Multi-targeting siRNA nanoparticles for simultaneous inhibition of PI3K and Rac1 in PTEN-deficient prostate cancer

Min Ju Kim; Hyosuk Kim; Xueliang Gao; Ju Hee Ryu; Yoosoo Yang; Ick Chan Kwon; Thomas M. Roberts; Sun Hwa Kim

Journal of Industrial and Engineering Chemistry, Vol.99, 196-203, July, 2021

DOI10.1016/j.jiec.2021.04.024 Export Citation

Multi-targeting siRNA nanoparticles for simultaneous inhibition of PI3K and Rac1 in PTEN-deficient prostate cancer

Min Ju Kim^{1, 2}, Hyosuk Kim¹, Xueliang Gao³, Ju Hee Ryu¹, Yoosoo Yang¹, Ick Chan Kwon^{1, 2}, Thomas M. Roberts^{4, 5, †}, and Sun Hwa Kim^{1, †}

¹Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, 5, Hwarang-ro 14-gil, Seongbuk-gu, Seoul 02792, Republic of Korea
²KU-KIST Graduate School of Converging Science and Technology, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Republic of Korea
³Department of Cell and Molecular Pharmacology and Experimental Therapeutics, College of Medicine, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, USA, Korea
⁴Department of Cancer Biology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA
⁵Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 25 Shattuck Street, Boston, MA 02215, USA

E-mail:,

The phosphoinositide 3-kinase (PI3K) pathway playing an important role in cell proliferation, growth, and survival is one of the most frequently dysregulated pathways in cancer. However, PI3K inhibitors, used as a monotherapy, have shown limited therapeutic efficacies and high rates of side effects from acquired resistance to PI3K inhibition via feedback loop-mediated pathway reactivation and poor tolerability of small-molecule inhibitors. Here, we proposed a multi-targeting siRNA delivery system using polymerized siRNA-based nanoparticle formulations (Msi-NPs) as a PI3K-targeted anticancer therapy for simultaneous ablation of Rac1 and p110β-subunit of PI3K linked by a Rac-PI3K positive feedback loop. Msi-NPs could self-assemble from polymerized siRNAs targeting Rac1 and p110β together with thiolated glycol chitosan. The combinatory inhibition of Rac1 and p110β successfully inhibited the PI3K signaling pathway in PI3K tumor suppressor phosphatase and tensin homolog (PTEN) deficient prostate cancer cells, resulting in significant delays in cell proliferation and migration. The Msi-NP delivery system can provide an alternative therapeutic strategy to overcome the challenges in PI3K inhibitor monotherapy.

Keywords:PI3K pathway;PTEN deficiency;RNAi;Multi-targeting siRNA

[References]

