Vectors for inhaled gene therapy in lung cancer. Application for Nano oncology and safety of bio nanotechnology

International Journal of Molecular Sciences

Volumn 13, Issue 9, 2012, Pages 10828-10862

  Zarogouldis, Paul ^a,b   Karamanos, Nikos K ^c   Porpodis, Konstantinos ^a   Domvri, Kalliopi ^a   Huang, Haidong ^d   Hohenforst Schimdt, Wolfgang ^e   Goldberg, Eugene P ^f   Zarogoulidis, Konstantinos ^a  

^a ARISTOTLE UNIVERSITY OF THESSALONIKI   (Greece)

^b RUHRLANDKLINIK   (Germany)

^c UNIVERSITY OF PATRAS   (Greece)

^d SECOND MILITARY MEDICAL UNIVERSITY   (China)

^e UNIVERSITY OF WÜRZBURG   (Germany)

^f J Crayton Pruitt Family Department of Biomedical Engineering   (United States)

Author keywords

Inhaled gene therapy; Lung cancer; Nanobiotechnology; Nanocomplexes; Non viral vectors

Indexed keywords

ADENOVIRUS VECTOR; AMINO ACID; APATITE; CARBONIC ACID; CHITOSAN; COPOLYMER; DOXORUBICIN; FRACTALKINE; GOLD NANOPARTICLE; GRANULOCYTE MACROPHAGE COLONY STIMULATING FACTOR; LACTOFERRIN; LIPOFECTAMINE; LIPOSOME; MACROGOL; OSTEOPONTIN; PLASMID DNA; POLYETHYLENEIMINE; POLYGLACTIN; POLYLYSINE; PROTAMINE SULFATE; UROCANIC ACID; AEROSOL;

AEROSOL; CANCER CHEMOTHERAPY; CANCER GENE THERAPY; CANCER IMMUNOTHERAPY; COMPLEX FORMATION; CROSS LINKING; DRUG FORMULATION; GENE EXPRESSION REGULATION; HUMAN; LIPOSOMAL GENE DELIVERY SYSTEM; LUNG CANCER; LUNG CARCINOGENESIS; LUNG FUNCTION TEST; LUNG TOXICITY; MOLECULAR WEIGHT; NANOBIOTECHNOLOGY; NONHUMAN; REVIEW; TOXICITY TESTING; TUMOR MICROENVIRONMENT; VIRAL GENE DELIVERY SYSTEM; ADMINISTRATION AND DOSAGE; ANIMAL; GENE THERAPY; GENE TRANSFER; GENE VECTOR; GENETICS; INHALATIONAL DRUG ADMINISTRATION; LUNG; LUNG NEOPLASMS; NANOMEDICINE; NANOTECHNOLOGY; PATHOLOGY; PROCEDURES; THERAPEUTIC USE;

ADMINISTRATION, INHALATION; AEROSOLS; ANIMALS; GENE TRANSFER TECHNIQUES; GENETIC THERAPY; GENETIC VECTORS; HUMANS; LUNG; LUNG NEOPLASMS; NANOMEDICINE; NANOTECHNOLOGY;

EID: 84866935335     PISSN: 16616596     EISSN: 14220067     Source Type: Journal    
DOI: 10.3390/ijms130910828     Document Type: Review

References (162)

