Efficient Gene Therapy of Pancreatic Cancer via a Peptide Nucleic Acid (PNA)-Loaded Layered Double Hydroxides (LDH) Nanoplatform
Zhiguo Yu
State Key Laboratory of High Performance Ceramics and Superfine Microstructures, Shanghai Institute of Ceramics, Chinese Academy of Sciences, 1295 Ding-Xi Road, Shanghai, 200050 P. R. China
Center of Materials Science and Optoelectronics Engineering, University of Chinese, Academy of Sciences, Beijing, 100049 P. R. China
Search for more papers by this authorCorresponding Author
Ping Hu
State Key Laboratory of High Performance Ceramics and Superfine Microstructures, Shanghai Institute of Ceramics, Chinese Academy of Sciences, 1295 Ding-Xi Road, Shanghai, 200050 P. R. China
E-mail: [email protected], [email protected]
Search for more papers by this authorYingying Xu
State Key Laboratory of High Performance Ceramics and Superfine Microstructures, Shanghai Institute of Ceramics, Chinese Academy of Sciences, 1295 Ding-Xi Road, Shanghai, 200050 P. R. China
School of Physical Science and Technology, ShanghaiTech University, Shanghai, 201210 P. R. China
Search for more papers by this authorQunqun Bao
State Key Laboratory of High Performance Ceramics and Superfine Microstructures, Shanghai Institute of Ceramics, Chinese Academy of Sciences, 1295 Ding-Xi Road, Shanghai, 200050 P. R. China
School of Physical Science and Technology, ShanghaiTech University, Shanghai, 201210 P. R. China
Search for more papers by this authorDalong Ni
State Key Laboratory of High Performance Ceramics and Superfine Microstructures, Shanghai Institute of Ceramics, Chinese Academy of Sciences, 1295 Ding-Xi Road, Shanghai, 200050 P. R. China
Search for more papers by this authorChenyang Wei
State Key Laboratory of High Performance Ceramics and Superfine Microstructures, Shanghai Institute of Ceramics, Chinese Academy of Sciences, 1295 Ding-Xi Road, Shanghai, 200050 P. R. China
Search for more papers by this authorCorresponding Author
Jianlin Shi
State Key Laboratory of High Performance Ceramics and Superfine Microstructures, Shanghai Institute of Ceramics, Chinese Academy of Sciences, 1295 Ding-Xi Road, Shanghai, 200050 P. R. China
E-mail: [email protected], [email protected]
Search for more papers by this authorZhiguo Yu
State Key Laboratory of High Performance Ceramics and Superfine Microstructures, Shanghai Institute of Ceramics, Chinese Academy of Sciences, 1295 Ding-Xi Road, Shanghai, 200050 P. R. China
Center of Materials Science and Optoelectronics Engineering, University of Chinese, Academy of Sciences, Beijing, 100049 P. R. China
Search for more papers by this authorCorresponding Author
Ping Hu
State Key Laboratory of High Performance Ceramics and Superfine Microstructures, Shanghai Institute of Ceramics, Chinese Academy of Sciences, 1295 Ding-Xi Road, Shanghai, 200050 P. R. China
E-mail: [email protected], [email protected]
Search for more papers by this authorYingying Xu
State Key Laboratory of High Performance Ceramics and Superfine Microstructures, Shanghai Institute of Ceramics, Chinese Academy of Sciences, 1295 Ding-Xi Road, Shanghai, 200050 P. R. China
School of Physical Science and Technology, ShanghaiTech University, Shanghai, 201210 P. R. China
Search for more papers by this authorQunqun Bao
State Key Laboratory of High Performance Ceramics and Superfine Microstructures, Shanghai Institute of Ceramics, Chinese Academy of Sciences, 1295 Ding-Xi Road, Shanghai, 200050 P. R. China
School of Physical Science and Technology, ShanghaiTech University, Shanghai, 201210 P. R. China
Search for more papers by this authorDalong Ni