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Ni J, Liu Q, Xie S, Carlson C, Von T, Vogel K, Riddle S, Benes C, Eck M, Roberts T, Gray N, Zhao J, Cancer Discov., 2, 425 (2012)
Cizmecioglu O, Ni J, Xie S, Zhao JJ, Roberts TM, Elife, 5 (2016)
Yuzugullu H, Baitsch L, Von T, Steiner A, Tong H, Ni J, Clayton LK, Bronson R, Roberts TM, Gritsman K, Zhao JJ, Nat. Commun., 6, 8501 (2015)
Kalaitzidis D, Neel BG, PLoS One, 3, e3776 (2008)
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Uthaman S, Pillarisetti S, Huh KM, Cho CS, Park IK, J. Ind. Eng. Chem. (2021).
Li T, Xue Y, Wang G, Gu T, Li Y, Zhu YY, Chen L, J. Cancer, 7, 1317 (2016)
Lee SH, Mok H, Jo S, Hong CA, Park TG, Biomaterials, 32, 2359 (2011)
Kim MG, Jo SD, Jeong JH, Kim SH, J. Ind. Eng. Chem., 64, 430 (2018)
Han SW, Lee JB, J. Ind. Eng. Chem., 64, 90 (2018)
Choi ES, Lim DK, Kim SH, J. Ind. Eng. Chem., 81, 71 (2020)
Lee JW, Oh JJ, Lee ES, Kim YP, Lee MH, J. Ind. Eng. Chem., 73, 182 (2019)
Lee SJ, Yook S, Yhee JY, Yoon HY, Kim MG, Ku SH, KiM SH, Park JH, Jeong JH, Kwon IC, Lee S, Lee H, Kim K, J. Control. Release, 220, 631 (2015)
Huh MS, Lee SY, Park S, Lee S, Chung H, Lee S, Choi Y, Oh YK, Park JH, Jeong SY, Choi K, Kim K, Kwon IC, J. Control. Release, 144, 134 (2010)
Lee SJ, Huh MS, Lee SY, Min S, Lee S, Koo H, Chu JU, Lee Chu JU, Lee KE, Jeon H, Choi Y, Choi K, Byun Y, Jeong SY, Park K, Kim K, Kwon IC, Angew. Chem.-Int. Edit., 51, 7203 (2012)
Vasudevan KM, Garraway LA, Curr. Top. Microbiol. Immunol., 347, 105 (2010)
Mendoza MC, Er EE, Blenis J, Trends Biochem. Sci., 36, 320 (2011)
Koussounadis A, Langdon SP, Um IH, Harrison DJ, Smith VA, Sci. Rep., 5, 10775 (2015)
Lin J, Amir A, Nat. Commun., 9, 4496 (2018)
Rodgers TD, Williams AM, Baran A, Reagan PM, Casulo C, Zent CS, Evans A, Friedberg JW, Barr P,, Leuk. Lymphoma, 1 (2020).
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Mizrachi A, Shamay Y, Shah J, Brook S, Soong J, Rajasekhar VK, Humm JL, et al., Nat. Commun., 8, 14292 (2017)
Nam HY, Kwon SM, Chung H, Lee SY, Kwon SH, Jeon H, Kim Y, Park JH, Kim J, Her S, Oh YK, Kwon IC, Kim K, Jeong SY, J. Control. Release, 135, 259 (2009)
Na JH, Koo H, Lee S, Han SJ, Lee KE, Kim S, Lee H, Lee S, Choi K, Kwon IC, Kim K, Mol. Pharm., 13, 3700 (2016)
Na JH, Lee SY, Lee S, Koo H, Min KH, Jeong SY, Yuk SH, Kim K, Kwon IC, J. Control. Release, 163, 2 (2012)
Garcia-Fuentes M, Alonso MJ, J. Control. Release, 161, 496 (2012)
Yoon HY, Son S, Lee SJ, You DG, Yhee JY, Park JH, Swierczewska M, Lee S, Kwon IC, Kim SH, Kim K, Pomper MG, Sci. Rep., 4, 6878 (2014)
Lee SY, HuhH MS, Lee S, Lee SJ, Chung H, Park JH, Oh YK, Choi K, Kim K, Kwon IC, J. Control. Release, 141, 339 (2010)
Shinoda W, Biochim. Biophys. Acta, 1858, 2254 (2016)
Lopez-Mirabal HR, Winther JR, Biochim. Biophys. Acta, 1783, 629 (2008)
Zhu G, Fan Z, Ding M, Zhang H, Mu L, Ding Y, Zhang Y, Jia B, Chen L, Chang Z, Wu W, Oncogene, 34, 5971 (2015)
Bid HK, Roberts RD, Manchanda PK, Houghton PJ, Mol. Cancer Ther., 12, 1925 (2013)
Bosco EE, Mulloy JC, Zheng Y, Cell. Mol. Life Sci., 66, 370 (2009)
Byrne KM, Monsefi N, Dawson JC, Degasperi A, Bukowski-Wills JC, et al., Cell Syst., 2, 38 (2016)
Dillon LM, Miller TW, Curr. Drug Targets, 15, 65 (2014)

[Referenced By]

[1] Zhang J, Gao X, Schmit F, Adelmant G, Eck MJ, Marto JA, Zhao JJ, Roberts TM, Cell Rep., 20, 549 (2017)

[2] Ni J, Liu Q, Xie S, Carlson C, Von T, Vogel K, Riddle S, Benes C, Eck M, Roberts T, Gray N, Zhao J, Cancer Discov., 2, 425 (2012)

[3] Cizmecioglu O, Ni J, Xie S, Zhao JJ, Roberts TM, Elife, 5 (2016)

[4] Yuzugullu H, Baitsch L, Von T, Steiner A, Tong H, Ni J, Clayton LK, Bronson R, Roberts TM, Gritsman K, Zhao JJ, Nat. Commun., 6, 8501 (2015)

[5] Kalaitzidis D, Neel BG, PLoS One, 3, e3776 (2008)

[6] Rosenzweig SA, Adv. Cancer Res., 138, 71 (2018)

[7] Uthaman S, Pillarisetti S, Huh KM, Cho CS, Park IK, J. Ind. Eng. Chem. (2021).