1. Siegel, R.; Naishadham, D.; Jemal, A. Cancer statistics, 2012. CA Cancer J. Clin. 2012, 62, 10-29.
2. Peng, G.; Hakim, M.; Broza, Y.Y.; Billan, S.; Abdah-Bortnyak, R.; Kuten, A.; Tisch, U.; Haick, H. Detection of lung, breast, colorectal, and prostate cancers from exhaled breath using a single array of nanosensors. Br. J. Cancer 2010, 103, 542-551.
3. Barash, O.; Peled, N.; Tisch, U.; Bunn, P.A., Jr.; Hirsch, F.R.; Haick, H. Classification of lung cancer histology by gold nanoparticle sensors. Nanomedicine 2012, 8, 580-589.
4. Hakim, M.; Billan, S.; Tisch, U. Bad breath: Can analysis of exhaled breath help sniff out cancer? Expert Rev. Mol. Diagn. 2011, 11, 469-471.
5. Peng, G.; Tisch, U.; Adams, O.; Hakim, M.; Shehada, N.; Broza, Y.Y.; Billan, S.; Abdah-Bortnyak, R.; Kuten, A.; Haick, H. Diagnosing lung cancer in exhaled breath using gold nanoparticles. Nat. Nanotechnol. 2009, 4, 669-673.
6. Peng, G.; Tisch, U.; Haick, H. Detection of nonpolar molecules by means of carrier scattering in random networks of carbon nanotubes: Toward diagnosis of diseases via breath samples. Nano Lett. 2009, 9, 1362-1368.
7. Dovgolevsky, E.; Tisch, U.; Haick, H. Chemically sensitive resistors based on monolayer-capped cubic nanoparticles: Towards configurable nanoporous sensors. Small 2009, 5, 1158-1161.
8. Zarogoulidis, K.; Eleftheriadou, E.; Kontakiotis, T.; Gerasimou, G.; Zarogoulidis, P.; Sapardanis, I.; Galaktidou, G.; Sakkas, L.; Gotzamani-Psarrakou, A.; Karatzas, N. Long acting somatostatin analogues in combination to antineoplastic agents in the treatment of small cell lung cancer patients. Lung Cancer 2012, 76, 84-88.
9. Liu, L.; Wu, J.; Zhong, R.; Wu, C.; Zou, L.; Yang, B.; Chen, W.; Zhu, B.; Duan, S.; Yu, D.; et al. Multi-loci analysis reveals the importance of genetic variations in sensitivity of platinum-based chemotherapy in non-small-cell lung cancer. Mol. Carcinog. 2012, doi:10.1002/mc.21942.
10. Wang, M.; Zhao, J.; Zhang, L.M.; Li, H.; Yu, J.P.; Ren, X.B.; Wang, C.L. Combined Erlotinib and Cetuximab overcome the acquired resistance to epidermal growth factor receptors tyrosine kinase inhibitor in non-small-cell lung cancer. J. Cancer Res. Clin. Oncol. 2012, doi:10.1007/s00432-012-1291-2.
11. Gridelli, C.; Rossi, A.; Airoma, G.; Bianco, R.; Costanzo, R.; Daniele, B.; Chiara, G.D.; Grimaldi, G.; Irtelli, L.; Maione, P.; et al.Treatment of pulmonary neuroendocrine tumours: State of the art and future developments. Cancer Treat. Rev. 2012, doi:10.1016/j.ctrv.2012.06.012.
12. Michaelsen, S.R.; Christensen, C.L.; Sehested, M.; Cramer, F.; Poulsen, T.T.; Patterson, A.V.; Poulsen, H.S. Single agent- and combination treatment with two targeted suicide gene therapy systems is effective in chemo-resistant small cell lung cancer (SCLC) cells. J. Gene Med. 2012, doi:10.1002/jgm.2630. lung cancer; inhaled gene therapy; non-viral vectors; nanocomplexes; nanobiotechnology
13. Metro, G.; Chiari, R.; Duranti, S.; Siggillino, A.; Fischer, M.J.; Giannarelli, D.; Ludovini, V.; Bennati, C.; Marcomigni, L.; Baldi, A.; et al. Impact of specific mutant KRAS on clinical outcome of EGFR-TKI-treated advanced non-small cell lung cancer patients with an EGFR wild type genotype. Lung Cancer 2012, doi:10.1016/j.lungcan.2012.06.005.
14. Passaro, A.; Palazzo, A.; Trenta, P.; Mancini, M.L.; Morano, F.; Cortesi, E. Molecular and clinical analysis of predictive biomarkers in non-small-cell lung Cancer. Curr. Med. Chem. 2012, doi:: 10.2174/092986712801661149.
15. Liu, P.; Morrison, C.; Wang, L.; Xiong, D.; Vedell, P.; Cui, P.; Hua, X.; Ding, F.; Lu, Y.; James, M.; et al. Identification of somatic mutations in non-small cell lung carcinomas using whole-exome sequencing. Carcinogenesis 2012, doi:10.1093/carcin/bgs148.
16. Markman, M. Intraperitoneal chemotherapy in the management of ovarian cancer: Focus on carboplatin. Ther. Clin. Risk Manag. 2009, 5, 161-168.
17. Fujiwara, S.; Wada, H.; Miyata, H.; Kawada, J.; Kawabata, R.; Nishikawa, H.; Gnjatic, S.; Sedrak, C.; Sato, E.; Nakamura, Y.; et al. Clinical trial of the intratumoral administration of labeled DC combined with systemic chemotherapy for esophageal cancer. J. Immunother. 2012, 35, 513-521.
18. Zarogoulidis, P.; Eleftheriadou, E.; Sapardanis, I.; Zarogoulidou, V.; Lithoxopoulou, H.; Kontakiotis, T.; Karamanos, N.; Zachariadis, G.; Mabroudi, M.; Zisimopoulos, A.; et al. Feasibility and effectiveness of inhaled carboplatin in NSCLC patients. Invest. New Drugs 2012, 30, 1628-1640.
19. Zarogoulidis, P.; Chatzaki, E.; Porpodis, K.; Domvri, K.; Hohenforst-Schmidt, W.; Goldberg, E.P.; Karamanos, N.; Zarogoulidis, K. Inhaled chemotherapy in lung cancer: Future concept of nanomedicine. Int. J. Nanomed. 2012, 7, 1551-1572.
20. Zarogoulidis, P.; Chatzaki, E.; Hohenforst-Schmidt, W.; Goldberg, E.P.; Galaktidou, G.; Kontakiotis, T.; Karamanos, N.; Zarogoulidis, K. Management of malignant pleural effusion by suicide gene therapy in advanced stage lung cancer: A case series and literature review. Cancer Gene Ther. 2012, doi:10.1038/cgt.2012.36.