State Key Laboratory of High Performance Ceramics and Superfine Microstructures, Shanghai Institute of Ceramics, Chinese Academy of Sciences, 1295 Ding-Xi Road, Shanghai, 200050 P. R. China
Search for more papers by this authorChenyang Wei
State Key Laboratory of High Performance Ceramics and Superfine Microstructures, Shanghai Institute of Ceramics, Chinese Academy of Sciences, 1295 Ding-Xi Road, Shanghai, 200050 P. R. China
Search for more papers by this authorCorresponding Author
Jianlin Shi
State Key Laboratory of High Performance Ceramics and Superfine Microstructures, Shanghai Institute of Ceramics, Chinese Academy of Sciences, 1295 Ding-Xi Road, Shanghai, 200050 P. R. China
E-mail: [email protected], [email protected]
Search for more papers by this authorAbstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignant tumors with extremely poor prognosis due to the later stage diagnosis when surgical resection is no longer applicable. Alternatively, the traditional gene therapy which drives pancreatic cancer cells into an inactive state and inhibiting the proliferation and metastasis, presents potentials to safely inhibit pancreatic cancer progression, but unfortunately has received limited success to date. Here, an efficient gene therapy of pancreatic cancer is shown via a peptide nucleic acid (PNA)-loaded layered double hydroxides (LDHs) nanoplatform. Compared with the traditional DNA- or RNA-based gene therapies, the gene therapy using PNA features great advantages in recognizing and hybridizing with the target mutant sequences to form PNA–DNA hybrids with significantly enhanced stability due to the absence of electrostatic repulsion, and the constrained flexibility of the polyamide backbone. Moreover, ultrasmall LDHs are engineered to load PNA and the obtained PNA-loaded LDH platform (LDHs/PNA) is capable of efficiently and selectively targeting the intranuclear mutant sequences thanks to the proton sponge effect. Treatments with LDHs/PNA demonstrate markedly inhibited growth of pancreatic cancer xenografts via a cancer cell proliferation suppression mechanism. The results demonstrate the great potentials of LDHs/PNA as a highly promising gene therapy agent for PDAC.
Conflict of Interest
The authors declare no conflict of interest.
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References
- 1a) M. Carpelan-Holmstrom, S. Nordling, E. Pukkala, R. Sankila, J. Luttges, G. Kloppel, C. Haglund, Gut 2005, 54, 385; b) D. Tang, Q. Wu, Z. Yuan, J. Xu, H. Zhang, Z. Jin, Q. Zhang, M. Xu, Z. Wang, Z. Dai, H. Fang, Z. Li, C. Lin, C. Shi, M. Xu, X. Sun, D. Wang, Neoplasma 2019, 66, 446.
- 2H. Q. Ying, A. C. Kimmelman, C. A. Lyssiotis, S. J. Hua, G. C. Chu, E. Fletcher-Sananikone, J. W. Locasale, J. Son, H. L. Zhang, J. L. Coloff, H. Y. Yan, W. Wang, S. J. Chen, A. Viale, H. W. Zheng, J. H. Paik, C. Lim, A. R. Guimaraes, E. S. Martin, J. Chang, A. F. Hezel, S. R. Perry, J. Hu, B. Y. Gan, Y. H. Xiao, J. M. Asara, R. Weissleder, Y. A. Wang, L. Chin, L. C. Cantley, R. A. DePinho, Cell 2012, 149, 656.
- 3A. Viale, P. Pettazzoni, C. A. Lyssiotis, H. Q. Ying, N. Sanchez, M. Marchesini, A. Carugo, T. Green, S. Seth, V. Giuliani, M. Kost-Alimova, F. Muller, S. Colla, L. Nezi, G. Genovese, A. K. Deem, A. Kapoor, W. T. Yao, E. Brunetto, Y. Kang, M. Yuan, J. M. Asara, Y. A. Wang, T. P. Heffernan, A. C. Kimmelman, H. M. Wang, J. B. Fleming, L. C. Cantley, R. A. DePinho, G. F. Draetta, Nature 2014, 514, 628.
- 4X. F. Zheng, J. L. Carstens, J. Kim, M. Scheible, J. Kaye, H. Sugimoto, C. C. Wu, V. S. LeBleu, R. Kalluri, Nature 2015, 527, 525.
