Journal Home > Volume 10 , Issue 2
Nano Research 2017, 10(2): 690-703 https://doi.org/10.1007/s12274-016-1328-y
Research Article | Issue | Published: 10 November 2016

Hyaluronidase-triggered anticancer drug and siRNA delivery from cascaded targeting nanoparticles for drug- resistant breast cancer therapy

Show Author's Information Jie Ding1,2,  Tingxizi Liang1,  Ying Zhou1,  Zhiwei He2,  Qianhao Min1( ),  Liping Jiang1( ),  Junjie Zhu1
State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210093, China
Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, China-America Cancer Research Institute, Guangdong Medical University, Dongguan 523808, China
Keywords:
hyaluronic acid, siRNA, drug-resistant breast cancer, breast tumor cell-penetrating peptide, rattle mesoporous silica
Cite this article:
Ding J, Liang T, Zhou Y, et al. Hyaluronidase-triggered anticancer drug and siRNA delivery from cascaded targeting nanoparticles for drug- resistant breast cancer therapy. Nano Research, 2017, 10(2): 690-703. https://doi.org/10.1007/s12274-016-1328-y
Download citation
EndNote(RIS)
BibTeX

578

Views

26

Downloads

Citations

50

Crossref

N/A

WoS

50

Scopus

2

CSCD

Abstract Full text Electronic supplementary material About this article

Drug resistance renders standard chemotherapy ineffective in the treatment of connective tissue growth factor (CTGF)-overexpressing breast cancer. By co-embedding the breast tumor cell-penetrating peptide (PEGA-pVEC) and hyaluronic acid (HA) as a targeting media, novel cascaded targeting nanoparticles (HACT NPs) were created on a rattle mesoporous silica (rmSiO2) scaffold for the pinpoint delivery of siRNAs along with an anticancer drug, aiming at overcoming the drug resistance of CTGF-overexpressing breast cancer in vivo. The targeting nanoparticles selectively accumulated in the vasculature under the guidance of the PEGA-pVEC peptide, cascaded by receptor-mediated endocytosis with the aid of another targeting agent, HA, presenting a greater in vivo tumor targeting ability than single targeting ligand vectors. In addition, an HA shell prevented the leakage of therapeutic drugs during the cargo transport process, until the hyaluronidase (HAase)-triggered degradation upon lysosomes entering, guaranteeing a controllable drug release inside the target cells. When the protective shell disintegrates, the released siRNA took charge to silence the gene associated with drug resistance, CTGF, thus facilitating doxorubicin-induced apoptosis. The cascaded targeting media (PEGA-pVEC and HA) advances precision-guided therapy in vivo, while the encapsulation of siRNAs into a chemotherapy drug delivery system provides an efficient strategy for the treatment of drug resistance cancers.


menu
Abstract
Full text
Outline
Electronic supplementary material
About this article

Hyaluronidase-triggered anticancer drug and siRNA delivery from cascaded targeting nanoparticles for drug- resistant breast cancer therapy

Show Author's information Jie Ding1,2, Tingxizi Liang1, Ying Zhou1, Zhiwei He2, Qianhao Min1( ), Liping Jiang1( ), Junjie Zhu1
State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210093, China
Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, China-America Cancer Research Institute, Guangdong Medical University, Dongguan 523808, China

Abstract

Drug resistance renders standard chemotherapy ineffective in the treatment of connective tissue growth factor (CTGF)-overexpressing breast cancer. By co-embedding the breast tumor cell-penetrating peptide (PEGA-pVEC) and hyaluronic acid (HA) as a targeting media, novel cascaded targeting nanoparticles (HACT NPs) were created on a rattle mesoporous silica (rmSiO2) scaffold for the pinpoint delivery of siRNAs along with an anticancer drug, aiming at overcoming the drug resistance of CTGF-overexpressing breast cancer in vivo. The targeting nanoparticles selectively accumulated in the vasculature under the guidance of the PEGA-pVEC peptide, cascaded by receptor-mediated endocytosis with the aid of another targeting agent, HA, presenting a greater in vivo tumor targeting ability than single targeting ligand vectors. In addition, an HA shell prevented the leakage of therapeutic drugs during the cargo transport process, until the hyaluronidase (HAase)-triggered degradation upon lysosomes entering, guaranteeing a controllable drug release inside the target cells. When the protective shell disintegrates, the released siRNA took charge to silence the gene associated with drug resistance, CTGF, thus facilitating doxorubicin-induced apoptosis. The cascaded targeting media (PEGA-pVEC and HA) advances precision-guided therapy in vivo, while the encapsulation of siRNAs into a chemotherapy drug delivery system provides an efficient strategy for the treatment of drug resistance cancers.