21. Yu, K.N.; Minai-Tehrani, A.; Chang, S.H.; Hwang, S.K.; Hong, S.H.; Kim, J.E.; Shin, J.Y.; Park, S.J.; Kim, J.H.; Kwon, J.T.; et al. Aerosol delivery of small hairpin osteopontin blocks pulmonary metastasis of breast cancer in mice. PLoS One 2010, 5, e15623.
22. Tatsumura, T.; Yamamoto, K.; Murakami, A.; Tsuda, M.; Sugiyama, S. New chemotherapeutic method for the treatment of tracheal and bronchial cancers-Nebulization chemotherapy. Gan No Rinsho 1983, 29, 765-770.
23. Hershey, A.E.; Kurzman, I.D.; Forrest, L.J.; Bohling, C.A.; Stonerook, M.; Placke, M.E.; Imondi, A.R.; Vail, D.M. Inhalation chemotherapy for macroscopic primary or metastatic lung tumors: Proof of principle using dogs with spontaneously occurring tumors as a model. Clin. Cancer Res. 1999, 5, 2653-2659.
24. Hureaux, J.; Lagarce, F.; Gagnadoux, F.; Vecellio, L.; Clavreul, A.; Roger, E.; Kempf, M.; Racineux, J.L.; Diot, P.; Benoit, J.P.; et al. Lipid nanocapsules: Ready-to-use nanovectors for the aerosol delivery of paclitaxel. Eur. J. Pharm. Biopharm. 2009, 73, 239-246.
25. El-Gendy, N.; Berkland, C. Combination chemotherapeutic dry powder aerosols via controlled nanoparticle agglomeration. Pharm. Res. 2009, 26, 1752-1763.
26. Knight, V.; Koshkina, N.V.; Golunski, E.; Roberts, L.E.; Gilbert, B.E. Cyclosporin A aerosol improves the anticancer effect of paclitaxel aerosol in mice. Trans. Am. Clin. Climatol. Assoc. 2004, 115, 395-404; Discussion 404.
27. Wittgen, B.P.; Kunst, P.W.; Perkins, W.R.; Lee, J.K.; Postmus, P.E. Assessing a system to capture stray aerosol during inhalation of nebulized liposomal cisplatin. J. Aerosol. Med. 2006, 19, 385-391.
28. Tseng, C.L.; Su, W.Y.; Yen, K.C.; Yang, K.C.; Lin, F.H. The use of biotinylated-EGF-modified gelatin nanoparticle carrier to enhance cisplatin accumulation in cancerous lungs via inhalation. Biomaterials 2009, 30, 3476-3485.
29. Wittgen, B.P.; Kunst, P.W.; van der Born, K.; van Wijk, A.W.; Perkins, W.; Pilkiewicz, F.G.; Perez-Soler, R.; Nicholson, S.; Peters, G.J.; Postmus, P.E. Phase I study of aerosolized SLIT cisplatin in the treatment of patients with carcinoma of the lung. Clin. Cancer Res. 2007, 13, 2414-2421.
30. Otterson, G.A.; Villalona-Calero, M.A.; Hicks, W.; Pan, X.; Ellerton, J.A.; Gettinger, S.N.; Murren, J.R. Phase I/II study of inhaled doxorubicin combined with platinum-based therapy for advanced non-small cell lung cancer. Clin. Cancer Res. 2010, 16, 2466-2473.
31. Otterson, G.A.; Villalona-Calero, M.A.; Sharma, S.; Kris, M.G.; Imondi, A.; Gerber, M.; White, D.A.; Ratain, M.J.; Schiller, J.H.; Sandler, A.; et al. Phase I study of inhaled Doxorubicin for patients with metastatic tumors to the lungs. Clin. Cancer Res. 2007, 13, 1246-1252.
32. Verschraegen, C.F.; Gilbert, B.E.; Loyer, E.; Huaringa, A.; Walsh, G.; Newman, R.A.; Knight, V. Clinical evaluation of the delivery and safety of aerosolized liposomal 9-nitro-20(s)-camptothecin in patients with advanced pulmonary malignancies. Clin. Cancer Res. 2004, 10, 2319-2326.
33. Chirmule, N.; Hughes, J.V.; Gao, G.P.; Raper, S.E.; Wilson, J.M. Role of E4 in eliciting CD4 T-cell and B-cell responses to adenovirus vectors delivered to murine and nonhuman primate lungs. J. Virol. 1998, 72, 6138-6145.
34. Gautam, A.; Densmore, C.L.; Waldrep, J.C. Pulmonary cytokine responses associated with PEI-DNA aerosol gene therapy. Gene Ther. 2001, 8, 254-257.
35. West, J.; Rodman, D.M. Gene therapy for pulmonary diseases. Chest 2001, 119, 613-617.
36. Manunta, M.D.; McAnulty, R.J.; Tagalakis, A.D.; Bottoms, S.E.; Campbell, F.; Hailes, H.C.; Tabor, A.B.; Laurent, G.J.; O'Callaghan, C.; Hart, S.L. Nebulisation of receptor-targeted nanocomplexes for gene delivery to the airway epithelium. PLoS One 2011, 6, e26768.
37. Gautam, A.; Densmore, C.L.; Xu, B.; Waldrep, J.C. Enhanced gene expression in mouse lung after PEI-DNA aerosol delivery. Mol. Ther. 2000, 2, 63-70.
38. Zamora-Avila, D.E.; Zapata-Benavides, P.; Franco-Molina, M.A.; Saavedra-Alonso, S.; Trejo-Avila, L.M.; Resendez-Perez, D.; Mendez-Vazquez, J.L.; Isaias-Badillo, J.; Rodriguez-Padilla, C. WT1 gene silencing by aerosol delivery of PEI-RNAi complexes inhibits B16-F10 lung metastases growth. Cancer Gene Ther. 2009, 16, 892-899.
39. Densmore, C.L. The re-emergence of aerosol gene delivery: A viable approach to lung cancer therapy. Curr. Cancer Drug Targets 2003, 3, 275-286.
40. Frederiksen, K.S.; Abrahamsen, N.; Cristiano, R.J.; Damstrup, L.; Poulsen, H.S. Gene delivery by an epidermal growth factor/DNA polyplex to small cell lung cancer cell lines expressing low levels of epidermal growth factor receptor. Cancer Gene Ther. 2000, 7, 262-268.
41. Kim, H.W.; Park, I.K.; Cho, C.S.; Lee, K.H.; Beck, G.R., Jr.; Colburn, N.H.; Cho, M.H. Aerosol delivery of glucosylated polyethylenimine/phosphatase and tensin homologue deleted on chromosome 10 complex suppresses Akt downstream pathways in the lung of K-ras null mice. Cancer Res. 2004, 64, 7971-7976.
42. Zou, Y.; Tornos, C.; Qiu, X.; Lia, M.; Perez-Soler, R. p53 aerosol formulation with low toxicity and high efficiency for early lung cancer treatment. Clin. Cancer Res. 2007, 13, 4900-4908.
