Sequential Targeting TGF‐β Signaling and KRAS Mutation Increases Therapeutic Efficacy in Pancreatic Cancer. Issue 24 (29th April 2019)

• Record Type: Journal Article
• Authors: Pei, Yuanyuan; Chen, Liang; Huang, Yukun; Wang, Jiahao; Feng, Jingxian; Xu, Minjun; Chen, Yu; Song, Qingxiang; Jiang, Gan; Gu, Xiao; Zhang, Qian; Gao, Xiaoling; Chen, Jun
• Is Part Of: Small. Volume 15:Issue 24(2019)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2019-04-29
• Subjects: KRAS -- pancreatic cancer -- sequential therapy -- TGF‐β; Nanotechnology -- Periodicals; Nanoparticles -- Periodicals; Microtechnology -- Periodicals; 620.5
• DOI: 10.1002/smll.201900631
• Languages: English
• ISSNs: 1613-6810

Abstract

Abstract: Pancreatic cancer is a highly aggressive malignancy that strongly resists extant treatments. The failure of existing therapies is majorly attributed to the tough tumor microenvironment (TME) limiting drug access and the undruggable targets of tumor cells. The formation of suppressive TME is regulated by transforming growth factor beta (TGF‐β) signaling, while the poor response and short survival of almost 90% of pancreatic cancer patients results from the oncogenic KRAS mutation. Hence, simultaneously targeting both the TGF‐β and KRAS pathways might dismantle the obstacles of pancreatic cancer therapy. Here, a novel sequential‐targeting strategy is developed, in which antifibrotic fraxinellone‐loaded CGKRK‐modified nanoparticles (Frax‐NP‐CGKRK) are constructed to regulate TGF‐β signaling and siRNA‐loaded lipid‐coated calcium phosphate (LCP) biomimetic nanoparticles (siKras‐LCP‐ApoE3) are applied to interfere with the oncogenic KRAS. Frax‐NP‐CGKRK successfully targets the tumor sites through the recognition of overexpressed heparan sulfate proteoglycan, reverses the activated cancer‐associated fibroblasts (CAFs), attenuates the dense stroma barrier, and enhances tumor blood perfusion. Afterward, siKras‐LCP‐ApoE3 is efficiently internalized by the tumor cells through macropinocytosis and specifically silencing KRAS mutation. Compared with gemcitabine, this sequential‐targeting strategy significantly elongates the lifespans of pancreatic tumor‐bearing animals, hence providing a promising approach for pancreatic cancer therapy. Abstract : Fraxinellone‐loaded CGKRK‐modified nanoparticles are prepared for regulating transforming growth factor beta signals in the suppressive tumor microenvironment. Based on this, the dense stroma is modulated and the intratumor blood perfusion is enhanced, meaning the delivery barrier of the following siRNA‐loaded lipid‐coated calcium phosphate (LCP) biomimetic high‐density lipoprotein nanoparticles (siKras‐LCP‐ApoE3) are internalized and specifically silence KRAS mutation and kill cancer cells.