Construction of folate-conjugated epirubicin liposomes for enhancing the cellular uptake and the co-localization with nuclei of invasive breast cancer cells

doi:10.5246/jcps.2018.04.024

Abstract

Abstract:

Drug resistance of anthracycline in the invasive cancer is associated with the lowered cellular drug uptake and diminished co-localization of drug with nuclei. In the present study, we aimed to construct the folate-conjugated epirubicin liposomes by incorporating a synthesized folate-lipid derivative; and to assess the effects on cellular drug uptake, co-localization of drug with nuclei and efficacy in treatment of invasive breast cancer cells. The studies were performed on invasive human breast cancer cells. The folate-PEG₂₀₀₀-DSPE conjugate was synthesized, and the constructed folate-conjugated epirubicin liposomes were approximately 100 nm in size. The in vitro studies demonstrated that the folate-conjugated epirubicin liposomes had the strongest cellular drug uptake and co-localization with nuclei of the invasive breast cancer cells. Besides, the liposomes displayed the most significant efficacy in killing the invasive cancer cells, in preventing their invasive potential, and in penetrating ability into breast cancer spheroid as well. In conclusion, the constructed folate-conjugated epirubicin liposomes were able to enhance the efficacy in treatment of invasive breast cancer by improving the cellular drug uptake and increasing the co-localization with nuclei, hence offering a new strategy for potentially eradicating the invasive breast cancer cells.

Key words: Folate conjugated liposomes, Epirubicin, Cellular uptake, Co-localization with nuclei, Invasive breast cancer

CLC Number:

R943

Supporting:

Yingzi Bu, Limin Mu, Lei Liu, Wanliang Lu. Construction of folate-conjugated epirubicin liposomes for enhancing the cellular uptake and the co-localization with nuclei of invasive breast cancer cells[J]. Journal of Chinese Pharmaceutical Sciences, 2018, 27(4): 229-240.

References

[1] Youlden, D.; Cramb, S.; Dunn, N.; Muller, J.; Pyke, C.; Baade, P.D. The descriptive epidemiology of female breast cancer: an international comparison of screening, incidence, survival and mortality. Cancer Epidemiol. 2012, 36, 237-248.

[2] Porter, H.; Perry, A.; Kingsley, C.; Tran, N.L.; Keegan, A.D. IRS1 is highly expressed in localized breast tumors and regulates the sensitivity of breast cancer cells to chemotherapy, while IRS2 is highly expressed in invasive breast tumors. Cancer Lett. 2015, 338, 239-248.

[3] Mu, L.M.; Ju, R.J.; Liu, R.; Bu, Y.Z.; Zhang, J.Y.; Li, X.Q.; Zeng, F.; Lu, W.L. Dual-functional drug liposomes in treatment of resistant cancers. Adv. Drug Deliv. Rev. 2017, 115, 46-56.

[4] Conte, P.F.; Gennari, A.; Landucci, E.; Orlandini, C. Role of epirubicin in advanced breast cancer. Clin. Breast. Cancer. 2000, 1, S46-51.

[5] Cowell, I.G.; Austin, C.A. Mechanism of generation of therapy related leukemia in response to anti-topoisomerase II agents. Int. J. Environ. Res. Public. Health. 2012, 9, 2075-2091.

[6] Coukell, A.J.; Faulds, D. Epirubicin. An updated review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in the management of breast cancer. Drugs. 1997, 53, 453-482.

[7] Alberg, A.J.; Selhub, J.; Shah, K.V.; Viscidi, R.P.; Comstock, G.W.; Helzlsouer, K.J. The risk of cervical cancer in relation to serum concentrations of folate, vitamin B12, and homocysteine. Cancer Epidemiol. Biomarkers Prev. 2000, 9, 761-764.

[8] Li, Y.; Huang, T.; Zheng, Y.; Muka, T.; Troup, J.; Hu, F.B. Folic Acid Supplementation and the Risk of Cardiovascular Diseases: A Meta-Analysis of Randomized Controlled Trials. J. Am. Heart Assoc. 2016, 15, 5.

[9] Christen, W.G.; Glynn, R.J.; Chew, E.Y.; Albert, C.M.; Manson, J.E. Folic acid, pyridoxine, and cyanocobalamin combination treatment and age-related macular degeneration in women: the Women's Antioxidant and Folic Acid Cardiovascular Study. Arch. Intern. Med. 2009, 169, 335-341.

[10] Leamon, C.; Reddy, J.A. Folate-targeted chemotherapy. Adv. Drug Deliv. Rev. 2004, 56, 1127-1141.

[11] Giovannucci, E. Epidemiologic studies of folate and colorectal neoplasia: a review. J. Nutr. 2002, 132, 2350S-2355S.

[12] Ross, J.F.; Chaudhuri, P.K.; Ratnam, M. Differential regulation of folate receptor isoforms in normal and malignant tissues in vivo and in established cell lines. Physiologic and clinical implications. Cancer. 1994, 73, 2432-2443.

[13] Garin-Chesa, P.; Campbell, I.; Saigo, P.E.; Lewis, J.L.; Old, L.J.; Rettig, W.J. Trophoblast and ovarian cancer antigen LK26. Sensitivity and specificity in immunopathology and molecular identification as a folate-binding protein. Am. J. Pathol. 1993, 142, 557-567.

[14] Jhaveri, M.S.; Rait, A.S.; Chung, K.N.; Trepel, J.B.; Chang, E.H. Antisense oligonucleotides targeted to the human alpha folate receptor inhibit breast cancer cell growth and sensitize the cells to doxorubicin treatment. Mol. Cancer Ther. 2004, 3, 1505-1512.

[15] Zhang, Y.; Li, R.J.; Ing, X.; Tian, W.; Yao, H.J.; Men, Y.; You, Y.; Zhang, L.; Ju, R.J.; Wang, X.X.; Zhou, J.; Chen, J.X.; Li, N.; Lu, W.L. Targeting therapy with mitosomal daunorubicin plus amlodipine has the potential to circumvent intrinsic resistant breast cancer. Mol. Pharm. 2011, 8, 162-175.

[16] Li, X.; Ryan, G.R.; Lu, W.L.; Hong, H.Y.; Liang, G.W.; Zhang, Y.T.; Liu, Y.; Long, C.; Ma, X.; Yuan, L.; Wang, J.C.; Zhang, X.; Zhang, Q. A novel stealth liposomal topotecan with amlodipine: apoptotic effect is associated with deletion of intracellular Ca2+ by amlodipine thus leading to an enhanced antitumor activity in leukemia. J. Controlled Release. 2006, 112, 186-198.

[17] Matsumura, Y.; Maeda, H. A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs. Cancer Res. 1986, 46, 6387-6392.

[18] Robinson, B.D.; Sica, G.L.; Liu, Y.F.; Rohan, T.E.; Gertler, F.B.; Condeelis, J.S.; Jones, J.G. Tumor microenvironment of metastasis in human breast carcinoma: a potential prognostic marker linked to hematogenous dissemination. Clin. Cancer Res. 2009, 15, 2433-2441.

[19] Wyckoff, J.B.; Wang, Y.; Lin, E.Y.; Li, J.F.; Goswami, S.; Stanley, E.R.; Segall, J.E.; Pollard, J.W.; Condeelis, J. Direct visualization of macrophage-assisted tumor cell intravasation in mammary tumors. Cancer Res. 2007, 67, 2649-2656.