43. Gautam, A.; Densmore, C.L.; Melton, S.; Golunski, E.; Waldrep, J.C. Aerosol delivery of PEI-p53 complexes inhibits B16-F10 lung metastases through regulation of angiogenesis. Cancer Gene Ther. 2002, 9, 28-36.
44. Lumb, A.B.; Nunn, J.F. Nunn's Applied Respiratory Physiology, 5th ed.; Butterworth-Heinemann: Oxford, UK; Boston, MA, USA, 2000; p 687.
45. El-Chemaly, S.; Levine, S.J.; Moss, J. Lymphatics in lung disease. Ann. N. Y. Acad.Sci. 2008, 1131, 195-202.
46. Cryan, S.A. Carrier-based strategies for targeting protein and peptide drugs to the lungs. AAPS J. 2005, 7, E20-E41.
47. Leclerc, J.; Courcot-Ngoubo Ngangue, E.; Cauffiez, C.; Allorge, D.; Pottier, N.; Lafitte, J.J.; Debaert, M.; Jaillard, S.; Broly, F.; Lo-Guidice, J.M. Xenobiotic metabolism and disposition in human lung: Transcript profiling in non-tumoral and tumoral tissues. Biochimie 2011, 93, 1012-1027.
48. Bosquillon, C. Drug transporters in the lung-Do they play a role in the biopharmaceutics of inhaled drugs? J. Pharm. Sci. 2010, 99, 2240-2255.
49. Corti, A.; Pastorino, F.; Curnis, F.; Arap, W.; Ponzoni, M.; Pasqualini, R. Targeted drug delivery and penetration into solid tumors. Med. Res. Rev. 2011, doi:10.1002/med.20238.
50. Waite, C.L.; Roth, C.M. Nanoscale drug delivery systems for enhanced drug penetration into solid tumors: Current progress and opportunities. Crit. Rev. Biomed. Eng. 2012, 40, 21-41.
51. Cuong, N.V.; Hsieh, M.F. Molecular targeting of liposomal nano-particles to lymphatic system. Curr. Cancer Drug Targets 2011, 11, 147-155.
52. Shinohara, H. Distribution of lymphatic stomata on the pleural surface of the thoracic cavity and the surface topography of the pleural mesothelium in the golden hamster. Anat. Rec 1997, 249, 16-23.
53. Swift, D.L. Aerosols and humidity therapy. Generation and respiratory deposition of therapeutic aerosols. Am. Rev. Respir. Dis. 1980, 122, 71-77.
54. Houtmeyers, E.; Gosselink, R.; Gayan-Ramirez, G.; Decramer, M. Regulation of mucociliary clearance in health and disease. Eur. Respir. J. 1999, 13, 1177-1188.
55. Dolovich, M.B.; Killian, D.; Wolff, R.K.; Obminski, G.; Newhouse, M.T. Pulmonary aerosol deposition in chronic bronchitis: Intermittent positive pressure breathing vs. quiet breathing. Am. Rev. Respir. Dis. 1977, 115, 397-402.
56. Dolovich, M.B.; Sanchis, J.; Rossman, C.; Newhouse, M.T. Aerosol penetrance: A sensitive index of peripheral airways obstruction. J. Appl. Physiol. 1976, 40, 468-471.
57. Messina, M.S.; Smaldone, G.C. Evaluation of quantitative aerosol techniques for use in bronchoprovocation studies. J. Allergy Clin. Immunol. 1985, 75, 252-257.
58. Nunn, J.F. Nunn's Applied Respiratory Physiology; 4th ed.; Butterworth-Heinemann: Oxford, UK; Boston, MA, USA, 1993; p 658.
59. Zarogoulidis, P.; Papanas, N.; Kouliatsis, G.; Spyratos, D.; Zarogoulidis, K.; Maltezos, E. Inhaled insulin: Too soon to be forgotten? J. Aerosol. Med. Pulm. Drug Deliv. 2011, 24, 213-223.
60. Gautam, A.; Densmore, C.L.; Golunski, E.; Xu, B.; Waldrep, J.C. Transgene expression in mouse airway epithelium by aerosol gene therapy with PEI-DNA complexes. Mol. Ther. 2001, 3, 551-556.
61. Densmore, C.L.; Kleinerman, E.S.; Gautam, A.; Jia, S.F.; Xu, B.; Worth, L.L.; Waldrep, J.C.; Fung, Y.K.; T'Ang, A.; Knight, V. Growth suppression of established human osteosarcoma lung metastases in mice by aerosol gene therapy with PEI-p53 complexes. Cancer Gene Ther. 2001, 8, 619-627.
62. Davies, L.A.; McLachlan, G.; Sumner-Jones, S.G.; Ferguson, D.; Baker, A.; Tennant, P.; Gordon, C.; Vrettou, C.; Baker, E.; Zhu, J.; et al. Enhanced lung gene expression after aerosol delivery of concentrated pDNA/PEI complexes. Mol. Ther. 2008, 16, 1283-1290.
63. Gautam, A.; Waldrep, J.C.; Kleinerman, E.S.; Xu, B.; Fung, Y.K.; T'Ang, A.; Densmore, C.L. Aerosol gene therapy for metastatic lung cancer using PEI-p53 complexes. Methods Mol. Med. 2003, 75, 607-618.
64. Gautam, A.; Waldrep, J.C.; Orson, F.M.; Kinsey, B.M.; Xu, B.; Densmore, C.L. Topical gene therapy for pulmonary diseases with PEI-DNA aerosol complexes. Methods Mol. Med. 2003, 75, 561-572.
65. Davis, J.N.; Stagg, D. Interrelationships of the volume and time components of individual breaths in resting man. J. Physiol. 1975, 245, 481-498.
66. Anderson, M.; Svartengren, M.; Bylin, G.; Philipson, K.; Camner, P. Deposition in asthmatics of particles inhaled in air or in helium-oxygen. Am. Rev. Respir. Dis. 1993, 147, 524-528.
67. Summers, Q.A. Inhaled drugs and the lung. Clin. Exp. Allergy 1991, 21, 259-268.
68. Labiris, N.R.; Dolovich, M.B. Pulmonary drug delivery. Part II: The role of inhalant delivery devices and drug formulations in therapeutic effectiveness of aerosolized medications. Br. J. Clin. Pharmacol. 2003, 56, 600-612.
69. Labiris, N.R.; Dolovich, M.B. Pulmonary drug delivery. Part I: Physiological factors affecting therapeutic effectiveness of aerosolized medications. Br. J. Clin. Pharmacol. 2003, 56, 588-599.
70. Dong, A.Q.; Kong, M.J.; Ma, Z.Y.; Qian, J.F.; Xu, X.H. Down-regulation of IGF-IR using small, interfering, hairpin RNA (siRNA) inhibits growth of human lung cancer cell line A549 in vitro and in nude mice. Cell Biol. Int. 2007, 31, 500-507.
