Targeted delivery of microRNA-145 to metastatic breast cancer by peptide conjugated branched PEI gene carrier

Hwa Jeong Lee; Ran Namgung; Won Jong Kim; Jae Il Kim; In-Kyu Park

Macromolecular Research, Vol.21, No.11, 1201-1209, November, 2013

DOI10.1007/s13233-013-1161-z Export Citation

Targeted delivery of microRNA-145 to metastatic breast cancer by peptide conjugated branched PEI gene carrier

Hwa Jeong Lee, Ran Namgung¹, Won Jong Kim¹, Jae Il Kim², and In-Kyu Park^†

Department of Biomedical Sciences and Center for Biomedical Human Resources (BK-21 Project), Chonnam National University Medical School, Gwangju, 501-746, Korea
¹Department of Chemistry, BK21 Program, Polymer Research Institute, Pohang University of Science and Technology, Gyeongbuk, 790-784, Korea
²Department of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, 500-712, Korea

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Development of a targeted polymeric gene delivery system is essential for reducing the non-specific uptake and toxicity of the gene carriers. In this study, we have tested the specificity of the cell penetrating peptide (DS 4-3), screened by phage display technique, towards metastatic breast cancer cells. This peptide has shown specificity towards metastatic breast cancer cells, which was confirmed through endocytosis inhibition study. Furthermore, the DS 4-3 peptide was conjugated to bPEI, to deliver the therapeutic miR-145. Tumor suppressor miR-145 inhibited tumor cell growth, and significantly suppressed cell invasion. The DS 4-3 peptide conjugated branched PEI (DSbPEI)/pLuc nanoparticles showed increased transfection in malignant murine breast cancer cells at the neutral surface charge (N/P molar ratio of 3), compared to scramble peptide conjugated bPEI/pLuc nanoparticles, without causing any cytotoxicity. This specific increase in transfection with DS-bPEI/pLuc nanoparticles was not found in the cancer cells that originated from different tissue, such as HeLa cervical cancer cells, or in the normal cells, such as NIH-3T3 murine fibroblast cells. Thus, the specific transfection of miR-145 in metastatic breast cancer cells mediated by DS-bPEI resulted in enhanced reduction in proliferation.

Keywords:cell-penetrating peptides;tissue targeting;gene delivery;metastatic breast cancer;microRNA-145

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[2] Leong CT, Ong CK, Tay SK, Huynh H, Oncogene, 26, 870 (2007)

[3] Huang L, Ao Q, Zhang Q, Yang X, Xing H, Li F, Chen G, Zhou J, Wang S, Xu G, Meng L, Lu Y, Ma D, J. Cancer Res. Clin. Oncol., 136, 447 (2010)

[4] Soutschek J, Akinc A, Bramlage B, Charisse K, Constien R, Donoghue M, Elbashir S, Geick A, Hadwiger P, Harborth J, John M, Kesavan V, Lavine G, Pandey RK, Racie T, Rajeev KG, Rohl I, Toudjarska I, Wang G, Wuschko S, Bumcrot D, Koteliansky V, Limmer S, Man, Nature, 432, 173 (2004)

[5] Kasinski AL, Slack FJ, Cancer Res., 72, 5576 (2012)

[6] Weidhaas JB, Babar I, Nallur SM, Trang P, Roush S, Boehm M, Gillespie E, Slack FJ, Cancer Res., 67, 11111 (2007)

[7] Ye X, Liu Z, Hemida MG, Yang D, PLoS One, 6, e21215 (2011)

[8] Ylosmaki E, Lavilla-Alonso S, Jaamaa S, Vaha-Koskela M, Hallstrom TA, Hemminki A, Arola J, Makisalo H, Saksela K, PLoS One, 8, e54506 (2013)

[9] Zhang H, Pu J, Qi T, Qi M, Yang C, Li S, Huang K, Zheng L, Tong Q, Oncogene, 10.1038/onc.2012.574 (2012).

