TY - JOUR
T1 - Self-carried nanodrug (SCND-SIS3)
T2 - A targeted therapy for lung cancer with superior biocompatibility and immune boosting effects
AU - Lian, Guang Yu
AU - Wan, Yingpeng
AU - Mak, Thomas Shiu Kwong
AU - Wang, Qing Ming
AU - Zhang, Jinfeng
AU - Chen, Jiaoyi
AU - Wang, Zi Ying
AU - Li, Min
AU - Tang, Patrick Ming Kuen
AU - Huang, Xiao Ru
AU - Lee, Chun Sing
AU - Yu, Xue Qing
AU - Lan, Hui Yao
N1 - We thank Dr. Hong-Jian Zhu from Melbourne University for kindly gifting the adenoviral Smad3 luciferase reporter construct pAd.CAGA12-luc. This study was supported by research grants from the Guangdong–Hong Kong–Macao Joint Labs Program from Guangdong Science and Technology (2019B121205005) and the Innovation and Technology Fund of Hong Kong (ITS/138/17).
Publisher Copyright:
© 2022 The Author(s). Published by Elsevier Ltd.
PY - 2022/9
Y1 - 2022/9
N2 - Transforming growth factor β (TGF-β) is a well-known key mediator for the progression and metastasis of lung carcinoma. However, cost-effective anti-TGF-β therapeutics for lung cancer remain to be explored. Specifically, the low efficacy in drug delivery greatly limits the clinical application of small molecular inhibitors of TGF-β. In the present study, specific inhibitor of Smad3 (SIS3) is developed into a self-carried nanodrug (SCND-SIS3) using the reprecipitation method, which largely improves its solubility and bioavailability while reduces its nephrotoxicity. Compared to unmodified-SIS3, SCND-SIS3 demonstrates better anti-cancer effects through inducing tumor cell apoptosis, inhibiting angiogenesis, and boosting NK cell-mediated immune responses in syngeneic Lewis Lung Cancer (LLC) mouse model. Better still, it could achieve comparable anti-cancer effect with just one-fifth the dose of unmodified-SIS3. Mechanistically, RNA-sequencing analysis and cytokine array results unveil a TGF-β/Smad3-dependent immunoregulatory landscape in NK cells. In particular, SCND-SIS3 promotes NK cell cytotoxicity by ameliorating Smad3-mediated transcriptional inhibition of Ndrg1. Furthermore, improved NK cell cytotoxicity by SCND-SIS3 is associated with higher expression of activation receptor Nkp46, and suppressed levels of Trib3 and TSP1 as compared with unmodified-SIS3. Taken together, SCND-SIS3 possesses superior anti-cancer effects with enhanced bioavailability and biocompatibility, therefore representing as a novel therapeutic strategy for lung carcinoma with promising clinical potential.
AB - Transforming growth factor β (TGF-β) is a well-known key mediator for the progression and metastasis of lung carcinoma. However, cost-effective anti-TGF-β therapeutics for lung cancer remain to be explored. Specifically, the low efficacy in drug delivery greatly limits the clinical application of small molecular inhibitors of TGF-β. In the present study, specific inhibitor of Smad3 (SIS3) is developed into a self-carried nanodrug (SCND-SIS3) using the reprecipitation method, which largely improves its solubility and bioavailability while reduces its nephrotoxicity. Compared to unmodified-SIS3, SCND-SIS3 demonstrates better anti-cancer effects through inducing tumor cell apoptosis, inhibiting angiogenesis, and boosting NK cell-mediated immune responses in syngeneic Lewis Lung Cancer (LLC) mouse model. Better still, it could achieve comparable anti-cancer effect with just one-fifth the dose of unmodified-SIS3. Mechanistically, RNA-sequencing analysis and cytokine array results unveil a TGF-β/Smad3-dependent immunoregulatory landscape in NK cells. In particular, SCND-SIS3 promotes NK cell cytotoxicity by ameliorating Smad3-mediated transcriptional inhibition of Ndrg1. Furthermore, improved NK cell cytotoxicity by SCND-SIS3 is associated with higher expression of activation receptor Nkp46, and suppressed levels of Trib3 and TSP1 as compared with unmodified-SIS3. Taken together, SCND-SIS3 possesses superior anti-cancer effects with enhanced bioavailability and biocompatibility, therefore representing as a novel therapeutic strategy for lung carcinoma with promising clinical potential.
KW - Lung carcinoma
KW - NK-mediated immune responses
KW - Self-carried nanodrug
KW - SIS3
KW - TGF-β/Smad3 signaling
KW - Tumor-targeting therapy
UR - https://www.scopus.com/pages/publications/85136301273
U2 - 10.1016/j.biomaterials.2022.121730
DO - 10.1016/j.biomaterials.2022.121730
M3 - Journal article
C2 - 35995622
AN - SCOPUS:85136301273
SN - 0142-9612
VL - 288
JO - Biomaterials
JF - Biomaterials
M1 - 121730
ER -