71. Kawabata, A.; Baoum, A.; Ohta, N.; Jacquez, S.; Seo, G.M.; Berkland, C.; Tamura, M. Intratracheal administration of a nanoparticle-based therapy with the angiotensin II type 2 receptor gene attenuates lung cancer growth. Cancer Res. 2012, 72, 2057-2067.
72. Zhong, Z.; Wan, Y.; Han, J.; Shi, S.; Zhang, Z.; Sun, X. Improvement of adenoviral vector-mediated gene transfer to airway epithelia by folate-modified anionic liposomes. Int. J. Nanomed. 2011, 6, 1083-1093.
73. Klonne, D.R.; Dodd, D.E.; Losco, P.E.; Troup, C.M.; Tyler, T.R. Two-week aerosol inhalation study on polyethylene glycol (PEG) 3350 in F-344 rats. Drug Chem. Toxicol. 1989, 12, 39-48.
74. Minai-Tehrani, A.; Park, Y.C.; Hwang, S.K.; Kwon, J.T.; Chang, S.H.; Park, S.J.; Yu, K.N.; Kim, J.E.; Shin, J.Y.; Kim, J.H.; et al. Aerosol delivery of kinase-deficient Akt1 attenuates Clara cell injury induced by naphthalene in the lungs of dual luciferase mice. J. Vet. Sci. 2011, 12, 309-317.
75. Maestrelli, P.; Schlunssen, V.; Mason, P.; Sigsgaard, T. Contribution of host factors and workplace exposure to the outcome of occupational asthma. Eur. Respir. Rev. 2012, 21, 88-96.
76. Godbey, W.T.; Wu, K.K.; Mikos, A.G. Tracking the intracellular path of poly(ethylenimine)/ DNA complexes for gene delivery. Proc. Natl. Acad. Sci. USA 1999, 96, 5177-5181.
77. Ferrari, S.; Pettenazzo, A.; Garbati, N.; Zacchello, F.; Behr, J.P.; Scarpa, M. Polyethylenimine shows properties of interest for cystic fibrosis gene therapy. Biochim. Biophys. Acta 1999, 1447, 219-225.
78. Densmore, C.L.; Orson, F.M.; Xu, B.; Kinsey, B.M.; Waldrep, J.C.; Hua, P.; Bhogal, B.; Knight, V. Aerosol delivery of robust polyethyleneimine-DNA complexes for gene therapy and genetic immunization. Mol. Ther. 2000, 1, 180-188.
79. Ernst, N.; Ulrichskotter, S.; Schmalix, W.A.; Radler, J.; Galneder, R.; Mayer, E.; Gersting, S.; Plank, C.; Reinhardt, D.; Rosenecker, J. Interaction of liposomal and polycationic transfection complexes with pulmonary surfactant. J. Gene Med. 1999, 1, 331-340.
80. Gautam, A.; Densmore, C.L.; Waldrep, J.C. Inhibition of experimental lung metastasis by aerosol delivery of PEI-p53 complexes. Mol. Ther. 2000, 2, 318-323.
81. Koshkina, N.V.; Agoulnik, I.Y.; Melton, S.L.; Densmore, C.L.; Knight, V. Biodistribution and pharmacokinetics of aerosol and intravenously administered DNA-polyethyleneimine complexes: Optimization of pulmonary delivery and retention. Mol. Ther. 2003, 8, 249-254.
82. Hasenpusch, G.; Pfeifer, C.; Aneja, M.K.; Wagner, K.; Reinhardt, D.; Gilon, M.; Ohana, P.; Hochberg, A.; Rudolph, C. Aerosolized BC-819 inhibits primary but not secondary lung cancer growth. PLoS One 2011, 6, e20760.
83. Duan, X.; Jia, S.F.; Koshkina, N.; Kleinerman, E.S. Intranasal interleukin-12 gene therapy enhanced the activity of ifosfamide against osteosarcoma lung metastases. Cancer 2006, 106, 1382-1388.
84. Tan, Y.; Li, S.; Pitt, B.R.; Huang, L. The inhibitory role of CpG immunostimulatory motifs in cationic lipid vector-mediated transgene expression in vivo. Hum. Gene Ther. 1999, 10, 2153-2161.
85. Freimark, B.D.; Blezinger, H.P.; Florack, V.J.; Nordstrom, J.L.; Long, S.D.; Deshpande, D.S.; Nochumson, S.; Petrak, K.L. Cationic lipids enhance cytokine and cell influx levels in the lung following administration of plasmid: Cationic lipid complexes. J. Immunol. 1998, 160, 4580-4586.
86. Li, S.; Wu, S.P.; Whitmore, M.; Loeffert, E.J.; Wang, L.; Watkins, S.C.; Pitt, B.R.; Huang, L. Effect of immune response on gene transfer to the lung via systemic administration of cationic lipidic vectors. Am. J. Physiol. 1999, 276, L796-L804.
87. Jia, S.F.; Worth, L.L.; Densmore, C.L.; Xu, B.; Duan, X.; Kleinerman, E.S. Aerosol gene therapy with PEI: IL-12 eradicates osteosarcoma lung metastases. Clin. Cancer Res. 2003, 9, 3462-3468.
88. Jia, S.F.; Worth, L.L.; Densmore, C.L.; Xu, B.; Zhou, Z.; Kleinerman, E.S. Eradication of osteosarcoma lung metastases following intranasal interleukin-12 gene therapy using a nonviral polyethylenimine vector. Cancer Gene Ther. 2002, 9, 260-266.
89. Cohen, J. IL-12 deaths: Explanation and a puzzle. Science 1995, 270, 908.
90. Tehrani, A.M.; Hwang, S.K.; Kim, T.H.; Cho, C.S.; Hua, J.; Nah, W.S.; Kwon, J.T.; Kim, J.S.; Chang, S.H.; Yu, K.N.; et al. Aerosol delivery of Akt controls protein translation in the lungs of dual luciferase reporter mice. Gene Ther. 2007, 14, 451-458.
91. Hwang, S.K.; Jin, H.; Kwon, J.T.; Chang, S.H.; Kim, T.H.; Cho, C.S.; Lee, K.H.; Young, M.R.; Colburn, N.H.; Beck, G.R., Jr.; et al.Aerosol-delivered programmed cell death 4 enhanced apoptosis, controlled cell cycle and suppressed AP-1 activity in the lungs of AP-1 luciferase reporter mice. Gene Ther. 2007, 14, 1353-1361.
92. Jere, D.; Yoo, M.K.; Arote, R.; Kim, T.H.; Cho, M.H.; Nah, J.W.; Choi, Y.J.; Cho, C.S. Poly (amino ester) composed of poly (ethylene glycol) and aminosilane prepared by combinatorial chemistry as a gene carrier. Pharm. Res. 2008, 25, 875-885.
93. Xu, C.X.; Jere, D.; Jin, H.; Chang, S.H.; Chung, Y.S.; Shin, J.Y.; Kim, J.E.; Park, S.J.; Lee, Y.H.; Chae, C.H.; et al. Poly(ester amine)-mediated, aerosol-delivered Akt1 small interfering RNA suppresses lung tumorigenesis. Am. J. Respir. Crit. Care Med. 2008, 178, 60-73.