- 5C. C. Ma, K. T. Nong, H. D. Zhu, W. W. Wang, X. Y. Huang, Z. Yuan, K. X. Ai, Tumor Biol. 2014, 35, 9163.
- 6A. D. Cox, S. W. Fesik, A. C. Kimmelman, J. Luo, C. J. Der, Nat. Rev. Drug Discovery 2014, 13, 828.
- 7P. E. Nielsen, M. Egholm, R. H. Berg, O. Buchardt, Science 1991, 254, 1497.
- 8D. Fischer, B. Osburg, H. Petersen, T. Kissel, U. Bickel, Drug Metab. Dispos. 2004, 32, 983.
- 9a) J. C. Norton, M. A. Piatyszek, W. E. Wright, J. W. Shay, D. R. Corey, Nat. Biotechnol. 1996, 14, 615; b) T. Ishihara, A. Kano, K. Obara, M. Saito, X. Chen, T. G. Park, T. Akaike, A. Maruyama, J. Controlled Release 2011, 155, 34; c) G. Cutrona, E. M. Carpaneto, M. Ulivi, S. Roncella, O. Landt, M. Ferrarini, L. C. Boffa, Nat. Biotechnol. 2000, 18, 300; d) J. Wang, E. Palecek, P. E. Nielsen, G. Rivas, X. H. Cai, H. Shiraishi, N. Dontha, D. B. Luo, P. A. M. Farias, J. Am. Chem. Soc. 1996, 118, 7667; e) P. Hu, S. J. Zhang, T. Wu, D. L. Ni, W. P. Fan, Y. Zhu, R. Qian, J. L. Shi, Adv. Mater. 2018, 30, 1690.
- 10a) J. S. Kastrup, M. Pilgaard, F. S. Jorgensen, P. E. Nielsen, H. Rasmussen, FEBS Lett. 1995, 363, 115; b) M. A. Bonham, S. Brown, A. L. Boyd, P. H. Brown, D. A. Bruckenstein, J. C. Hanvey, S. A. Thomson, A. Pipe, F. Hassman, J. E. Bisi, B. C. Froehler, M. D. Matteucci, R. W. Wagner, S. A. Noble, L. E. Babiss, Nucleic Acids Res. 1995, 23, 1197.
- 11C. E. Thomas, A. Ehrhardt, M. A. Kay, Nat. Rev. Genet. 2003, 4, 346.
- 12a) Z. Gu, A. Biswas, M. X. Zhao, Y. Tang, Chem. Soc. Rev. 2011, 40, 3638; b) R. A. Jain, Biomaterials 2000, 21, 2475; c) S. M. Sureban, R. May, F. G. Mondalek, D. Qu, S. Ponnurangam, P. Pantazis, S. Anant, R. P. Ramanujam, C. W. Houchen, J. Nanobiotechnol. 2011, 9, 40; d) Y. Guo, L. Wang, P. Lv, P. Zhang, Oncol. Lett. 2015, 9, 1065.
- 13R. Z. Ma, T. Sasaki, Adv. Mater. 2010, 22, 5082.
- 14G. Choi, T. H. Kim, J. M. Oh, J. H. Choy, Coord. Chem. Rev. 2018, 359, 32.
- 15a) M. Lamla, H. Seliger, D. Kaufmann, Drug Delivery 2010, 17, 263; b) Q. Wang, D. O'Hare, Chem. Rev. 2012, 112, 4124.
- 16J. Xu, Y. Liu, Y. Li, H. Wang, S. Stewart, K. Van der Jeught, P. Agarwal, Y. Zhang, S. Liu, G. Zhao, J. Wan, X. Lu, X. He, Nat. Nanotechnol. 2019, 14, 388.
- 17H. L. Zuo, W. Y. Chen, H. M. Cooper, Z. P. Xu, ACS Appl. Mater. Interfaces 2017, 9, 20444.
- 18S. J. Ross, A. S. Revenko, L. L. Hanson, R. Ellston, A. Staniszewska, N. Whalley, S. K. Pandey, M. Revill, C. Rooney, L. K. Buckett, S. K. Klein, K. Hudson, B. P. Monia, M. Zinda, D. C. Blakey, P. D. Lyne, A. R. Macleod, Sci. Transl. Med. 2017, 9, eaal5253.
