Systemic delivery of gemcitabine analogue and STAT3 siRNA promotes antitumor immunity against melanoma

Huan Yan; Zhanyan Liu; Guibin Lin; Fei Gu; Yan Liu; Yuxiao Xu; Xueli Kuang; Yuan Zhang

doi:10.1007/s12274-022-4525-x

Nano Research 2022, 15(10): 9057-9072 https://doi.org/10.1007/s12274-022-4525-x

Research Article | Issue | Published: 06 July 2022

Systemic delivery of gemcitabine analogue and STAT3 siRNA promotes antitumor immunity against melanoma

Show Author's Information Hide Author's Information Huan Yan^{¹^,²^,³^,⁴^,^§}, Zhanyan Liu^{¹^,²^,³^,⁴^,^§}, Guibin Lin^{¹^,²^,³^,⁴}, Fei Gu^{¹^,²^,³^,⁴}, Yan Liu^{¹^,²^,³^,⁴}, Yuxiao Xu^{¹^,²^,³^,⁴}, Xueli Kuang^{¹^,²^,³^,⁴}, Yuan Zhang^{¹^,²^,³^,⁴^,^§}(

)

1School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou 511442, China

2National Engineering Research Center for Tissue Restoration and Reconstruction, South China University of Technology, Guangzhou 510006, China

3Guangdong Provincial Key Laboratory of Biomedical Engineering, South China University of Technology, Guangzhou 510006, China

4Key Laboratory of Biomedical Materials and Engineering of the Ministry of Education, South China University of Technology, Guangzhou 510006, China

^§ Huan Yan, Zhanyan Liu, and Yuan Zhang contributed equally to this work.

Keywords:

nanoparticle, tumor microenvironment, immunosuppression, gemcitabine, STAT3 siRNA

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Controlled drug delivery

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Yan H, Liu Z, Lin G, et al. Systemic delivery of gemcitabine analogue and STAT3 siRNA promotes antitumor immunity against melanoma. Nano Research, 2022, 15(10): 9057-9072. https://doi.org/10.1007/s12274-022-4525-x

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Abstract Full text Electronic supplementary material About this article

Abstract

Immunosuppressive myeloid cells in the tumor microenvironment (TME) inhibit T-cell-mediated immune response and promote tumor progression. Therapeutically targeting both tumor cells and myeloid cells such as myeloid-derived suppressor cells (MDSCs), is expected to promote antitumor immunity. Gemcitabine (Gem) can serve as a chemotherapeutic drug and a MDSC-depleting agent. Aberrant activation of STAT3 promotes tumor cell growth and orchestrates the immunosuppressive activity of tumor-associated myeloid cells. Here we describe a strategy to kill tumor cells as well as inhibit the expansion and suppressive function of myeloid cells through the systemic delivery of gemcitabine monophosphate (GMP) and STAT3 siRNA (siSTAT3). To enhance their in vivo delivery efficiency, we formulate GMP and siSTAT3 into a lipid-coated calcium phosphate (LCP) nanoparticle and a liposome-protamine-hyaluronic acid (LPH) nanoparticle, respectively. Compared to the control and monotherapy groups, combined GMP and siSTAT3 nanoparticles effectively induced tumor cell death, downregulated a wide range of pro-tumor signaling pathways and immunosuppressive mediators, eliminated MDSCs, enhanced T cell effector functions in tumors and lymphoid compartments, and led to superior therapeutic efficacy in a syngeneic mouse melanoma model. Additionally, these nanoparticles can serve as adjuvant treatment to improve the therapeutic response of anti-PD-1-based immune checkpoint blockade therapy. Thus, the combination of gemcitabine chemotherapy and STAT3 inhibition through nanotechnology could effectively kill tumor cells, alleviate the immunosuppressive TME, and enhance endogenous antitumor immunity.