[10] Sachdeva M, Mo YY, Cancer Res., 70, 378 (2010)

[11] Dynoodt P, Speeckaert R, De Wever O, Chevolet I, Brochez L, Lambert J, Van Gele M, Int. J. Oncol., 42, 1443 (2013)

[12] Wu X, Li Z, Yao M, Wang H, Qu S, Chen X, Li J, Sun Y, Xu Y, Gu J, Acta Biochim. Biophys. Sin., 40, 217 (2008)

[13] LeMaistre CF, Meneghetti C, Howes L, Osborne CK, Breast Cancer Res. Treat., 32, 97 (1994)

[14] Gilyazova DG, Rosenkranz AA, Gulak PV, Lunin VG, Sergienko OV, Khramtsov YV, Timofeyev KN, Grin MA, Mironov AF, Rubin AB, Georgiev GP, Sobolev AS, Cancer Res., 66, 10534 (2006)

[15] Gerbal-Chaloin S, Gondeau C, Aldrian-Herrada G, Heitz F, Gauthier-Rouviere C, Divita G, Biol. Cell, 99, 223 (2007)

[16] Buerger C, Groner B, J. Cancer Res. Clin. Oncol., 129, 669 (2003)

[17] Yandek LE, Pokorny A, Floren A, Knoelke K, Langel U, Almeida PF, Biophys. J., 92, 2434 (2007)

[18] Nguyen J, Xie X, Neu M, Dumitrascu R, Reul R, Sitterberg J, Bakowsky U, Schermuly R, Fink L, Schmehl T, Gessler T, Seeger W, Kissel T, J. Gene. Med., 10, 1236 (2008)

[19] Salomone F, Cardarelli F, Di Luca M, Boccardi C, Nifosi R, Bardi G, Di Bari L, Serresi M, Beltram F, J. Control. Release, 163, 293 (2012)

[20] Fang SL, Fan TC, Fu HW, Chen CJ, Hwang CS, Hung TJ, Lin LY, Chang MD, PLoS One, 8, e57318 (2013)

[21] Ter-Avetisyan G, Tunnemann G, Nowak D, Nitschke M, Herrmann A, Drab M, Cardoso MC, J. Biol. Chem., 284, 3370 (2009)

[22] Saalik P, Niinep A, Pae J, Hansen M, Lubenets D, Langel U, Pooga M, J. Control. Release, 153, 117 (2011)

[23] Takeuchi T, Kosuge M, Tadokoro A, Sugiura Y, Nishi M, Kawata M, Sakai N, Matile S, Futaki S, ACS Chem. Biol., 1, 299 (2006)

[24] Fotin-Mleczek M, Welte S, Mader O, Duchardt F, Fischer R, Hufnagel H, Scheurich P, Brock R, J. Cell Sci., 118, 3339 (2005)

[25] Whitney M, Crisp JL, Olson ES, Aguilera TA, Gross LA, Ellies LG, Tsien RY, J. Biol. Chem., 285, 22532 (2010)

[26] Chauhan A, Tikoo A, Kapur AK, Singh M, J. Control. Release, 117, 148 (2007)

[27] Lee Y, Nam HY, Kim J, Lee M, Yockman JW, Shin SK, Kim SW, Mol. Ther., 20, 1360 (2012)

[28] Bachtarzi H, Stevenson M, Subr V, Ulbrich K, Seymour LW, Fisher KD, J. Control. Release, 150, 196 (2011)

[29] Anwer K, Rhee BG, Mendiratta SK, Crit. Rev. Ther. Drug Carrier Syst., 20, 249 (2003)

[30] Namgung R, Singha K, Yu MK, Jon S, Kim YS, Ahn Y, Park IK, Kim WJ, Biomaterials, 31, 4204 (2010)

[31] Kwon SM, Nam HY, Nam T, Park K, Lee S, Kim K, Kwon IC, Kim J, Kang D, Park JH, Jeong SY, J. Control. Release, 128, 89 (2008)