Synthesis and Characterization of Nanoparticles with Hydrogen Peroxide Sensitivity, Targeting and Fluorscence for Atherosclerosis

doi:10.7503/cjcu20180033

Abstract

Abstract:

A multifunctional nanomicelle was designed for atherosclerosis theranostics, which was synthesized by decorating the poly(2-hydroxyethyl methacrylate)(PHEMA) with simvastatin(Sim) prodrug, fluorescent polyethylene glycol(FPEG) and the macrophages targeting molecules(ISO-1). The as-obtained polymer was confirmed by nuclear magnetic resonance(¹H NMR), Fourier transform infrared spectroscopy(FTIR) and gel permeation chromatography(GPC). The nanoparticle size and morphology were determined by dynamic light scattering(DLS) and transmission electron microscopy(TEM), which was spherical and with the size of about 100 nm. The MTT assay confirmed the biocompatibility of the nanomicelles. The targeting property was evaluated by cell uptake assay and observed via confocal laser scanning microscopy(CLSM). The results suggest that this multifunctional H₂O₂-respective targeting nanomicelles could become an effective tool for atherosclerosis therapy.

Key words: Amphiphilic nanoparticles, Hydrogen peroxide sensitivity, Drug release, Fluorescent polymer, Atherosclerosis

CLC Number:

O631

TrendMD:

FANG Chao,ZHU Hanyu,LIU Ye,ZHAO Waiou,LI Yapeng,WANG Jingyuan. Synthesis and Characterization of Nanoparticles with Hydrogen Peroxide Sensitivity, Targeting and Fluorscence for Atherosclerosis[J]. Chem. J. Chinese Universities, 2018, 39(9): 2071.

Figures/Tables 10

Scheme 1 Synthesis of multifunctional polymer PHEMA-Sim-FPEG-ISO-1

Scheme 2 Synthesis routes of PSFI

Fig.1 1H NMR spectrum(A), FTIR spectra(B) and GPC curves(C) of PSFI Peaks 1—8 are corresponding to the positions 1—8 in Scheme 2. a. PHEMA; b. PHEMA-Sim; c. PSFI.

Table 1 Characteristics of PHEMA-Sim-FPEG

n(Sim)-n(FPEG)	10⁴ cmc/(mg·mL^-1)	Size/nm	PDI	Yield/g	Yield rate(%)
1-1	77.60	225.5±2.4	0.189±0.035	0.844	53.4
2-1	63.30	211.2±5.6	0.221±0.022	0.468	45.9
3-1	25.20	192.6±3.8	0.205±0.019	0.397	47.6
4-1	8.69	154.3±4.2	0.211±0.017	0.324	43.8
5-1	8.90	165.5±1.0	0.169±0.035	0.268	39.2

Fig.2 TEM image(A) and DLS(B) of PSFI

Fig.3 Fluorescence excitation spectra(A) and emission spectra(B) of FPEG in PBS(a), PSFI in PBS(b) and PSFI in 1 mmol/L H2O2(c)

Fig.4 Drug release curves of PSFI in H2O2c(H2O2)/(mmol·L-1): a. 0; b. 0.25; c. 0.50; d. 0.75; e. 1.

Fig.5 Cytotoxicity evaluation of PSFI in macrophages RAW264.7(A) and endothelial cells RBMEC(B) and PHEMA-Sim-FPEG, PHEMA-Sim-RhoB, PHEMA-Sim-5-FAM, PHEMA-Sim-PEG@QDs in macrophages RAW264.7 24 h(C)

Fig.6 Confocal laser scanning microscope images of blank(A1—A4), PSF(B1—B4) and PSFI(C1—C4) in macrophages RAW264.7(A1—C1) F-actin; (A2—C2) nuclear; (A3—C3) nanoparticles; (A4—C4) merge.

Fig.7 Confolcal laser scanning microscope images of blank(A1—A4), PSF(B1—B4) and PSFI(C1—C4) in endothelial cells RBMEC in mice(A1—C1) F-actin; (A2—C2) nuclear; (A3—C3) nanoparticles; (A4—C4) merge.