94. Park, M.R.; Han, K.O.; Han, I.K.; Cho, M.H.; Nah, J.W.; Choi, Y.J.; Cho, C.S. Degradable polyethylenimine-alt-poly(ethylene glycol) copolymers as novel gene carriers. J. Control. Release 2005, 105, 367-380.
95. Pitard, B.; Bello-Roufai, M.; Lambert, O.; Richard, P.; Desigaux, L.; Fernandes, S.; Lanctin, C.; Pollard, H.; Zeghal, M.; Rescan, P.Y.; et al. Negatively charged self-assembling DNA/poloxamine nanospheres for in vivo gene transfer. Nucleic Acids Res. 2004, 32, e159.
96. Richard-Fiardo, P.; Cambien, B.; Pradelli, E.; Beilvert, F.; Pitard, B.; Schmid-Antomarchi, H.; Schmid-Alliana, A. Effect of fractalkine-Fc delivery in experimental lung metastasis using DNA/704 nanospheres. Cancer Gene Ther. 2011, 18, 761-772.
97. Xing, Z.; Ohkawara, Y.; Jordana, M.; Graham, F.; Gauldie, J. Transfer of granulocyte-macrophage colony-stimulating factor gene to rat lung induces eosinophilia, monocytosis, and fibrotic reactions. J. Clin. Invest. 1996, 97, 1102-1110.
98. Xing, Z.; Braciak, T.; Jordana, M.; Croitoru, K.; Graham, F.L.; Gauldie, J. Adenovirus-mediated cytokine gene transfer at tissue sites. Overexpression of IL-6 induces lymphocytic hyperplasia in the lung. J. Immunol. 1994, 153, 4059-4069.
99. Arndt, C.A.; Koshkina, N.V.; Inwards, C.Y.; Hawkins, D.S.; Krailo, M.D.; Villaluna, D.; Anderson, P.M.; Goorin, A.M.; Blakely, M.L.; Bernstein, M.; et al. Inhaled granulocyte-macrophage colony stimulating factor for first pulmonary recurrence of osteosarcoma: Effects on disease-free survival and immunomodulation. a report from the Children's Oncology Group. Clin. Cancer Res. 2010, 16, 4024-4030.
100. Takagi, T.; Nakano, Y.; Takekoshi, S.; Inagami, T.; Tamura, M. Hemizygous mice for the angiotensin II type 2 receptor gene have attenuated susceptibility to azoxymethane-induced colon tumorigenesis. Carcinogenesis 2002, 23, 1235-1241.
101. Kanehira, T.; Tani, T.; Takagi, T.; Nakano, Y.; Howard, E.F.; Tamura, M. Angiotensin II type 2 receptor gene deficiency attenuates susceptibility to tobacco-specific nitrosamine-induced lung tumorigenesis: Involvement of transforming growth factor-beta-dependent cell growth attenuation. Cancer Res. 2005, 65, 7660-7665.
102. Takeda, K.; Smyth, M.J.; Cretney, E.; Hayakawa, Y.; Yamaguchi, N.; Yagita, H.; Okumura, K. Involvement of tumor necrosis factor-related apoptosis-inducing ligand in NK cell-mediated and IFN-gamma-dependent suppression of subcutaneous tumor growth. Cell. Immunol. 2001, 214, 194-200.
103. Kedinger, V.; Muller, S.; Gronemeyer, H. Targeted expression of tumor necrosis factor-related apoptosis-inducing ligand TRAIL in skin protects mice against chemical carcinogenesis. Mol. Cancer 2011, 10, 34.
104. Jin, H.; Kim, T.H.; Hwang, S.K.; Chang, S.H.; Kim, H.W.; Anderson, H.K.; Lee, H.W.; Lee, K.H.; Colburn, N.H.; Yang, H.S.; et al. Aerosol delivery of urocanic acid-modified chitosan/programmed cell death 4 complex regulated apoptosis, cell cycle, and angiogenesis in lungs of K-ras null mice. Mol. Cancer Ther. 2006, 5, 1041-1049.
105. Koping-Hoggard, M.; Tubulekas, I.; Guan, H.; Edwards, K.; Nilsson, M.; Varum, K.M.; Artursson, P. Chitosan as a nonviral gene delivery system. Structure-property relationships and characteristics compared with polyethylenimine in vitro and after lung administration in vivo. Gene Ther. 2001, 8, 1108-1121.
106. Jiang, H.L.; Park, I.K.; Shin, N.R.; Yoo, H.S.; Akaike, T.; Cho, C.S. Controlled release of Bordetella bronchiseptica dermonecrotoxin (BBD) vaccine from BBD-loaded chitosan microspheres in vitro. Arch. Pharm. Res. 2004, 27, 346-350.
107. Okamoto, H.; Shiraki, K.; Yasuda, R.; Danjo, K.; Watanabe, Y. Chitosan-interferon-beta gene complex powder for inhalation treatment of lung metastasis in mice. J. Control. Release 2011, 150, 187-195.
108. Okamoto, H.; Nishida, S.; Todo, H.; Sakakura, Y.; Iida, K.; Danjo, K. Pulmonary gene delivery by chitosan-pDNA complex powder prepared by a supercritical carbon dioxide process. J. Pharm. Sci. 2003, 92, 371-380.
109. Huang, Y.C.; Vieira, A.; Huang, K.L.; Yeh, M.K.; Chiang, C.H. Pulmonary inflammation caused by chitosan microparticles. J. Biomed. Mater. Res. A 2005, 75, 283-287.
110. Takeuchi, H.; Matsui, Y.; Sugihara, H.; Yamamoto, H.; Kawashima, Y. Effectiveness of submicron-sized, chitosan-coated liposomes in oral administration of peptide drugs. Int. J. Pharm. 2005, 303, 160-170.
111. Lotze, M.T.; Kost, T.A. Viruses as gene delivery vectors: Application to gene function, target validation, and assay development. Cancer Gene Ther. 2002, 9, 692-699.
112. Thomas, M.; Ge, Q.; Lu, J.J.; Chen, J.; Klibanov, A.M. Cross-linked small polyethylenimines: While still nontoxic, deliver DNA efficiently to mammalian cells in vitro and in vivo. Pharm. Res. 2005, 22, 373-380.
113. Panyam, J.; Labhasetwar, V. Biodegradable nanoparticles for drug and gene delivery to cells and tissue. Adv. Drug Deliv. Rev. 2003, 55, 329-347.
114. Wang, Y.Q.; Su, J.; Wu, F.; Lu, P.; Yuan, L.F.; Yuan, W.E.; Sheng, J.; Jin, T. Biscarbamate cross-linked polyethylenimine derivative with low molecular weight, low cytotoxicity, and high efficiency for gene delivery. Int. J. Nanomed. 2012, 7, 693-704.
