PEG-peptide conjugate containing cathepsin B degradation unit as a doxorubicin carrier system

A drug delivery system (DDS) containing a cathepsin B degradable sequence and pH-responsive histidines was prepared by methoxypolyethylene glycol and peptide conjugation. Doxorubicin was attached to the carrier system using amide linkage to give the final form of the DDS, denoted as mPEG-AT3-DOX. mPEG-AT3-DOX exhibited a bimodal size distribution at about 15 and 30 nm independent of pH, whereas the size of the control DDS containing no peptide sequence, mPEG-DOX, was measured as ∼ 15–20 nm. At the end of 72 h, % doxorubicin release from both of the DDSs was observed to be below 8.5 ± 3% in the absence of cathepsin B, and it increased to 17 ± 2% in the presence of cathepsin B for mPEG-AT3-DOX. Complete degradation of AT3 peptide within 3 h upon incubation with cathepsin B suggests that lower than expected doxorubicin release is likely due to the aggregation tendency of mPEG-AT3-DOX. Absolute IC50 values indicated that the cytotoxicity trend of the samples is in the order of free DOX ≥ mPEG-AT3-DOX >mPEG-DOX. Considering these results, PEG-peptide-doxorubicin conjugates can be promising candidates in cancer therapy if they are designed to have more pronounced pH-responsive behavior to increase the drug release rate.