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About this article

Systemic delivery of gemcitabine analogue and STAT3 siRNA promotes antitumor immunity against melanoma

Show Author's information Hide Author's Information Huan Yan^{¹^,²^,³^,⁴^,^§}, Zhanyan Liu^{¹^,²^,³^,⁴^,^§}, Guibin Lin^{¹^,²^,³^,⁴}, Fei Gu^{¹^,²^,³^,⁴}, Yan Liu^{¹^,²^,³^,⁴}, Yuxiao Xu^{¹^,²^,³^,⁴}, Xueli Kuang^{¹^,²^,³^,⁴}, Yuan Zhang^{¹^,²^,³^,⁴^,^§}(

)

1School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou 511442, China

2National Engineering Research Center for Tissue Restoration and Reconstruction, South China University of Technology, Guangzhou 510006, China

3Guangdong Provincial Key Laboratory of Biomedical Engineering, South China University of Technology, Guangzhou 510006, China

4Key Laboratory of Biomedical Materials and Engineering of the Ministry of Education, South China University of Technology, Guangzhou 510006, China

^§ Huan Yan, Zhanyan Liu, and Yuan Zhang contributed equally to this work.

Abstract

Keywords: nanoparticle, tumor microenvironment, immunosuppression, gemcitabine, STAT3 siRNA

References(61)

Nefedova, Y.; Nagaraj, S.; Rosenbauer, A.; Muro-Cacho, C.; Sebti, S. M.; Gabrilovich, D. I. Regulation of dendritic cell differentiation and antitumor immune response in cancer by pharmacologic-selective inhibition of the janus-activated kinase 2/signal transducers and activators of transcription 3 pathway. Cancer Res. 2005, 65, 9525–9535.

DOI Google Scholar

Gabrilovich, D. I.; Ostrand-Rosenberg, S.; Bronte, V. Coordinated regulation of myeloid cells by tumours. Nat. Rev. Immunol. 2012, 12, 253–268.

DOI Google Scholar

Umansky, V.; Blattner, C.; Gebhardt, C.; Utikal, J. The role of myeloid-derived suppressor cells (MDSC) in cancer progression. Vaccines (Basel) 2016, 4, 36.

DOI Google Scholar

Dufait, I.; Valckenborgh, E. V.; Menu, E.; Escors, D.; De Ridder, M.; Breckpot, K. Signal transducer and activator of transcription 3 in myeloid-derived suppressor cells: An opportunity for cancer therapy. Oncotarget 2016, 7, 42698–42715.

Google Scholar

Nefedova, Y.; Huang, M.; Kusmartsev, S.; Bhattacharya, R.; Cheng, P. Y.; Salup, R.; Jove, R.; Gabrilovich, D. Hyperactivation of STAT3 is involved in abnormal differentiation of dendritic cells in cancer. J. Immunol. 2004, 172, 464–474.

DOI Google Scholar

Fleming, V.; Hu, X. Y.; Weber, R.; Nagibin, V.; Groth, C.; Altevogt, P.; Utikal, J.; Umansky, V. Targeting myeloid-derived suppressor cells to bypass tumor-induced immunosuppression. Front. Immunol. 2018, 9, 398.

DOI Google Scholar

Yu, H.; Pardoll, D.; Jove, R. STATs in cancer inflammation and immunity: A leading role for STAT3. Nat. Rev. Cancer 2009, 9, 798–809.

DOI Google Scholar

Albeituni, S. H.; Ding, C. L.; Yan, J. Hampering immune suppressors: Therapeutic targeting of myeloid-derived suppressor cells in cancer. Cancer J. 2013, 19, 490–501.

DOI Google Scholar

Condamine, T.; Gabrilovich, D. I. Molecular mechanisms regulating myeloid-derived suppressor cell differentiation and function. Trends Immunol. 2011, 32, 19–25.

DOI Google Scholar

Kortylewski, M.; Kujawski, M.; Wang, T. H.; Wei, S.; Zhang, S. M.; Pilon-Thomas, S.; Niu, G. L.; Kay, H.; Mulé, J.; Kerr, W. G. et al. Inhibiting Stat3 signaling in the hematopoietic system elicits multicomponent antitumor immunity. Nat. Med. 2005, 11, 1314–1321.

DOI Google Scholar

Bromberg, J.; Darnell Jr, J. E. The role of STATs in transcriptional control and their impact on cellular function. Oncogene 2000, 19, 2468–2473.

DOI Google Scholar

Yu, H.; Jove, R. The STATs of cancer—New molecular targets come of age. Nat. Rev. Cancer 2004, 4, 97–105.

