In Vitro and In Vivo Co-delivery of siRNA and Doxorubicin by Folate-PEG-Appended Dendrimer/Glucuronylglucosyl-β-Cyclodextrin Conjugate

Springer Science and Business Media LLC - Tập 21 - Trang 1-10 - 2019
Ahmed Fouad Abdelwahab Mohammed1,2,3, Taishi Higashi1,4, Keiichi Motoyama1, Ayumu Ohyama1,3, Risako Onodera5, Khaled Ali Khaled2, Hatem Abdelmonsef Sarhan2, Amal Kamal Hussein2, Hidetoshi Arima1,3
1Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan
2Department of Pharmaceutics, Faculty of Pharmacy, Minia University, Minia, Egypt
3Program for Leading Graduate Schools “HIGO (Health Life Science: Interdisciplinary and Glocal Oriented) Program”, Kumamoto University, Kumamoto, Japan
4Priority Organization for Innovation and Excellence, Kumamoto University, Kumamoto, Japan
5School of Pharmacy, Building Regional Innovation Ecosystems, Kumamoto University, Kumamoto, Japan

Tóm tắt

We have previously reported the utility of folate-polyethylene glycol-appended dendrimer conjugate with glucuronylglucosyl-β-cyclodextrin (Fol-PEG-GUG-β-CDE) (generation 3) as a tumor-selective carrier for siRNA against polo-like kinase 1 (siPLK1) in vitro. In the present study, we evaluated the potential of Fol-PEG-GUG-β-CDE as a carrier for the low-molecular antitumor drug doxorubicin (DOX). Further, to fabricate advanced antitumor agents, we have prepared a ternary complex of Fol-PEG-GUG-β-CDE/DOX/siPLK1 and evaluated its antitumor activity both in vitro and in vivo. Fol-PEG-GUG-β-CDE released DOX in an acidic pH and enhanced the cellular accumulation and cytotoxic activity of DOX in folate receptor-α (FR-α)-overexpressing KB cells. Importantly, the Fol-PEG-GUG-β-CDE/DOX/siPLK1 ternary complex exhibited higher cytotoxic activity than a binary complex of Fol-PEG-GUG-β-CDE with DOX or siPLK1 in KB cells. In addition, the cytotoxic activity of the ternary complex was reduced by the addition of folic acid, a competitor against FR-α. Furthermore, the ternary complex showed a significant antitumor activity after intravenous administration to the tumor-bearing mice. These results suggest that Fol-PEG-GUG-β-CDE has the potential of a tumor-selective co-delivery carrier for DOX and siPLK1.

