A three-drug co-delivery system based on reduction-sensitive polymeric prodrug to effectively reverse multi-drug resistance

Abstract

In the present study, we prepared a multi-drug delivery system based on reduction-sensitive paclitaxel (PTX) polymeric prodrug(PEG-b-PMPMC-g-PTX, PMP) polymersomes to co-deliver PTX, doxorubicin hydrochloride(DOX·HCl) and the P-glycoprotein(P-gp) inhibitor Tariquidar(TQR) to effectively reverse drug resistance by inhibiting the expression of P-gp and improving the accumulation of the encapsulated anticancer drugs. The PTX was linked to the backbone by reduction-sensitive disulphide, making the polymersomes prone to collapse in the reductive environment and to release the drugs. Transmission electron microscope(TEM) was used to confirm the morphology of polymeric assemblies. Moreover, the rupture process of polymersomes was verified by dynamic light scattering (DLS). The results of confocal laser scanning microscopy(CLSM) and flow cytometry indicate that the PMP/DOX·HCl/TQR three-drug-loaded polymersomes show the strongest fluorescence intensity for DOX·HCl compared with PMP/DOX·HCl polymersomes and free DOX·HCl in drug-resistant MCF-7/ADR cells. More importantly, the PMP/DOX·HCl/TQR multi-drug co-delivery system shows a greater growth-inhibitory effect on tumour cells than the other two samples, including PMP/DOX·HCl nanoparticles without the TQR component and free DOX·HCl, when co-incubated with either nonresistant HeLa cells or drug-resistant MCF-7/ADR cells. This growth-inhibitory effect was especially evident in drug-resistant cells. These results imply that the co-delivery of PTX, DOX·HCl and TQR based on reduction-sensitive polymeric prodrug may be promising for overcoming multi-drug resistance in tumour treatments.

Keywords

Multi-drug resistance / co-Delivery / Polymersome

References

[1] Liao L., Liu J., Dreaden E. C., Morton S. W., Shopsowitz K. E., Hammond P. T., Johnson J. A. J. Am. Chem. Soc., 2014, 136(16): 5896.

[2] Riviere M. K., Dubois F., Zohar S. Stat. Med., 2015, 34(1): 1.

[3] Sonpavde G., Pond G. R., Choueiri T. K., Mullane S., Niegisch G., Albers P., Necchi A. d., Lorenzo G., Buonerba C., Rozzi A., Matsu-moto K., Lee J. L., Kitamura H., Kume H., Bellmunt J. Eur. Urol., 2016, 69(4): 634.

[4] James N. D., Sydes M. R., Clarke N. W., Mason M. D., Dearnaley D. P., Spears M. R., Ritchie A. W. S., Parker C. C., Russell J. M., Attard G., de Bono J., Cross W., Jones R. J., Thalmann G., Amos C., Ma-theson D., Millman R., Alzouebi M., Beesley S., Birtle A. J., Brock S., Cathomas R., Chakraborti P., Chowdhury S., Cook A., Elliott T., Gale J., Gibbs S., Graham J. D., Hetherington J., Hughes R., Laing R., McKinna F., McLaren D. B., O’Sullivan J. M., Parikh O., Peedell C., Protheroe A., Robinson A. J., Srihari N., Srinivasan R., Staffurth J., Sundar S., Tolan S., Tsang D., Wagstaff J., Parmar M. K. B. In-vestigators S., Lancet, 2016, 387(10024): 1163.

[5] Hecht J. R., Bang Y. J., Qin S. K., Chung H. C., Xu J. M. M., Park J. O., Jeziorski K., Shparyk Y., Hoff P. M., Sobrero A., Salman P., Li J., Protsenko S. A., Wainberg Z. A., Buyse M., Afenjar K., Houe V., Garcia A., Kaneko T., Huang Y., Khan-Wasti S., Santillana S., Press M. F., Slamon D. J. Clin. Oncol., 2016, 34(5): 443.

[6] Hu Q., Sun W., Wang C., Gu Z. Adv. Drug. Deliv. Rev., 2016, 98: 19.

[7] Scarano W., de Souza P., Stenzel M. H. Biomater. Sci., 2015, 3(1): 163.

[8] Wang H., Zhao Y., Wu Y., Hu Y. L., Nan K. H., Nie G. J., Chen H. Biomaterials, 2011, 32(32): 8281.

[9] Ma L., Kohli M., Smith A. Acs Nano, 2013, 7(11): 9518.