- 19Y. Nakasone, H. Ooi, Y. Kamiya, H. Asanuma, M. Terazima, J. Am. Chem. Soc. 2016, 138, 9001.
- 20X. D. Su, R. Kanjanawarut, ACS Nano 2009, 3, 2751.
- 21G. F. Xiao, H. Y. Zeng, Q. J. Huang, W. Zhang, J. Z. Du, H. Z. Duan, C. R. Chen, J. Nanosci. Nanotechnol. 2018, 18, 5256.
- 22K. Ladewig, Z. P. Xu, G. Q. Lu, Expert Opin. Drug Delivery 2009, 6, 907.
- 23J. H. Choy, S. Y. Kwak, J. S. Park, Y. J. Jeong, J. Portier, J. Am. Chem. Soc. 1999, 121, 1399.
- 24T. Hibino, Chem. Mater. 2004, 16, 5482.
- 25C. A. Brown, M. A. Pavlosky, T. E. Westre, Y. Zhang, B. Hedman, K. O. Hodgson, E. I. Solomon, J. Am. Chem. Soc. 1995, 117, 715.
- 26a) S. X. Wu, J. G. Huang, C. Li, Y. Q. Liang, J. Colloid Interface Sci. 2004, 270, 309; b) J. T. Kloprogge, R. L. Frost, J Solid State Chem. 1999, 146, 506.
- 27J. H. Choy, S. Y. Kwak, Y. J. Jeong, J. S. Park, Angew. Chem., Int. Ed. 2000, 39, 4042.
- 28J. Das, B. S. Patra, N. Baliarsingh, K. M. Parida, Appl. Clay Sci. 2006, 32, 252.
- 29a) D. Schmaljohann, Adv. Drug Delivery Rev. 2006, 58, 1655; b) Y. Ding, D. Sun, G. L. Wang, H. G. Yang, H. F. Xu, J. H. Chen, Y. Xie, Z. Q. Wang, Int. J. Nanomed. 2015, 10, 6199.
- 30a) X. Mei, S. M. Xu, T. Y. Hu, L. Q. Peng, R. Gao, R. Z. Liang, M. Wei, D. Evans, X. Duan, Nano Res. 2018, 11, 195;
b) Z. P. Xu, M. Niebert, K. Porazik, T. L. Walker, H. M. Cooper, A. P. J. Middelberg, P. P. Gray, P. F. Bartlett, G. Q. Lu, J. Controlled Release 2008, 130, 86;
c) O. Boussif, F. Lezoualc'h, M. A. Zanta, M. D. Mergny, D. Scherman, B. Demeneix, J. P. Behr, Proc. Natl. Acad. Sci. USA 1995, 92, 7297;
d) Q. Li, Blood 2018, 132, 2.
10.1182/blood-2018-99-115124 Google Scholar
- 31I. Mambetsariev, I. Amanam, A. Nam, R. Salgia, J. Thorac. Oncol. 2017, 12, S1723.
- 32M. Y. Wu, Q. S. Meng, Y. Chen, P. F. Xu, S. J. Zhang, Y. P. Li, L. X. Zhang, M. Wang, H. L. Yao, J. L. Shi, Adv. Funct. Mater. 2014, 24, 4273.
- 33S. Elmore, Toxicol. Pathol. 2007, 35, 495.
- 34S. Kamerkar, V. S. LeBleu, H. Sugimoto, S. Yang, C. F. Ruivo, S. A. Melo, J. J. Lee, R. Kalluri, Nature 2017, 546, 498.
- 35J. V. McCann, L. Xiao, D. J. Kim, O. F. Khan, P. S. Kowalski, D. G. Anderson, C. V. Pecot, S. H. Azam, J. S. Parker, Y. S. Tsai, A. S. Wolberg, S. D. Turner, K. Tatsumi, N. Mackman, A. C. Dudley, J. Clin. Invest. 2019, 129, 1654.