DOI Google Scholar

Soleimani, A. H.; Garg, S. M.; Paiva, I. M.; Vakili, M. R.; Alshareef, A.; Huang, Y. H.; Molavi, O.; Lai, R.; Lavasanifar, A. Micellar nano-carriers for the delivery of STAT3 dimerization inhibitors to melanoma. Drug Deliv. Transl. Res. 2017, 7, 571–581.

DOI Google Scholar

Lin, L.; Hutzen, B.; Zuo, M. X.; Ball, S.; Deangelis, S.; Foust, E.; Pandit, B.; Ihnat, M. A.; Shenoy, S. S.; Kulp, S. et al. Novel STAT3 phosphorylation inhibitors exhibit potent growth-suppressive activity in pancreatic and breast cancer cells. Cancer Res. 2010, 70, 2445–2454.

DOI Google Scholar

Wang, H.; Liu, Z.; Guan, L. N.; Li, J. K.; Chen, S. Y.; Yu, W. Y.; Lai, M. D. LYW-6, a novel cryptotanshinone derived STAT3 targeting inhibitor, suppresses colorectal cancer growth and metastasis. Pharmacol. Res. 2020, 153, 104661.

DOI Google Scholar

Huang, W.; Dong, Z.; Chen, Y.; Wang, F.; Wang, C. J.; Peng, H.; He, Y.; Hangoc, G.; Pollok, K.; Sandusky, G. et al. Small-molecule inhibitors targeting the DNA-binding domain of STAT3 suppress tumor growth, metastasis and STAT3 target gene expression in vivo. Oncogene 2016, 35, 783–792.

DOI Google Scholar

Escobar, Z.; Bjartell, A.; Canesin, G.; Evans-Axelsson, S.; Sterner, O.; Hellsten, R.; Johansson, M. H. Preclinical characterization of 3β-(N-acetyl l-cysteine methyl ester)-2aβ, 3-dihydrogaliellalactone (GPA512), a prodrug of a direct STAT3 inhibitor for the treatment of prostate cancer. J. Med. Chem. 2016, 59, 4551–4562.

DOI Google Scholar

Fuh, B. ; Sobo, M. ; Cen, L. ; Josiah, D. ; Hutzen, B. ; Cisek, K. ; Bhasin, D. ; Regan, N. ; Lin, L. ; Chan, C. et al. LLL-3 inhibits STAT3 activity, suppresses glioblastoma cell growth and prolongs survival in a mouse glioblastoma model. Br. J. Cancer 2009, 100, 106–112.

Bai, L. C.; Zhou, H. B.; Xu, R. Q.; Zhao, Y. J.; Chinnaswamy, K.; McEachern, D.; Chen, J. Y.; Yang, C. Y.; Liu, Z. M.; Wang, M. et al. A potent and selective small-molecule degrader of STAT3 achieves complete tumor regression in vivo. Cancer Cell 2019, 36, 498–511.e17.

DOI Google Scholar

Mayr, B.; Montminy, M. Transcriptional regulation by the phosphorylation-dependent factor CREB. Nat. Rev. Mol. Cell Biol. 2001, 2, 599–609.

Google Scholar

Coleman IV, D. R.; Ren, Z. Y.; Mandal, P. K.; Cameron, A. G.; Dyer, G. A.; Muranjan, S.; Campbell, M.; Chen, X. M.; McMurray, J. S. Investigation of the binding determinants of phosphopeptides targeted to the SRC homology 2 domain of the signal transducer and activator of transcription 3. Development of a high-affinity peptide inhibitor. J. Med. Chem. 2005, 48, 6661–6670.

Google Scholar

Furtek, S. L.; Backos, D. S.; Matheson, C. J.; Reigan, P. Strategies and approaches of targeting STAT3 for cancer treatment. ACS Chem. Biol. 2016, 11, 308–318.

DOI Google Scholar

Arnold, L. A.; Kosinski, A.; Estébanez-Perpiñá, E.; Guy, R. K. Inhibitors of the interaction of a thyroid hormone receptor and coactivators: Preliminary structure–activity relationships. J. Med. Chem. 2007, 50, 5269–5280.