Tài liệu tham khảo

American cancer society, https://www.cancer.org/research/cancer-facts-statistics/global.html. Fire A, Xu S, Montgomery MK, Kostas SA, Driver SE, Mello CC. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature. 1998;391(6669):806–11. Liu Z, Sun Q, Wang X. PLK1, a potential target for cancer therapy. Transl Oncol. 2017;10(1):22–32. Uekama K, Hirayama F, Irie T. Cyclodextrin drug carrier systems. Chem Rev. 1998;98(5):2045–76. Ceborska M. Folate appended cyclodextrins for drug, DNA, and siRNA delivery. Eur J Pharm Biopharm. 2017;120:133–45. Zhao F, Yin H, Zhang Z, Li J. Folic acid modified cationic γ-cyclodextrin-oligoethylenimine star polymer with bioreducible disulfide linker for efficient targeted gene delivery. Biomacromolecules. 2013;14(2):476–84. Zhao F, Yin H, Li J. Supramolecular self-assembly forming a multifunctional synergistic system for targeted co-delivery of gene and drug. Biomaterials. 2014;35(3):1050–62. Li J, Loh XJ. Cyclodextrin-based supramolecular architectures: syntheses, structures, and applications for drug and gene delivery. Adv Drug Deliv Rev. 2008;60(9):1000–17. Zhang J, Ma PX. Cyclodextrin-based supramolecular systems for drug delivery: recent progress and future perspective. Adv Drug Deliv Rev. 2013;65(9):1215–33. Higashi T, Iohara D, Motoyama K, Arima H. Supramolecular pharmaceutical sciences: a novel concept combining pharmaceutical sciences and supramolecular chemistry with a focus on cyclodextrin-based supermolecules. Chem Pharm Bull. 2018;66(3):207–16. Anno T, Higashi T, Motoyama K, Hirayama F, Uekama K, Arima H. Possible enhancing mechanisms for gene transfer activity of glucuronylglucosyl-β-cyclodextrin/dendrimer conjugate. Int J Pharm. 2012;426(1–2):239–47. Mohammed AFA, Higashi T, Motoyama K, Ohyama A, Onodera R, Khaled KA, et al. Targeted siRNA delivery to tumor cells by folate-PEG-appended dendrimer/glucuronylglucosyl-β-cyclodextrin conjugate. J Incl Phenom Macrocycl Chem. 2019:in press;93:41–52. Silber JH, Barber G. Doxorubicin-induced cardiotoxicity. N Engl J Med. 1995;333(20):1359–60. Wang Y, Cao X, Guo R, Shen M, Zhang M, Zhu M, et al. Targeted delivery of doxorubicin into cancer cells using a folic acid–dendrimer conjugate. Polym Chem. 2011;2(8):1754–60. Al-Jamal KT, Al-Jamal WT, Wang JT, Rubio N, Buddle J, Gathercole D, et al. Cationic poly-L-lysine dendrimer complexes doxorubicin and delays tumor growth in vitro and in vivo. ACS Nano. 2013;7(3):1905–17. Choi SK, Thomas T, Li MH, Kotlyar A, Desai A, Baker JR Jr. Light-controlled release of caged doxorubicin from folate receptor-targeting PAMAM dendrimer nanoconjugate. Chem Commun. 2010;46(15):2632–4. Han L, Huang R, Liu S, Huang S, Jiang C. Peptide-conjugated PAMAM for targeted doxorubicin delivery to transferrin receptor overexpressed tumors. Mol Pharm. 2010;7(6):2156–65. Mohammed AFA, Ohyama A, Higashi T, Motoyama K, Khaled KA, Sarhan HA, et al. Preparation and evaluation of polyamidoamine dendrimer conjugate with glucuronylglucosyl-β-cyclodextrin (G3) as a novel carrier for siRNA. J Drug Target. 2014;22(10):927–34. Ohyama A, Higashi T, Motoyama K, Arima H. In vitro and in vivo tumor-targeting siRNA delivery using folate-PEG-appended dendrimer (G4)/α-cyclodextrin conjugates. Bioconjug Chem. 2016;27(3):521–32. Arima H, Chihara Y, Arizono M, Yamashita S, Wada K, Hirayama F, et al. Enhancement of gene transfer activity mediated by mannosylated dendrimer/α-cyclodextrin conjugate (generation 3, G3). J Control Release. 2006;116(1):64–74. Corbett TH, Griswold DP Jr, Roberts BJ, Peckham JC, Schabel FM Jr. Biology and therapeutic response of a mouse mammary adenocarcinoma (16/C) and its potential as a model for surgical adjuvant chemotherapy. Cancer Treat Rep. 1978;62(10):1471–88. Ke W, Zhao Y, Huang R, Jiang C, Pei Y. Enhanced oral bioavailability of doxorubicin in a dendrimer drug delivery system. J Pharm Sci. 2008;97(6):2208–16. Chandra S, Dietrich S, Lang H, Bahadur D. Dendrimer–doxorubicin conjugate for enhanced therapeutic effects for cancer. J Mater Chem. 2011;21(15):5729–37. Yamanoi T, Yoshida N, Oda Y, Akaike E, Tsutsumida M, Kobayashi N, et al. Synthesis of mono-glucose-branched cyclodextrins with a high inclusion ability for doxorubicin and their efficient glycosylation using Mucor hiemalis endo-β-N-acetylglucosaminidase. Bioorg Med Chem Lett. 2005;15(4):1009–13. Anno T, Higashi T, Hayashi Y, Motoyama K, Jono H, Ando Y, et al. Potential use of glucuronylglucosyl-β-cyclodextrin/dendrimer conjugate (G2) as a siRNA carrier for the treatment of familial amyloidotic polyneuropathy. J Drug Target. 2014;22(10):883–90. Reddy JA, Low PS. Folate-mediated targeting of therapeutic and imaging agents to cancers. Crit Rev Ther Drug Carrier Syst. 1998;15(6):587–627. Strebhardt K. Multifaceted polo-like kinases: drug targets and antitargets for cancer therapy. Nat Rev Drug Discov. 2010;9(8):643–60. Spankuch B, Kurunci-Csacsko E, Kaufmann M, Strebhardt K. Rational combinations of siRNAs targeting Plk1 with breast cancer drugs. Oncogene. 2007;26(39):5793–807. Hu K, Law JH, Fotovati A, Dunn SE. Small interfering RNA library screen identified polo-like kinase-1 (PLK1) as a potential therapeutic target for breast cancer that uniquely eliminates tumor-initiating cells. Breast Cancer Res. 2012;14(1):R22. Chen Y, Wu JJ, Huang L. Nanoparticles targeted with NGR motif deliver c-myc siRNA and doxorubicin for anticancer therapy. Mol Ther. 2010;18(4):828–34. Wang Y, Gao S, Ye WH, Yoon HS, Yang YY. Co-delivery of drugs and DNA from cationic core-shell nanoparticles self-assembled from a biodegradable copolymer. Nat Mater. 2006;5(10):791–6. Xiong XB, Lavasanifar A. Traceable multifunctional micellar nanocarriers for cancer-targeted co-delivery of MDR-1 siRNA and doxorubicin. ACS Nano. 2011;5(6):5202–13. Taratula O, Kuzmov A, Shah M, Garbuzenko OB, Minko T. Nanostructured lipid carriers as multifunctional nanomedicine platform for pulmonary co-delivery of anticancer drugs and siRNA. J Control Release. 2013;171(3):349–57. Quintana A, Raczka E, Piehler L, Lee I, Myc A, Majoros I, et al. Design and function of a dendrimer-based therapeutic nanodevice targeted to tumor cells through the folate receptor. Pharm Res. 2002;19(9):1310–6. Singh P, Gupta U, Asthana A, Jain NK. Folate and folate-PEG-PAMAM dendrimers: synthesis, characterization, and targeted anticancer drug delivery potential in tumor bearing mice. Bioconjug Chem. 2008;19(11):2239–52. Salmaso S, Semenzato A, Caliceti P, Hoebeke J, Sonvico F, Dubernet C, et al. Specific antitumor targetable β-cyclodextrin-poly(ethylene glycol)-folic acid drug delivery bioconjugate. Bioconjug Chem. 2004;15(5):997–1004. Okamatsu A, Motoyama K, Onodera R, Higashi T, Koshigoe T, Shimada Y, et al. Design and evaluation of folate-appended α-, β-, and γ-cyclodextrins having a caproic acid as a tumor selective antitumor drug carrier in vitro and in vivo. Biomacromolecules. 2013;14(12):4420–8. Okamatsu A, Motoyama K, Onodera R, Higashi T, Koshigoe T, Shimada Y, et al. Folate-appended β-cyclodextrin as a promising tumor targeting carrier for antitumor drugs in vitro and in vivo. Bioconjug Chem. 2013;24(4):724–33.