Keywords: hyaluronic acid, siRNA, drug-resistant breast cancer, breast tumor cell-penetrating peptide, rattle mesoporous silica

References(36)

1

Siegel, R.; Naishadham, D.; Jemal, A. Cancer statistics, 2012. CA Cancer J. Clin. 2012, 62, 10–29.
DOI Google Scholar
2

Siegel, R.; DeSantis, C.; Virgo, K.; Stein, K.; Mariotto, A.; Smith, T.; Cooper, D.; Gansler, T.; Lerro, C.; Fedewa, S. et al. Cancer treatment and survivorship statistics, 2012. CA Cancer J. Clin. 2012, 62, 220–241.
DOI Google Scholar
3

Bork, P. The modular architecture of a new family of growth regulators related to connective tissue growth factor. FEBS Lett. 1993, 327, 125–130.
DOI Google Scholar
4

Lau, L. F.; Lam, S. C. T. The CCN family of angiogenic regulators: The integrin connection. Exp. Cell Res. 1999, 248, 44–57.
DOI Google Scholar
5

Kondo, S.; Kubota, S.; Shimo, T.; Nishida, T.; Yosimichi, G.; Eguchi, T.; Sugahara, T.; Takigawa, M. Connective tissue growth factor increased by hypoxia may initiate angiogenesis in collaboration with matrix metalloproteinases. Carcinogenesis 2002, 23, 769–776.
DOI Google Scholar
6

Xie, D.; Nakachi, K.; Wang, H.; Elashoff, R.; Koeffler, H. P. Elevated levels of connective tissue growth factor, WISP-1, and CYR61 in primary breast cancers associated with more advanced features. Cancer Res. 2001, 61, 8917–8923.
Google Scholar
7

Chen, P. S.; Wang, M. Y.; Wu, S. N.; Su, J. L.; Hong, C. C.; Chuang, S. E.; Chen, M. W.; Hua, K. T.; Wu, Y. L.; Cha, S. T. et al. CTGF enhances the motility of breast cancer cells via an integrin-αvβ3-ERK1/2-dependent S100A4- upregulated pathway. J. Cell Sci. 2007, 120, 2053–2065.
DOI Google Scholar
8

Mehlen, P.; Puisieux, A. Metastasis: A question of life or death. Nat. Rev. Cancer 2006, 6, 449–458.
DOI Google Scholar
9

Wang, M. Y.; Chen, P. S.; Prakash, E.; Hsu, H. C.; Huang, H. Y.; Lin, M. T.; Chang, K. J.; Kuo, M. L. Connective tissue growth factor confers drug resistance in breast cancer through concomitant up-regulation of Bcl-xL and cIAP1. Cancer Res. 2009, 69, 3482–3491.
DOI Google Scholar
10
Salcher, E. E.; Wagner, E. Chemically programmed polymers for targeted DNA and siRNA transfection. In Nucleic Acid Transfection; Bielke, W.; Erbacher, C., Eds.; Springer: Berlin, Heidelberg, Germany, 2010; pp 227–249.https://doi.org/10.1007/128_2010_69
DOI
11

Pecot, C. V.; Calin, G. A.; Coleman, R. L.; Lopez-Berestein, G.; Sood, A. K. RNA interference in the clinic: Challenges and future directions. Nat. Rev. Cancer 2011, 11, 59–67.
DOI Google Scholar
12