DOI Google Scholar

Caboni, L.; Lloyd, D. G. Beyond the ligand-binding pocket: Targeting alternate sites in nuclear receptors. Med. Res. Rev. 2013, 33, 1081–1118.

DOI Google Scholar

Younis, A.; Siddique, M. I.; Kim, C. K.; Lim, K. B. RNA interference (RNAi) induced gene silencing: A promising approach of hi-tech plant breeding. Int. J. Biol. Sci. 2014, 10, 1150–1158.

DOI Google Scholar

Oguri, T.; Achiwa, H.; Sato, S.; Bessho, Y.; Takano, Y.; Miyazaki, M.; Muramatsu, H.; Maeda, H.; Niimi, T.; Ueda, R. The determinants of sensitivity and acquired resistance to gemcitabine differ in non-small cell lung cancer: A role of ABCC5 in gemcitabine sensitivity. Mol. Cancer Ther. 2006, 5, 1800–1806.

DOI Google Scholar

Mandruzzato, S. ; Solito, S. ; Falisi, E. ; Francescato, S. ; Chiarion-Sileni, V. ; Mocellin, S. ; Zanon, A. ; Rossi, C. R. ; Nitti, D. ; Bronte, V. et al. IL4Rα⁺ myeloid-derived suppressor cell expansion in cancer patients. J. Immunol. 2009, 182, 6562–6568.

Zhang, Y. ; Satterlee, A. ; Huang, L. In vivo gene delivery by nonviral vectors: Overcoming hurdles? Mol. Ther. 2012, 20, 1298–1304.

Workman, P.; Aboagye, E. O.; Balkwill, F.; Balmain, A.; Bruder, G.; Chaplin, D. J.; Double, J. A.; Everitt, J.; Farningham, D. A. H.; Glennie, M. J. et al. Guidelines for the welfare and use of animals in cancer research. Br. J. Cancer 2010, 102, 1555–1577.

DOI Google Scholar

Zhang, Y.; Bush, X.; Yan, B. F.; Chen, J. A. Gemcitabine nanoparticles promote antitumor immunity against melanoma. Biomaterials 2019, 189, 48–59.

DOI Google Scholar

Zhang, Y.; Schwerbrock, N. M.; Rogers, A. B.; Kim, W. Y.; Huang, L. Codelivery of VEGF siRNA and gemcitabine monophosphate in a single nanoparticle formulation for effective treatment of NSCLC. Mol. Ther. 2013, 21, 1559–1569.

DOI Google Scholar

Qi, L. M.; Ma, J. M.; Shen, J. L. Synthesis of copper nanoparticles in nonionic water-in-oil microemulsions. J. Colloid Interface Sci. 1997, 186, 498–500.

DOI Google Scholar

Mozafari, M. R.; Reed, C. J.; Rostron, C.; Kocum, C.; Piskin, E. Formation and characterisation of non-toxic anionic liposomes for delivery of therapeutic agents to the pulmonary airways. Cell. Mol. Biol. Lett. 2002, 7, 243–244.

Google Scholar

Zhang, Y.; Kim, W. Y.; Huang, L. Systemic delivery of gemcitabine triphosphate via LCP nanoparticles for NSCLC and pancreatic cancer therapy. Biomaterials 2013, 34, 3447–3458.

DOI Google Scholar

Al Zaid Siddiquee, K. ; Turkson, J. STAT3 as a target for inducing apoptosis in solid and hematological tumors. Cell Res. 2008, 18, 254–267.

Ostrand-Rosenberg, S. Myeloid derived-suppressor cells: Their role in cancer and obesity. Curr. Opin. Immunol. 2018, 51, 68–75.

DOI Google Scholar

Yang, J. B.; Chatterjee-Kishore, M.; Staugaitis, S. M.; Nguyen, H.; Schlessinger, K.; Levy, D. E.; Stark, G. R. Novel roles of unphosphorylated STAT3 in oncogenesis and transcriptional regulation. Cancer Res. 2005, 65, 939–947.