References 42

[1]	Mark E. L., Claudia C., Antoine M., Max L. S., Francois F., Philip M. R., Sarayu R., Tina B., Maarten P., Steven S., Stephan R., Ronald E. G., Luis C. Z., Gert S., Josbert M. M., Christopher H. C., Erik S. G., Zahi A. F., Willem J. M., ACS Nano, 2015, 9(2), 1837—1847
[2]	Tuttolomondo A., Di R. D., Pecoraro R., Arnao V., Pinto A., Licata G., Curr. Pharm. Design, 2012, 18(28), 4266—4288
[3]	Hadeel A. Y., J. Fac. Med. Baghdad, 2014, 56(2), 186—190
[4]	Yamashita T., Sasaki N., Kasahara K., Hirata K. I., J. Cardiol., 2015, 66(1), 1—8
[5]	Schiener M., Hossann M., Viola J. R., Ortega-Gomez A., Weber C., Lauber K., Lindner L. H., Soehnlein O., Trends Mol. Med., 2014, 20(5), 71—81
[6]	Wong B. W., Meredith A., Lin D., Mcmanus B. M., Can. J. Cardiol., 2012, 28(6), 631—641
[7]	Petros R. A., De Simone J. M., Nat. Rev. Drug Discov., 2015, 9, 615—627
[8]	Brannon P. L., Blanchette J. O., Adv. Drug Deliver Rev., 2004, 56(11), 1649—1659
[9]	Tapeinos C., Pandit A., Adv. Mater., 2016, 28(27), 5553—5585
[10]	Madamanchi N. R., Vendrov A., Runge M. S., Arterioscl. Throm. Vas., 2005, 25(1), 29—38
[11]	Tong R., Tang L., Ma L., Tu C., Baumgartner R., Cheng J., Chem. Soc. Rev., 2014, 43(20), 6982—7012
[12]	Zhang Y., Yu J., Bomba H. N., Zhu Y., Gu Z., Chem. Rev., 2016, 116(19), 12536—12563
[13]	Sun X. C., Yang H., Wang J. Z., Ma R. J., An Y. L., Shi L. Q., Chem. J. Chinese Universities, 2014, 35(7), 1570—1578
	(孙小成, 杨浩, 王建祖, 马如江, 安英丽, 史林启. 高等学校化学学报, 2014, 35(7), 1570—1578)
[14]	Lee S. H., Gupta M. K., Bang J. B., Bae H., Sung H. J., Adv. Healthcare Mater., 2013, 2(6), 908—915
[15]	Yan Q., Yuan J. Y., Chem. J. Chinese Universities, 2012, 33(9), 1877—1885
	(闫强, 袁金颖. 高等学校化学学报, 2012, 33(9), 1877—1885)
[16]	Liu X., Xiang J. J., Zhu D. C., Jiang L. M., Zhou Z. X., Tang J. B., Liu X. R., Huang Y. Z., Shen Y. Q., Adv. Mater., 2016, 28(9), 1743—1752
[17]	Xu Q. H., He C. L., Xiao C. S., Chen X. S., Macromol. Biosci., 2016, 16(5), 635—646
[18]	Christos T., Abhay P., Adv. Mater., 2016, 28, 5553—5585
[19]	Marian V., Dieter L., Jan M., Mark T. D., Milan M., Joshua T., Int. J. Biochem. & Cell Biology, 2007, 39, 44—84
[20]	Barnes T. C., Anderson M. E., Edwards S. W., Moots R. J., Rheumatology, 2012, 51, 1166—1169
[21]	Manuela C., Ileana M., Curr. Med. Chem., 2017, 24, 550—567
[22]	Velasquez J. C., Weiss D., Joseph G., Landazuri N., Taylor W. R., Circulation, 2008, 118(18), S510
[23]	Wang Y. L., Sun G. Y., Zhang Y., He J. J., Zheng S., Lin J. N., Mol. Med. Rep., 2016, 14, 3559—3564
[24]	Guanying C., Indrajit R., Chunhui Y., Paras N.P., Chem. Rev., 2016, 116, 2826—2885
[25]	Mahmoud E., Gyu S., Soon-Mi L., Guorong S., Karen L.W., Chem. Rev., 2015, 115, 10967—11011
[26]	Karel U., Kateǐina H., Vladimir S., Aristides B., Jiǐí T., Radek Z., Chem. Rev., 2016, 116, 5338—5431
[27]	Calandra T., Roger T., Nat. Rev. Immunol., 2003, 3(10), 791—800
[28]	Chang D., Wang Y. C., Zhang S. J., Bai Y. Y., Liu D. F., Zang F. C., Wang G. Z., Wang B. H., Ju S. H., Biomaterials, 2015, 68, 67—76
[29]	Gui R. J., An X. Q., Huang W. X., Anal. Chim. Acta, 2013, 767, 134—140
[30]	Gyawali D., Zhou S. Y., Tran R. T., Zhang Y., Liu C., Bai X. C., Yan. J., Adv. Healthcare Mater., 2014, 3(2), 182—186
[31]	Yang J., Zhang Y., Gautam S., Liu L., Dey J., Chen W., Mason R. P., Serrano C. A., Schug K. A., Tang L. P., Natl. Acad. Sci. USA, 2009, 106(25), 10086—10091
[32]	Cheng K. F., Al-Abed Y., Bioorg. Med. Chem. Lett., 2006, 16(13), 3376—3379
[33]	Gao H., Matyjaszewski K., J. Am. Chem. Soc., 2007, 129(20), 6633—6639
[34]	Wang J., Greszta DMatyjaszewski K., Polym. Mater. Sci. Eng., 1995, 73, 416—417
[35]	Jiao Z., Liu N., Chen Z. M., Pharm. Dev. Technol., 2012, 17, 164—169
[36]	Lee D., Khaja S., Velasquezcastano J. C., Madhuri D., Carrie S., John P. W., Taylor R., Niren M., Nat. Mater., 2007, 6(10), 765—769
[37]	Carsten S., Stephan L. M., Martin P., Pieter A., Clin. Exp. Pharmacol. P, 2003, 30, 249—253
[38]	Burak C. S., Ayse S. Ş., Exp. Therap. Med., 2014, 8, 1660—1664
[39]	Calin M., Manduteanu I., Curr. Med. Chem., 2017, 24, 550—567
[40]	Brown B. G., Zhao Q. X., Chait A., N. Engl. J. Med., 2001, 345(22), 1583—1592
[41]	Pavia C. S., Folds J. D., Baseman J. B., Infect. Immun., 1977, 17(3), 651—654
[42]	Sarala B., Atish R., Pradip K. G., Vitthal N. Y., Divya K., Anshu C., Pooja B., Shaila S., Somesh S., Ram A. V., Nilesh M. D., Bioorg. Med. Chem. Lett., 2005, 19(16), 4773—4776