[8] Li T, Xue Y, Wang G, Gu T, Li Y, Zhu YY, Chen L, J. Cancer, 7, 1317 (2016)

[9] Lee SH, Mok H, Jo S, Hong CA, Park TG, Biomaterials, 32, 2359 (2011)

[10] Kim MG, Jo SD, Jeong JH, Kim SH, J. Ind. Eng. Chem., 64, 430 (2018)

[11] Han SW, Lee JB, J. Ind. Eng. Chem., 64, 90 (2018)

[12] Choi ES, Lim DK, Kim SH, J. Ind. Eng. Chem., 81, 71 (2020)

[13] Lee JW, Oh JJ, Lee ES, Kim YP, Lee MH, J. Ind. Eng. Chem., 73, 182 (2019)

[14] Lee SJ, Yook S, Yhee JY, Yoon HY, Kim MG, Ku SH, KiM SH, Park JH, Jeong JH, Kwon IC, Lee S, Lee H, Kim K, J. Control. Release, 220, 631 (2015)

[15] Huh MS, Lee SY, Park S, Lee S, Chung H, Lee S, Choi Y, Oh YK, Park JH, Jeong SY, Choi K, Kim K, Kwon IC, J. Control. Release, 144, 134 (2010)

[16] Lee SJ, Huh MS, Lee SY, Min S, Lee S, Koo H, Chu JU, Lee Chu JU, Lee KE, Jeon H, Choi Y, Choi K, Byun Y, Jeong SY, Park K, Kim K, Kwon IC, Angew. Chem.-Int. Edit., 51, 7203 (2012)

[17] Vasudevan KM, Garraway LA, Curr. Top. Microbiol. Immunol., 347, 105 (2010)

[18] Mendoza MC, Er EE, Blenis J, Trends Biochem. Sci., 36, 320 (2011)

[19] Koussounadis A, Langdon SP, Um IH, Harrison DJ, Smith VA, Sci. Rep., 5, 10775 (2015)

[20] Lin J, Amir A, Nat. Commun., 9, 4496 (2018)

[21] Rodgers TD, Williams AM, Baran A, Reagan PM, Casulo C, Zent CS, Evans A, Friedberg JW, Barr P,, Leuk. Lymphoma, 1 (2020).

[22] Rodon J, Dienstmann R, Serra V, Tabernero J, Nat. Rev. Clin. Oncol., 10, 143 (2013)

[23] Mizrachi A, Shamay Y, Shah J, Brook S, Soong J, Rajasekhar VK, Humm JL, et al., Nat. Commun., 8, 14292 (2017)

[24] Nam HY, Kwon SM, Chung H, Lee SY, Kwon SH, Jeon H, Kim Y, Park JH, Kim J, Her S, Oh YK, Kwon IC, Kim K, Jeong SY, J. Control. Release, 135, 259 (2009)

[25] Na JH, Koo H, Lee S, Han SJ, Lee KE, Kim S, Lee H, Lee S, Choi K, Kwon IC, Kim K, Mol. Pharm., 13, 3700 (2016)

[26] Na JH, Lee SY, Lee S, Koo H, Min KH, Jeong SY, Yuk SH, Kim K, Kwon IC, J. Control. Release, 163, 2 (2012)

[27] Garcia-Fuentes M, Alonso MJ, J. Control. Release, 161, 496 (2012)

[28] Yoon HY, Son S, Lee SJ, You DG, Yhee JY, Park JH, Swierczewska M, Lee S, Kwon IC, Kim SH, Kim K, Pomper MG, Sci. Rep., 4, 6878 (2014)

[29] Lee SY, HuhH MS, Lee S, Lee SJ, Chung H, Park JH, Oh YK, Choi K, Kim K, Kwon IC, J. Control. Release, 141, 339 (2010)

[30] Shinoda W, Biochim. Biophys. Acta, 1858, 2254 (2016)

[31] Lopez-Mirabal HR, Winther JR, Biochim. Biophys. Acta, 1783, 629 (2008)

[32] Zhu G, Fan Z, Ding M, Zhang H, Mu L, Ding Y, Zhang Y, Jia B, Chen L, Chang Z, Wu W, Oncogene, 34, 5971 (2015)

[33] Bid HK, Roberts RD, Manchanda PK, Houghton PJ, Mol. Cancer Ther., 12, 1925 (2013)

[34] Bosco EE, Mulloy JC, Zheng Y, Cell. Mol. Life Sci., 66, 370 (2009)

[35] Byrne KM, Monsefi N, Dawson JC, Degasperi A, Bukowski-Wills JC, et al., Cell Syst., 2, 38 (2016)

[36] Dillon LM, Miller TW, Curr. Drug Targets, 15, 65 (2014)