Google Scholar

Gato-Cañas, M.; de Morentin, X. M.; Blanco-Luquin, I.; Fernandez-Irigoyen, J.; Zudaire, I.; Liechtenstein, T.; Arasanz, H.; Lozano, T.; Casares, N.; Chaikuad, A. et al. A core of kinase-regulated interactomes defines the neoplastic MDSC lineage. Oncotarget 2015, 6, 27160–27175.

DOI Google Scholar

Wang, J. ; Zhang, Y. ; Yin, K. ; Xu, P. Q. ; Tian, J. ; Ma, J. ; Tian, X. Y. ; Wang, Y. G. ; Tang, X. Y. ; Xu, H. X. et al. IL-17A weakens the antitumor immunity by inhibiting apoptosis of MDSCs in Lewis lung carcinoma bearing mice. Oncotarget 2017, 8, 4814–4825.

Chalmin, F.; Mignot, G.; Bruchard, M.; Chevriaux, A.; Végran, F.; Hichami, A.; Ladoire, S.; Derangère, V.; Vincent, J.; Masson, D. et al. Stat3 and Gfi-1 transcription factors control Th17 cell immunosuppressive activity via the regulation of ectonucleotidase expression. Immunity 2012, 36, 362–373.

DOI Google Scholar

Pearson, G.; Robinson, F.; Gibson, T. B.; Xu, B. E.; Karandikar, M.; Berman, K.; Cobb, M. H. Mitogen-activated protein (MAP) kinase pathways: Regulation and physiological functions. Endocr. Rev. 2001, 22, 153–183.

Google Scholar

Grohmann, U.; Mondanelli, G.; Belladonna, M. L.; Orabona, C.; Pallotta, M. T.; Iacono, A.; Puccetti, P.; Volpi, C. Amino-acid sensing and degrading pathways in immune regulation. Cytokine Growth Factor Rev. 2017, 35, 37–45.

DOI Google Scholar

Speiser, D. E.; Ho, P. C.; Verdeil, G. Regulatory circuits of T cell function in cancer. Nat. Rev. Immunol. 2016, 16, 599–611.

DOI Google Scholar

Schouppe, E.; Van Overmeire, E.; Laoui, D.; Keirsse, J.; Van Ginderachter, J. A. Modulation of CD8⁺ T-cell activation events by monocytic and granulocytic myeloid-derived suppressor cells. Immunobiology 2013, 218, 1385–1391.

DOI Google Scholar

Cheng, P. Y.; Corzo, C. A.; Luetteke, N.; Yu, B.; Nagaraj, S.; Bui, M. M.; Ortiz, M.; Nacken, W.; Sorg, C.; Vogl, T. et al. Inhibition of dendritic cell differentiation and accumulation of myeloid-derived suppressor cells in cancer is regulated by S100A9 protein. J. Exp. Med. 2008, 205, 2235–2249.

DOI Google Scholar

Eriksson, E.; Wenthe, J.; Irenaeus, S.; Loskog, A.; Ullenhag, G. Gemcitabine reduces MDSCs, tregs and TGFβ-1 while restoring the teff/treg ratio in patients with pancreatic cancer. J. Transl. Med. 2016, 14, 282.

DOI Google Scholar

Kumar, V.; Patel, S.; Tcyganov, E.; Gabrilovich, D. I. The nature of myeloid-derived suppressor cells in the tumor microenvironment. Trends Immunol. 2016, 37, 208–220.

DOI Google Scholar

Murdoch, C.; Muthana, M.; Coffelt, S. B.; Lewis, C. E. The role of myeloid cells in the promotion of tumour angiogenesis. Nat. Rev. Cancer 2008, 8, 618–631.

DOI Google Scholar

Yang, L.; DeBusk, L. M.; Fukuda, K.; Fingleton, B.; Green-Jarvis, B.; Shyr, Y.; Matrisian, L. M.; Carbone, D. P.; Lin, P. C. Expansion of myeloid immune suppressor Gr+CD11b+ cells in tumor-bearing host directly promotes tumor angiogenesis. Cancer Cell 2004, 6, 409–421.

DOI Google Scholar

Goedegebuure, P.; Mitchem, J. B.; Porembka, M. R.; Tan, M. C. B.; Belt, B. A.; Wang-Gillam, A.; Gillanders, W. E.; Hawkins, W. G.; Linehan, D. C. Myeloid-derived suppressor cells: General characteristics and relevance to clinical management of pancreatic cancer. Curr. Cancer Drug Targets 2011, 11, 734–751.