115. Uchida, S.; Itaka, K.; Chen, Q.; Osada, K.; Ishii, T.; Shibata, M.A.; Harada-Shiba, M.; Kataoka, K. PEGylated polyplex with optimized peg shielding enhances gene introduction in lungs by minimizing inflammatory responses. Mol. Ther. 2012, 20, 1196-1203.
116. Brissault, B.; Kichler, A.; Leborgne, C.; Danos, O.; Cheradame, H.; Gau, J.; Auvray, L.; Guis, C. Synthesis, characterization, and gene transfer application of poly(ethylene glycol-b-ethylenimine) with high molar mass polyamine block. Biomacromolecules 2006, 7, 2863-2870.
117. Fan, W.; Wu, X.; Ding, B.; Gao, J.; Cai, Z.; Zhang, W.; Yin, D.; Wang, X.; Zhu, Q.; Liu, J.; et al. Degradable gene delivery systems based on Pluronics-modified low-molecular-weight polyethylenimine: Preparation, characterization, intracellular trafficking, and cellular distribution. Int. J. Nanomed. 2012, 7, 1127-1138.
118. Jiang, Z.; Sun, C.; Yin, Z.; Zhou, F.; Ge, L.; Liu, X.; Kong, F. Comparison of two kinds of nanomedicine for targeted gene therapy: Premodified or postmodified gene delivery systems. Int. J. Nanomed. 2012, 7, 2019-2031.
119. Margaris, K.N.; Black, R.A. Modelling the lymphatic system: Challenges and opportunities. J. R. Soc. Interface 2012, 9, 601-612.
120. Zeng, Q.; Han, J.; Zhao, D.; Gong, T.; Zhang, Z.; Sun, X. Protection of adenovirus from neutralizing antibody by cationic PEG derivative ionically linked to adenovirus. Int. J. Nanomed. 2012, 7, 985-997.
121. Schughart, K.; Bischoff, R.; Rasmussen, U.B.; Hadji, D.A.; Perraud, F.; Accart, N.; Boussif, O.; Silvestre, N.; Cordier, Y.; Pavirani, A.; et al. Solvoplex: A new type of synthetic vector for intrapulmonary gene delivery. Hum. Gene Ther. 1999, 10, 2891-2905.
122. Schughart, K.; Rasmussen, U.B. Solvoplex synthetic vector for intrapulmonary gene delivery. Preparation and use. Methods Mol. Med. 2002, 69, 83-94.
123. Cheang, T.Y.; Tang, B.; Xu, A.W.; Chang, G.Q.; Hu, Z.J.; He, W.L.; Xing, Z.H.; Xu, J.B.; Wang, M.; Wang, S.M. Promising plasmid DNA vector based on APTES-modified silica nanoparticles. Int. J. Nanomed. 2012, 7, 1061-1067.
124. He, X.; Nie, H.; Wang, K.; Tan, W.; Wu, X.; Zhang, P. In vivo study of biodistribution and urinary excretion of surface-modified silica nanoparticles. Anal. Chem. 2008, 80, 9597-9603.
125. Burns, A.A.; Vider, J.; Ow, H.; Herz, E.; Penate-Medina, O.; Baumgart, M.; Larson, S.M.; Wiesner, U.; Bradbury, M. Fluorescent silica nanoparticles with efficient urinary excretion for nanomedicine. Nano Lett. 2009, 9, 442-448.
126. Ma, W.; Chen, M.; Kaushal, S.; McElroy, M.; Zhang, Y.; Ozkan, C.; Bouvet, M.; Kruse, C.; Grotjahn, D.; Ichim, T.; et al. PLGA nanoparticle-mediated delivery of tumor antigenic peptides elicits effective immune responses. Int. J. Nanomed. 2012, 7, 1475-1487.
127. Li, M.; Panagi, Z.; Avgoustakis, K.; Reineke, J. Physiologically based pharmacokinetic modeling of PLGA nanoparticles with varied mPEG content. Int. J. Nanomed. 2012, 7, 1345-1356.
128. Shi, S.; Zhu, X.; Guo, Q.; Wang, Y.; Zuo, T.; Luo, F.; Qian, Z. Self-assembled mPEG-PCL-g-PEI micelles for simultaneous codelivery of chemotherapeutic drugs and DNA: Synthesis and characterization in vitro. Int. J. Nanomed. 2012, 7, 1749-1759.
129. Chowdhury, E.H.; Akaike, T. High performance DNA nano-carriers of carbonate apatite: Multiple factors in regulation of particle synthesis and transfection efficiency. Int. J. Nanomed. 2007, 2, 101-106.
130. Hossain, S.; Stanislaus, A.; Chua, M.J.; Tada, S.; Tagawa, Y.; Chowdhury, E.H.; Akaike, T. Carbonate apatite-facilitated intracellularly delivered siRNA for efficient knockdown of functional genes. J. Control. Release 2010, 147, 101-108.
131. Hossain, S.; Tada, S.; Akaike, T.; Chowdhury, E.H. Influences of electrolytes and glucose on formulation of carbonate apatite nanocrystals for efficient gene delivery to mammalian cells. Anal. Biochem. 2010, 397, 156-161.
132. Sudimack, J.; Lee, R.J. Targeted drug delivery via the folate receptor. Adv. Drug Deliv. Rev. 2000, 41, 147-162.
133. Li, H.Y.; Seville, P.C.; Williamson, I.J.; Birchall, J.C. The use of amino acids to enhance the aerosolisation of spray-dried powders for pulmonary gene therapy. J. Gene Med. 2005, 7, 343-353.
134. Li, H.Y.; Neill, H.; Innocent, R.; Seville, P.; Williamson, I.; Birchall, J.C. Enhanced dispersibility and deposition of spray-dried powders for pulmonary gene therapy. J. Drug Target. 2003, 11, 425-432.
135. Puvanakrishnan, P.; Park, J.; Chatterjee, D.; Krishnan, S.; Tunnell, J.W. In vivo tumor targeting of gold nanoparticles: Effect of particle type and dosing strategy. Int. J. Nanomed. 2012, 7, 1251-1258.
136. Hirsch, L.R.; Stafford, R.J.; Bankson, J.A.; Sershen, S.R.; Rivera, B.; Price, R.E.; Hazle, J.D.; Halas, N.J.; West, J.L. Nanoshell-mediated near-infrared thermal therapy of tumors under magnetic resonance guidance. Proc. Natl. Acad. Sci. USA 2003, 100, 13549-13554.
137. Loo, C.; Lowery, A.; Halas, N.; West, J.; Drezek, R. Immunotargeted nanoshells for integrated cancer imaging and therapy. Nano Lett. 2005, 5, 709-711.