Thompson, J. D. Clinical development of synthetic siRNA therapeutics. Drug Discov. Today Ther. Strateg. 2013, 10, e133–e138.
DOI Google Scholar
13

Peer, D.; Karp, J. M.; Hong, S.; Farokhzad, O. C.; Margalit, R.; Langer, R. Nanocarriers as an emerging platform for cancer therapy. Nat. Nanotechnol. 2007, 2, 751–760.
DOI Google Scholar
14

Jain, R. K.; Stylianopoulos, T. Delivering nanomedicine to solid tumors. Nat. Rev. Clin. Oncol. 2010, 7, 653–664.
DOI Google Scholar
15

Cabral, H.; Nishiyama, N.; Kataoka, K. Supramolecular nanodevices: From design validation to theranostic nano­medicine. Acc. Chem. Res. 2011, 44, 999–1008.
DOI Google Scholar
16

Mo, R.; Jiang, T. Y.; DiSanto, R.; Tai, W. Y.; Gu, Z. ATP- triggered anticancer drug delivery. Nat. Commun. 2014, 5, 3364.
DOI Google Scholar
17

Zhang, Q.; Ge, J. P.; Goebl, J.; Hu, Y. X.; Lu, Z. D.; Yin, Y. D. Rattle-type silica colloidal particles prepared by a surface-protected etching process. Nano Res. 2009, 2, 583–591.
DOI Google Scholar
18

Li, L. L.; Tang, F. Q.; Liu, H. Y.; Liu, T. L.; Hao, N. J.; Chen, D.; Teng, X.; He, J. Q. In vivo delivery of silica nanorattle encapsulated docetaxel for liver cancer therapy with low toxicity and high efficacy. ACS Nano 2010, 4, 6874–6882.
DOI Google Scholar
19

Yuan, F.; Leunig, M.; Huang, S. K.; Berk, D. A.; Papahadjopoulos, D.; Jain, R. K. Microvascular permeability and interstitial penetration of sterically stabilized (stealth) liposomes in a human tumor xenograft. Cancer Res. 1994, 54, 3352–3356.
Google Scholar
20

Campbell, R. B.; Fukumura, D.; Brown, E. B.; Mazzola, L. M.; Izumi, Y.; Jain, R.; Torchilin, K. V. P.; Munn, L. L. Cationic charge determines the distribution of liposomes between the vascular and extravascular compartments of tumors. Cancer Res. 2002, 62, 6831–6836.
Google Scholar
21

Heldin, C. H.; Rubin, K.; Pietras, K.; Östman, A. High interstitial fluid pressure-an obstacle in cancer therapy. Nat. Rev. Cancer 2004, 4, 806–813.
DOI Google Scholar
22

Burrows, F. J.; Thorpe, P. E. Vascular targeting—A new approach to the therapy of solid tumors. Pharmacol. Ther. 1994, 64, 155–174.
DOI Google Scholar
23

Hashizume, H.; Baluk, P.; Morikawa, S.; McLean, J. W.; Thurston, G.; Roberge, S.; Jain, R. K.; McDonald, D. M. Openings between defective endothelial cells explain tumor vessel leakiness. Am. J. Pathol. 2000, 156, 1363–1380.
DOI Google Scholar
24

Leu, A. J.; Berk, D. A.; Lymboussaki, A.; Alitalo, K.; Jain, R. K. Absence of functional lymphatics within a murine sarcoma: A molecular and functional evaluation. Cancer Res. 2000, 60, 4324–4327.
Google Scholar
25

Ding, J.; Yao, J.; Xue, J. J.; Li, R.; Bao, B.; Jiang, L. P.; Zhu, J. J.; He, Z. W. Tumor-homing cell-penetrating peptide linked to colloidal mesoporous silica encapsulated (–)-epigallocatechin-3-gallate as drug delivery system for breast cancer therapy in vivo. ACS Appl. Mater. Interfaces 2015, 7, 18145–18155.
DOI Google Scholar
26

