Cell type-specific pharmacological kinase inhibition for cancer chemoprevention.
Cell type-specific pharmacological kinase inhibition for cancer chemoprevention.
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DOI：
10.1016/j.nano.2017.11.004
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发表时间：
2018-03
期刊：
影响因子：
--
通讯作者：
Precision Liver Cancer Prevention Consortium
中科院分区：
文献类型：
--
作者：
Deshmukh M;Nakagawa S;Higashi T;Vincek A;Venkatesh A;Ruiz de Galarreta M;Koh AP;Goossens N;Hirschfield H;Bian CB;Fujiwara N;Ono A;Hoshida H;El-Abtah M;Ahmad NB;Lujambio A;Sanchez R;Fuchs BC;Poelstra K;Prakash J;Hoshida Y;Precision Liver Cancer Prevention Consortium
安全性是预防医学的前提，但无毒药物作为临床化学预防通常无效。在这里，我们提出了一种克服这一挑战的策略，通过将分子靶向剂特异性地递送到效应细胞类型以实现足够的效力，同时在癌症化学预防的背景下规避毒性。肝肌成纤维细胞驱动进行性纤维化，导致肝硬化和肝癌。在一个肿瘤驱动的肝癌大鼠模型中，一种小分子表皮生长因子受体抑制剂厄洛替尼通过一种多功能的基于纳米颗粒的系统特异性地递送到肌成纤维细胞，靶向在肝脏表面上独特表达的血小板衍生生长因子受体β。在全身给予厄洛替尼的情况下，肿瘤负荷降低至31%，通过肌成纤维细胞靶向递送，甚至在厄洛替尼剂量降低（等效厄洛替尼剂量降低7.3倍）和肝细胞损伤更少的情况下，肿瘤负荷进一步提高至21%。这些发现证明了一种策略，细胞类型特异性激酶抑制，用于更有效，更安全的精确癌症化学预防。开发了用于细胞类型特异性递送选择性激酶抑制剂的基于纳米颗粒的系统。该系统能够特异性抑制肝肌成纤维细胞（肝癌发展的主要驱动因素）中的表皮生长因子信号传导，并在降低药物剂量和毒性的情况下引发癌症化学预防作用。
Safety is prerequisite for preventive medicine, but non-toxic agents are generally ineffective as clinical chemoprevention. Here we propose a strategy overcoming this challenge by delivering molecular-targeted agent specifically to the effector cell type to achieve sufficient potency, while circumventing toxicity in the context of cancer chemoprevention. Hepatic myofibroblasts drive progressive fibrosis that results in cirrhosis and liver cancer. In a rat model of cirrhosis-driven liver cancer, a small molecule epidermal growth factor receptor inhibitor, erlotinib, was delivered specifically to myofibroblasts by a versatile nanoparticle-based system, targeting platelet-derived growth factor receptor-beta uniquely expressed on their surface in the liver. With systemic administration of erlotinib, tumor burden was reduced to 31%, which was further improved to 21% by myofibroblast-targeted delivery even with reduced erlotinib dose (7.3-fold reduction with equivalent erlotinib dose) and less hepatocyte damage. These findings demonstrate a strategy, cell type-specific kinase inhibition, for more effective and safer precision cancer chemoprevention. Nanoparticle-based system for cell type-specific delivery of selective kinase inhibitor was developed. The system enabled specific inhibition of epidermal growth factor signaling in hepatic myofibroblasts, the major driver of liver cancer development, and elicited cancer chemoprevention effect with reduced drug dose and toxicities.
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影响因子：
50.3
作者：
Nakagawa S;Wei L;Song WM;Higashi T;Ghoshal S;Kim RS;Bian CB;Yamada S;Sun X;Venkatesh A;Goossens N;Bain G;Lauwers GY;Koh AP;El-Abtah M;Ahmad NB;Hoshida H;Erstad DJ;Gunasekaran G;Lee Y;Yu ML;Chuang WL;Dai CY;Kobayashi M;Kumada H;Beppu T;Baba H;Mahajan M;Nair VD;Lanuti M;Villanueva A;Sangiovanni A;Iavarone M;Colombo M;Llovet JM;Subramanian A;Tager AM;Friedman SL;Baumert TF;Schwarz ME;Chung RT;Tanabe KK;Zhang B;Fuchs BC;Hoshida Y;Precision Liver Cancer Prevention Consortium
通讯作者：
Precision Liver Cancer Prevention Consortium
影响因子：
13.5
作者：
Fuchs, Bryan C.;Hoshida, Yujin;Fujii, Tsutomu;Wei, Lan;Yamada, Suguru;Lauwers, Gregory Y.;McGinn, Christopher M.;DePeralta, Danielle K.;Chen, Xintong;Kuroda, Toshihiko;Lanuti, Michael;Schmitt, Anthony D.;Gupta, Supriya;Crenshaw, Andrew;Onofrio, Robert;Taylor, Bradley;Winckler, Wendy;Bardeesy, Nabeel;Caravan, Peter;Golub, Todd R.;Tanabe, Kenneth K.
通讯作者：
Tanabe, Kenneth K.
DOI：
10.1080/23808993.2016.1174062
发表时间：
2016
影响因子：
1.2
作者：
Kim RS;Goossens N;Hoshida Y
通讯作者：
Hoshida Y
影响因子：
4.3
作者：
Goossens, Nicolas;Nakagawa, Shigeki;Hoshida, Yujin
通讯作者：
Hoshida, Yujin
影响因子：
24.5
作者：
Xu, L;Hui, AY;Eng, FJ
通讯作者：
Eng, FJ