138. Li, P.; Liu, D.; Miao, L.; Liu, C.; Sun, X.; Liu, Y.; Zhang, N. A pH-sensitive multifunctional gene carrier assembled via layer-by-layer technique for efficient gene delivery. Int. J. Nanomed. 2012, 7, 925-939.
139. Metz-Boutigue, M.H.; Jolles, J.; Mazurier, J.; Schoentgen, F.; Legrand, D.; Spik, G.; Montreuil, J.; Jolles, P. Human lactotransferrin: Amino acid sequence and structural comparisons with other transferrins. Eur. J. Biochem. 1984, 145, 659-676.
140. Teng, C.T.; Beard, C.; Gladwell, W. Differential expression and estrogen response of lactoferrin gene in the female reproductive tract of mouse, rat, and hamster. Biol. Reprod. 2002, 67, 1439-1449.
141. Choe, T.B.; Park, I.C.; Hong, S.I. Enhancement of cationic liposome-mediated transfection by lactoferrin. Biotechnol. Tech. 1998, 12, 577-581.
142. Gupta, A.K.; Curtis, A.S. Lactoferrin and ceruloplasmin derivatized superparamagnetic iron oxide nanoparticles for targeting cell surface receptors. Biomaterials 2004, 25, 3029-3040.
143. Legrand, D.; Pierce, A.; Elass, E.; Carpentier, M.; Mariller, C.; Mazurier, J. Lactoferrin structure and functions. Adv. Exp. Med. Biol. 2008, 606, 163-194.
144. Suzuki, Y.A.; Lopez, V.; Lonnerdal, B. Mammalian lactoferrin receptors: Structure and function. Cell. Mol. Life Sci. 2005, 62, 2560-2575.
145. Kong, F.; Zhou, F.; Ge, L.; Liu, X.; Wang, Y. Mannosylated liposomes for targeted gene delivery. Int. J. Nanomed. 2012, 7, 1079-1089.
146. Tomko, R.P.; Xu, R.; Philipson, L. HCAR and MCAR: The human and mouse cellular receptors for subgroup C adenoviruses and group B coxsackieviruses. Proc. Natl. Acad. Sci. USA 1997, 94, 3352-3356.
147. Ahn, C.H.; Chae, S.Y.; Bae, Y.H.; Kim, S.W. Biodegradable poly(ethylenimine) for plasmid DNA delivery. J. Control. Release 2002, 80, 273-282.
148. Densmore, C.L. Advances in noninvasive pulmonary gene therapy. Curr. Drug Deliv. 2006, 3, 55-63.
149. Eastman, S.J.; Lukason, M.J.; Tousignant, J.D.; Murray, H.; Lane, M.D.; St George, J.A.; Akita, G.Y.; Cherry, M.; Cheng, S.H.; Scheule, R.K. A concentrated and stable aerosol formulation of cationic lipid: DNA complexes giving high-level gene expression in mouse lung. Hum. Gene Ther. 1997, 8, 765-773.
150. Eastman, S.J.; Tousignant, J.D.; Lukason, M.J.; Murray, H.; Siegel, C.S.; Constantino, P.; Harris, D.J.; Cheng, S.H.; Scheule, R.K. Optimization of formulations and conditions for the aerosol delivery of functional cationic lipid: DNA complexes. Hum. Gene Ther. 1997, 8, 313-322.
151. Eastman, S.J.; Tousignant, J.D.; Lukason, M.J.; Chu, Q.; Cheng, S.H.; Scheule, R.K. Aerosolization of cationic lipid: pDNA complexes-In vitro optimization of nebulizer parameters for human clinical studies. Hum. Gene Ther. 1998, 9, 43-52.
152. Beck, S.E.; Laube, B.L.; Barberena, C.I.; Fischer, A.C.; Adams, R.J.; Chesnut, K.; Flotte, T.R.; Guggino, W.B. Deposition and expression of aerosolized rAAV vectors in the lungs of Rhesus macaques. Mol. Ther. 2002, 6, 546-554.
153. Dunlap, D.D.; Maggi, A.; Soria, M.R.; Monaco, L. Nanoscopic structure of DNA condensed for gene delivery. Nucleic Acids Res. 1997, 25, 3095-3101.
154. Rudolph, C.; Lausier, J.; Naundorf, S.; Muller, R.H.; Rosenecker, J. In vivo gene delivery to the lung using polyethylenimine and fractured polyamidoamine dendrimers. J. Gene Med. 2000, 2, 269-278.
155. Rudolph, C.; Ortiz, A.; Schillinger, U.; Jauernig, J.; Plank, C.; Rosenecker, J. Methodological optimization of polyethylenimine (PEI)-based gene delivery to the lungs of mice via aerosol application. J. Gene Med. 2005, 7, 59-66.
156. Kooijmans, S.A.; Vader, P.; van Dommelen, S.M.; van Solinge, W.W.; Schiffelers, R.M. Exosome mimetics: A novel class of drug delivery systems. Int. J. Nanomed. 2012, 7, 1525-1541.
157. Ma, Y.; Zhao, X.; Li, J.; Shen, Q. The comparison of different daidzein-PLGA nanoparticles in increasing its oral bioavailability. Int. J. Nanomed. 2012, 7, 559-570.
158. Kanwar, J.R.; Palmano, K.P.; Sun, X.; Kanwar, R.K.; Gupta, R.; Haggarty, N.; Rowan, A.; Ram, S.; Krissansen, G.W. "Iron-saturated" lactoferrin is a potent natural adjuvant for augmenting cancer chemotherapy. Immunol. Cell Biol. 2008, 86, 277-288.
159. Mack, C.A.; Song, W.R.; Carpenter, H.; Wickham, T.J.; Kovesdi, I.; Harvey, B.G.; Magovern, C.J.; Isom, O.W.; Rosengart, T.; Falck-Pedersen, E.; et al. Circumvention of anti-adenovirus neutralizing immunity by administration of an adenoviral vector of an alternate serotype. Hum. Gene Ther. 1997, 8, 99-109.
160. Parks, R.J.; Bramson, J.L.; Wan, Y.; Addison, C.L.; Graham, F.L. Effects of stuffer DNA on transgene expression from helper-dependent adenovirus vectors. J. Virol. 1999, 73, 8027-8034.
161. Otake, K.; Ennist, D.L.; Harrod, K.; Trapnell, B.C. Nonspecific inflammation inhibits adenovirus-mediated pulmonary gene transfer and expression independent of specific acquired immune responses. Hum. Gene Ther. 1998, 9, 2207-2222.
162. Belur, L.R.; Frandsen, J.L.; Dupuy, A.J.; Ingbar, D.H.; Largaespada, D.A.; Hackett, P.B.; Scott McIvor, R. Gene insertion and long-term expression in lung mediated by the Sleeping Beauty transposon system. Mol. Ther. 2003, 8, 501-507.