PDF

___

1. Qin, S. Y.; Zhang, A. Q.; Cheng, S. X.; Rong, L.; Zhang, X. Z. Biomaterials 2017, 112, 234-247.
2. Tong, R.; Cheng, J. J. Macromol. Sci. Polymer Rev. 2007, 47, 345-381.
3. Li, Z.; Tan, S.; Li, S.; Shen, Q.; Wang, K. Oncol. Rep. 2017, 38, 611-624.
4. Sun, Q.; Zhou, Z.; Qiu, N.; Shen, Y. Adv. Mater. 2017, 29, 1606628.
5. Fukumori, Y.; Ichikawa, H. Adv. Powder Technol. 2006, 17, 1-28.
6. Zaimy, M.; Saffarzadeh, N.; Mohammadi, A.; Pourghadamyari, H.; Izadi, P.; Sarli, A.; Moghaddam, L.; Paschepari, S.; Azizi, H.; Torkamandi, S. Cancer Gene Ther. 2017, 24, 233-243.
7. Ulbrich, K.; Hola, K.; Subr, V.; Bakandritsos, A.; Tucek, J.; Zboril, R. ˘ Chem. Rev. 2016, 116, 5338-5431.
8. Bae, Y. H.; Park, K. J. Control. Release 2011, 153, 198-205.
9. Gabizon, A.; Shmeeda, H.; Horowitz, A. T.; Zalipsky, S. Adv. Drug Deliv. Rev. 2004, 56, 1177-1192.
10. Liang, X. J.; Chen, C.; Zhao, Y.; Wang, P. C. Methods Mol. Biol. 2010, 596, 467-488.
11. Maeda, H. Adv. Enzyme Regul. 2001, 41, 189-207.
12. Maeda, H. Proc. Jpn. Acad., Ser. B Phys. Biol. Sci. 2012, 88, 53-71.
13. Maeda, H.; Bharate, G.; Daruwalla, J. Eur. J. Pharm. Biopharm. 2009, 71, 409-419.
14. Yuan, Y.; Cai, T.; Xia, X.; Zhang, R.; Chiba, P.; Cai, Y. Drug Deliv. 2016, 23, 3350-3357.
15. Peer, D.; Karp, J. M.; Hong, S.; Farokhzad, O. C.; Margalit, R.; Langer, R. Nat. Nanotechnol. 2007, 2, 751-760.
16. Torchilin, V. Adv. Drug Deliv. Rev. 2011, 63, 131-135.
17. Maruyama, K. Adv. Drug Deliv. Rev. 2011, 63, 161-169.
18. Gabizon, A. A.; Patil, Y.; La-Beck, N. M. Drug Resist. Updat. 2016, 29, 90-106.
19. Brys, A. K.; Gowda, R.; Loriaux, D. B.; Robertson, G. P.; Mosca, P. J. Biotechnol. Adv. 2016, 34, 565-577.
20. Persidis, A. Nat. Biotechnol. 1999, 17, 94-95.
21. Saraswathy, M.; Gong, S. Biotechnol. Adv. 2013, 31, 1397-1407.
22. Ozben, T. FEBS Lett. 2006, 580, 2903-2909.
23. Yin, Q.; Shen, J.; Zhang, Z.; Yu, H.; Li, Y. Adv. Drug Deliv. Rev. 2013, 65, 1699-1715.
24. Huang, Y.; Cole, S. P.; Cai, T.; Cai, Y. Oncol. Lett. 2016, 12, 11-15.
25. Patel, N. R.; Pattni, B. S.; Abouzeid, A. H.; Torchilin, V. P. Adv. Drug Deliv. Rev. 2013, 65, 1748-1762.
26. Chistiakov, D. A.; Myasoedova, V. A.; Orekhov, A. N.; Bobryshev, Y. V. Curr. Pharm. Des. 2017, 23, 3301-3308.
27. Ganta, S.; Devalapally, H.; Shahiwala, A.; Amiji, M. J. Control. Release 2008, 126, 187-204.
28. Gillies, E. R.; Fr´echet, J. M. Bioconjug. Chem. 2005, 16, 361-368.
29. Guo, X.; Shi, C.; Wang, J.; Di, S.; Zhou, S. Biomaterials 2013, 34, 4544-4554.
30. Hu, X.; Liu, S.; Huang, Y.; Chen, X.; Jing, X. Biomacromolecules 2010, 11, 2094-2102.
31. Jin, Y.; Huang, Y.; Yang, H.; Liu, G.; Zhao, R. Chem. Commun. 2015, 51, 14454-14457.
32. Lee, E. S.; Gao, Z.; Bae, Y. H. J. Control. Release 2008, 132, 164-170.
33. Lee, E. S.; Na, K.; Bae, Y. H. J. Control. Release 2005, 103, 405-418.
34. Shenoy, D.; Little, S.; Langer, R.; Amiji, M. Mol. Pharm. 2005, 2, 357-366.
35. Zhou, L.; Cheng, R.; Tao, H.; Ma, S.; Guo, W.; Meng, F.; Liu, H.; Liu, Z.; Zhong, Z. Biomacromolecules 2011, 12, 1460-1467.
36. Sonawane, S. J.; Kalhapure, R. S.; Govender, T. Eur. J. Pharm. Sci. 2017, 99, 45-65.
37. Kanamala, M.; Wilson, W. R.; Yang, M.; Palmer, B. D.; Wu, Z. Biomaterials 2016, 85, 152-167.
38. Etrych, T.; Jelınkov´a, M.; Rıhov´a, B.; Ulbrich, K. ˇ J. Control. Release 2001, 73, 89-102.
39. Veronese, F. M.; Schiavon, O.; Pasut, G.; Mendichi, R.; Andersson, L.; Tsirk, A.; Ford, J.; Wu, G.; Kneller, S.; Davies, J. Bioconjug. Chem. 2005, 16, 775-784.
40. Schmid, B.; Chung, D. E.; Warnecke, A.; Fichtner, I.; Kratz, F. Bioconjug. Chem. 2007, 18, 702-716.
41. Nomura, T.; Katunuma, N. J. Med. Invest. 2005, 52, 1-9.
42. Yano, M.; Hirai, K.; Naito, Z.; Yokoyama, M.; Ishiwata, T.; Shiraki, Y.; Inokuchi, M.; Asano, G. Surg. Today 2001, 31, 385-389.
43. Studer, M.; Kroger, L. A.; DeNardo, S. J.; Kukis, D. L.; Meares, C. F. Bioconjug. Chem. 1992, 3, 424-429.
44. Harris, J. M.; Chess, R. B. Nat. Rev. Drug Discov. 2003, 2, 214-221.
45. Mishra, P.; Nayak, B.; Dey, R. Asian J. Pharm. Sci. 2016, 11, 337-348.
46. Veronese, F. M.; Pasut, G. Drug Discov. Today 2005, 10, 1451-1458.
47. Hamley, I. W. Biomacromolecules 2014, 15, 1543-1559.
48. von Roemeling, C.; Jiang, W.; Chan, C. K.; Weissman, I. L.; Kim, B. Y. Trends Biotechnol. 2017, 35, 159-171.
49. Fee, C. J.; Van Alstine, J. M. Chem. Eng. Sci. 2006, 61, 924-939. 50. Hong, G.; Zou, Y.; Antaris, A. L.; Diao, S.; Wu, D.; Cheng, K.; Zhang, X.; Chen, C.; Liu, B.; He, Y. et al. Nat. Commun. 2014, 5, 4206.
51. Cuong, N. V.; Jiang, J. L.; Li, Y. L.; Chen, J. R.; Jwo, S. C.; Hsieh, M. F. Cancers 2010, 3, 61-78.
52. Kourie, J.; Shorthouse, A. Am. J. Physiol., Cell Physiol. 2000, 278, C1063-C1087.
53. Balcı, B. MSc, Department of Chemical Engineering, ˙Izmir Institute of Technology, Turkey, 2016.
54. Gou, P.; Liu, W.; Mao, W.; Tang, J.; Shen, Y.; Sui, M. J. Mater. Chem. B 2013, 1, 284-292.
55. Meng, Z.; Luan, L.; Kang, Z.; Feng, S.; Meng, Q.; Liu, K. J. Mater. Chem. B 2017, 5, 74-84.
56. Midoux, P.; Pichon, C.; Yaouanc, J. J.; Jaffr`es, P. A. Br. J. Pharmacol. 2009, 157, 166-178.
57. Gong, X. W.; Wei, D. Z.; He, M. L.; Xiong, Y. C. Talanta 2007, 71, 381-384.
58. Stathopoulos, P.; Papas, S.; Tsikaris, V. J. Pept. Sci. 2006, 12, 227-232.
59. Configliacchi, E.; Razzano, G.; Rizzo, V.; Vigevani, A. J. Pharm. Biomed. Anal. 1996, 15, 123-129.