[10] Liu R., Wang Y., Ma Y., Wu Y., Guo Y., Xu L. Chem. Res. Chinese Universities, 2016, 32(5): 848.

[11] Meng H. A., Liong M., Xia T. A., Li Z. X., Ji Z. X., Zink J. I., Nel A. E. Acs Nano, 2010, 4(8): 4539.

[12] Shubin Z., Xue Q., Daihui Z., Jinming Z., Yi W., Yi G., Xu L. Chem. Res. Chinese Universities, 2015, 32(1): 149.

[13] Meng H., Wang M. Y., Liu H. Y., Liu X. S., Situ A., Wu B., Ji Z. X., Chang C. H., Nel A. E. Acs Nano, 2015, 9(4): 3540.

[14] Gandhi N. S., Tekade R. K., Chougule M. B. J. Controlled Release, 2014, 194: 238.

[15] Fan W. P., Shen B., Bu W. B., Chen F., He Q. J., Zhao K. L., Zhang S. J., Zhou L. P., Peng W. J., Xiao Q. F., Ni D. L., Liu J. N., Shi J. L. Biomaterials, 2014, 35(32): 8992.

[16] J. Appl. Polym. Sci., 2016, 133(42):

[17] Hu Q. D., Tang G. P., Chu P. K. Acc. Chem. Res., 2014, 47(7): 201.

[18] Yu H. J., Cui Z. R., Yu P. C., Guo C. Y., Feng B., Jiang T. Y., Wang S. L., Yin Q., Zhong D. F., Yang X. L., Zhang Z. W., Li Y. P. Adv. Funct. Mater., 2015, 25(17): 2489.

[19] Zhu C. H., Jung S., Luo S. B., Meng F. H., Zhu X. L., Park T. G., Zhong Z. Y. Biomaterials, 2010, 31(8): 2408.

[20] Zhu H. J., Chen H. B., Zeng X. W., Wang Z. Y., Zhang X. D., Wu Y. P., Gao Y. F., Zhang J. X., Liu K. W., Liu R. Y., Cai L. T., Mei L., Feng S. S. Biomaterials, 2014, 35(7): 239.

[21] Cheng R., Meng F., Deng C., Klok H. A., Zhong Z. Biomaterials, 2013, 34(14): 3647.

[22] Li Y. P., Xiao K., Zhu W., Deng W. B., Lam K. S. Adv. Drug Deli-very Rev., 2014, 66: 58.

[23] Mura S., Nicolas J., Couvreur P. Nat. Mater., 2013, 12(11): 991.

[24] Deng B., Ma P., Xie Y. Nanoscale, 2015, 7(30): 12773.

[25] Massaro M., Amorati R., Cavallaro G., Guernelli S., Lazzara G., Mi-lioto S., Noto R., Poma P., Riela S. Colloids Surf., B, 2016, 140: 505.

[26] Meng F., Hennink W. E., Zhong Z. Biomaterials, 2009, 30(12): 2180.

[27] Phillips D. J., Gibson M. I. Antioxid. Redox Signaling, 2014, 21(5): 786.

[28] Cheng R., Meng F., Deng C., Klok H., Zhong Z. Biomaterials, 2013, 34(14): 3647.

[29] Kuppusamy P., Li H., Ilangovan G., Cardounel A. J., Zweier J. L., Yamada K., Krishna M. C., Mitchell J. B. Cancer Res., 2002, 62(1): 307.

[30] Endicott A. J., Ling V. Annu. Rev. Biochem., 1989, 58: 137.

[31] Fletcher J. I., Williams R. T., Henderson M. J., Norris M. D., Haber M. Drug Resist. Updates, 2016, 26: 1.

[32] Li W., Zhang H., Assaraf Y. G., Zhao K., Xu X., Xie J., Yang D. H., Chen Z. S. Drug Resist. Updates, 2016, 27: 14.

[33] Duan X., Xiao J., Yin Q. R., Zhang Z. Y., Yu H., Mao S., Li Y. Acs Nano, 2013, 7(7): 5858.

[34] Yi X., Zhao D., Zhang Q., Xu J. Q., Yuan G. D., Zhuo R., Li F. Polym. Chem., 2016, 7(38): 5966.

[35] Talelli M., Barz M., Rijcken C. J. F., Kiessling F., Hennink W. E., Lammers T. Nano Today, 2015, 10(1): 93.