Supramolecular nanoparticles that target phosphoinositide-3-kinase overcome insulin resistance and exert pronounced antitumor efficacy.
Supramolecular nanoparticles that target phosphoinositide-3-kinase overcome insulin resistance and exert pronounced antitumor efficacy.
复制标题
靶向磷酸肌醇-3-激酶的超分子纳米颗粒克服了胰岛素抵抗并发挥显着的抗肿瘤功效。
DOI：
10.1158/0008-5472.can-12-4477
复制
发表时间：
2013
期刊：
影响因子：
11.2
通讯作者：
Sen
中科院分区：
文献类型：
--
作者：
Kulkarni,AshishA;Roy,Bhaskar;Rao,PoornimaS;Wyant,GregoryA;Mahmoud,Ayaat;Ramachandran,Madhumitha;Sengupta,Poulomi;Goldman,Aaron;Kotamraju,VenkataRamana;Basu,Sudipta;Mashelkar,RaghunathA;Ruoslahti,Erkki;Dinulescu,DanielaM;Sen
磷脂酰肌醇-3-激酶(PI3K)在肿瘤病因学中的中心地位已经得到了很好的证实，但PI3K抑制剂的临床翻译受到反馈信号、次理想的肿瘤内浓度和胰岛素抵抗“类别效应”的限制。这项研究旨在探索利用超分子纳米化学靶向PI3K来增强抗肿瘤疗效并潜在地克服这些限制。使用一种基于胆固醇的衍生物对PI3K抑制剂结构进行了合理的修饰，促进了由1-聚乙二醇磷脂酰胆碱和DSPE-[1，2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polythylene乙二醇组成的超分子纳米组装)]。对组装的超分子纳米粒子(SNP)进行了物理化学表征和体外功能评价。在4T1乳腺癌和K-RasLSL/+/Ptenfl/Floova卵巢癌模型中定量观察其抗肿瘤作用，并通过胰岛素敏感性试验评价其对血糖稳态的影响。使用PI103和PI828作为替代分子来设计SNPs，突出了正确看待设计原则的必要性；具体地说，活性分子的效力和连接物化学是决定疗效的关键原则，类似于抗体-药物结合物。我们发现，SNPs在体内对Akt、mTOR、S6K和4EBP的磷酸化具有暂时的持续抑制作用。与PI103和PI828相比，这些作用与提高抗肿瘤疗效和生存期有关。通过用肿瘤归宿多肽修饰纳米颗粒表面，进一步提高了疗效。值得注意的是，SNPs的使用消除了与其他PI3K抑制剂广泛相关的胰岛素抵抗。这项研究为使用超分子纳米化学来克服与PI3K抑制剂相关的当前挑战提供了临床前基础，为扩展到正在探索的用于癌症治疗的其他分子靶向疗法提供了范例。©2013 AACR。
The centrality of phosphoinositide-3-kinase (PI3K) in cancer etiology is well established, but clinical translation of PI3K inhibitors has been limited by feedback signaling, suboptimal intratumoral concentration, and an insulin resistance “class effect.” This study was designed to explore the use of supramolecular nanochemistry for targeting PI3K to enhance antitumor efficacy and potentially overcome these limitations. PI3K inhibitor structures were rationally modified using a cholesterol-based derivative, facilitating supramolecular nanoassembly withL-α-phosphatidylcholine and DSPE-PEG [1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polythylene glycol)]. The supramolecular nanoparticles (SNP) that were assembled were physicochemically characterized and functionally evaluatedin vitro. Antitumor efficacy was quantifiedin vivousing 4T1 breast cancer and K-RasLSL/+/Ptenfl/flovarian cancer models, with effects on glucose homeostasis evaluated using an insulin sensitivity test. The use of PI103 and PI828 as surrogate molecules to engineer the SNPs highlighted the need to keep design principles in perspective; specifically, potency of the active molecule and the linker chemistry were critical principles for efficacy, similar to antibody–drug conjugates. We found that the SNPs exerted a temporally sustained inhibition of phosphorylation of Akt, mTOR, S6K, and 4EBPin vivo. These effects were associated with increased antitumor efficacy and survival as compared with PI103 and PI828. Efficacy was further increased by decorating the nanoparticle surface with tumor-homing peptides. Notably, the use of SNPs abrogated the insulin resistance that has been associated widely with other PI3K inhibitors. This study provides a preclinical foundation for the use of supramolecular nanochemistry to overcome current challenges associated with PI3K inhibitors, offering a paradigm for extension to other molecularly targeted therapeutics being explored for cancer treatment.Cancer Res; 73(23); 6987–97. ©2013 AACR.
登录
查看更多内容
影响因子：
14
作者：
Chen, Kuan-Ju;Wolahan, Stephanie M.;Wang, Hao;Hsu, Chao-Hsiung;Chang, Hsing-Wei;Durazo, Armando;Hwang, Lian-Pin;Garcia, Mitch A.;Jiang, Ziyue K.;Wu, Lily;Lin, Yung-Ya;Tseng, Hsian-Rong
通讯作者：
Tseng, Hsian-Rong
挑选合适的患者
影响因子：
11.5
作者：
Alexa B. Turke;J. Engelman
通讯作者：
J. Engelman
影响因子：
50.3
作者：
Sugahara KN;Teesalu T;Karmali PP;Kotamraju VR;Agemy L;Girard OM;Hanahan D;Mattrey RF;Ruoslahti E
通讯作者：
Ruoslahti E
I类磷脂酰肌醇3-激酶的有效抑制剂的生物学特性：从PI-103到PI-540，PI-620到口服剂GDC-0941。
影响因子：
5.7
作者：
Raynaud FI;Eccles SA;Patel S;Alix S;Box G;Chuckowree I;Folkes A;Gowan S;De Haven Brandon A;Di Stefano F;Hayes A;Henley AT;Lensun L;Pergl-Wilson G;Robson A;Saghir N;Zhyvoloup A;McDonald E;Sheldrake P;Shuttleworth S;Valenti M;Wan NC;Clarke PA;Workman P
通讯作者：
Workman P
影响因子：
17.1
作者：
Sengupta, Shiladitya;Kulkarni, Ashish
通讯作者：
Kulkarni, Ashish