Li, K.; Liu, H.; Gao, W.; Chen, M.; Zeng, Y.; Liu, J. J.; Xu, L.; Wu, D. C. Mulberry-like dual-drug complicated nanocarriers assembled with apogossypolone amphiphilic starch micelles and doxorubicin hyaluronic acid nanoparticles for tumor combination and targeted therapy. Biomaterials 2015, 39, 131–144.
DOI Google Scholar
27

Myrberg, H.; Zhang, L. L.; Mäe, M.; Langel, Ü. Design of a tumor-homing cell-penetrating peptide. Bioconjugate Chem. 2008, 19, 70–75.
DOI Google Scholar
28

Essler, M.; Ruoslahti, E. Molecular specialization of breast vasculature: A breast-homing phage-displayed peptide binds to aminopeptidase P in breast vasculature. Proc. Natl. Acad. Sci. USA 2002, 99, 2252–2257.
DOI Google Scholar
29

Elmquist, A.; Lindgren, M.; Bartfai, T.; Langel, Ü. VE- cadherin-derived cell-penetrating peptide, pVEC, with carrier functions. Exp. Cell. Res. 2001, 269, 237–244.
DOI Google Scholar
30

Jiang, T. Y.; Mo, R.; Bellotti, A.; Zhou, J. P.; Gu, Z. Gel- liposome-mediated co-delivery of anticancer membrane- associated proteins and small-molecule drugs for enhanced therapeutic efficacy. Adv. Funct. Mater. 2014, 24, 2295–2304.
DOI Google Scholar
31

Wang, Z. Z.; Chen, Z. W.; Liu, Z.; Shi, P.; Dong, K.; Ju, E. G.; Ren, J. S.; Qu, X. G. A multi-stimuli responsive gold nanocage-hyaluronic platform for targeted photothermal and chemotherapy. Biomaterials 2014, 35, 9678–9688.
DOI Google Scholar
32

Zhang, F.; Wan, Y.; Yu, T.; Zhang, F. G.; Shi, Y. F.; Xie, S. H.; Li, Y. G.; Xu, L.; Tu, B.; Zhao, D. Y. Uniform nanostructured arrays of sodium rare-earth fluorides for highly efficient multicolor upconversion luminescence. Angew Chem., Int. Ed. 2007, 46, 7976–7979.
DOI Google Scholar
33

Bhang, S. H.; Won, N.; Lee, T. J.; Jin, H.; Nam, J.; Park, J.; Chung, H.; Park, H. S.; Sung, Y. E.; Hahn, S. K. et al. Hyaluronic acid-quantum dot conjugates for in vivo lymphatic vessel imaging. ACS Nano 2009, 3, 1389–1398.
DOI Google Scholar
34

Li, J.; Huo, M. R.; Wang, J.; Zhou, J. P.; Mohammad, J. M.; Zhang, Y. L.; Zhu, Q. N.; Waddad, A. Y.; Zhang, Q. Redox-sensitive micelles self-assembled from amphiphilic hyaluronic acid-deoxycholic acid conjugates for targeted intracellular delivery of paclitaxel. Biomaterials 2012, 33, 2310–2320.
DOI Google Scholar
35

Huber, W.; Koella, J. C. A comparison of three methods of estimating EC50 in studies of drug resistance of malaria parasites. Acta Trop. 1993, 55, 257–261.
DOI Google Scholar
36

Isacke, C. M.; Yarwood, H. The hyaluronan receptor, CD44. Int. J. Biochem. Cell Biol. 2002, 34, 718–721.
DOI Google Scholar
File
nr-10-2-690_ESM.pdf (2.2 MB)
Publication history
Copyright
Acknowledgements

Publication history

Received: 22 July 2016
Revised: 07 October 2016
Accepted: 12 October 2016
Published: 10 November 2016
Issue date: February 2017

Copyright

© Tsinghua University Press and Springer-Verlag Berlin Heidelberg 2016

Acknowledgements

Acknowledgements

This research was supported by National Natural Science Foundation of China (Nos. 21335004, 21475057, 21575061, and 21622505).

Return