DOI Google Scholar

Strawn, L. M.; McMahon, G.; App, H.; Schreck, R.; Kuchler, W. R.; Longhi, M. P.; Hui, T. H.; Tang, C.; Levitzki, A.; Gazit, A. et al. Flk-1 as a target for tumor growth inhibition. Cancer Res. 1996, 56, 3540–3545.

Google Scholar

Zou, S. L.; Tong, Q. Y.; Liu, B. W.; Huang, W.; Tian, Y.; Fu, X. H. Targeting STAT3 in cancer immunotherapy. Mol. Cancer 2020, 19, 145.

DOI Google Scholar

Venkatasubbarao, K.; Peterson, L.; Zhao, S. J.; Hill, P.; Cao, L.; Zhou, Q.; Nawrocki, S. T.; Freeman, J. W. Inhibiting signal transducer and activator of transcription-3 increases response to gemcitabine and delays progression of pancreatic cancer. Mol. Cancer 2013, 12, 104.

Google Scholar

Youn, J. I.; Nagaraj, S.; Collazo, M.; Gabrilovich, D. I. Subsets of myeloid-derived suppressor cells in tumor-bearing mice. J. Immunol. 2008, 181, 5791–5802.

DOI Google Scholar

Mencacci, A. ; Montagnoli, C. ; Bacci, A. ; Cenci, E. ; Pitzurra, L. ; Spreca, A. ; Kopf, M. ; Sharpe, A. H. ; Romani, L. CD80⁺Gr-1⁺ myeloid cells inhibit development of antifungal Th1 immunity in mice with candidiasis. J. Immunol. 2002, 169, 3180–3190.

Yang, R. C. ; Cai, Z. ; Zhang, Y. ; Yutzy IV, W. H. ; Roby K. F. ; Roden R. B. S. CD80 in immune suppression by mouse ovarian carcinoma-associated Gr-1⁺CD11b⁺ myeloid cells. Cancer Res. 2006, 66, 6807–6815.

Norian, L. A.; Rodriguez, P. C.; O'Mara, L. A.; Zabaleta, J.; Ochoa, A. C.; Cella, M.; Allen, P. M. Tumor-infiltrating regulatory dendritic cells inhibit CD8⁺ T cell function via l-arginine metabolism. Cancer Res. 2009, 69, 3086–3094.

DOI Google Scholar

Meireson, A.; Devos, M.; Brochez, L. IDO expression in cancer: Different compartment, different functionality. Front. Immunol. 2020, 11, 531491.

DOI Google Scholar

Attili, I. ; Karachaliou, N. ; Bonanno, L. ; Berenguer, J. ; Bracht, J. ; Codony-Servat, J. ; Codony-Servat, C. ; Ito, M. ; Rosell, R. STAT3 as a potential immunotherapy biomarker in oncogene-addicted non-small cell lung cancer. Ther. Adv. Med. Oncol. 2018, 10, 1758835918763744.

Casey, S. C.; Baylot, V.; Felsher, D. W. The MYC oncogene is a global regulator of the immune response. Blood 2018, 131, 2007–2015.

DOI Google Scholar

Weber, R.; Fleming, V.; Hu, X. Y.; Nagibin, V.; Groth, C.; Altevogt, P.; Utikal, J.; Umansky, V. Myeloid-derived suppressor cells hinder the anti-cancer activity of immune checkpoint inhibitors. Front. Immunol. 2018, 9, 1310.

DOI Google Scholar

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Publication history

Received: 13 January 2022

Revised: 06 May 2022

Accepted: 09 May 2022

Published: 06 July 2022

Issue date: September 2022

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Acknowledgements

This work was supported by the Basic and Applied Basic Research Foundation of Guangdong Province (No. 2020A1515111204), the Fundamental Research Funds for the Central Universities (No. 2020ZYGXZR099), the Recruitment Program of Global Experts, the National Natural Science Foundation of China (No. 82172080). We would like to thank the Research Core Facilities at the South China University of Technology.