle. Nanotechnology 2017; 28: 025101.

    Article  PubMed  Google Scholar 

  36. Chorny M, Fishbein I, Tengood JE, Adamo RF, Alferiev IS, Levy RJ . Site-specific gene delivery to stented arteries using magnetically guided zinc oleate-based nanoparticles loaded with adenoviral vectors. FASEB J 2013; 27: 2198–2206.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Wenzel D, Rieck S, Vosen S, Mykhaylyk O, Trueck C, Eberbeck D et al. Identification of magnetic nanoparticles for combined positioning and lentiviral transduction of endothelial cells. Pharm Res 2012; 29: 1242–1254.

    Article  CAS  PubMed  Google Scholar 

  38. Choi JW, Park JW, Na Y, Jung SJ, Hwang JK, Choi D et al. Using a magnetic field to redirect an oncolytic adenovirus complexed with iron oxide augments gene therapy efficacy. Biomaterials 2015; 65: 163–174.

    Article  CAS  PubMed  Google Scholar 

  39. Meyer DE, Chilkoti A . Genetically encoded synthesis of protein-based polymers with precisely specified molecular weight and sequence by recursive directional ligation: examples from the elastin-like polypeptide system. Biomacromolecules 2002; 3: 357–367.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was funded in part by NIH grant R21AR068013 (PK) and by Institutional Research Grant number 93-032-16 from the American Cancer Society (PK). We thank Dr Haura for kindly donating A549, H1650, H23 and H292 cells.

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Correspondence to P Koria.

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Monfort, D., Koria, P. Recombinant elastin-based nanoparticles for targeted gene therapy. Gene Ther 24, 610–620 (2017). https://doi.org/10.1038/gt.2017.54

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