Nanomicellar TGX221 blocks xenograft tumor growth of prostate cancer in nude mice.
Nanomicellar TGX221 blocks xenograft tumor growth of prostate cancer in nude mice.
复制标题
Nanomicellar TGX221 可阻断裸鼠前列腺癌异种移植肿瘤的生长。
DOI：
10.1002/pros.22941
复制
发表时间：
2015-05
期刊：
影响因子：
2.8
通讯作者：
Li, Benyi
中科院分区：
文献类型：
--
作者：
Chen, Ruibao;Zhao, Yunqi;Huang, Yan;Yang, Qiuhong;Zeng, Xing;Jiang, Wencong;Liu, Jihong;Thrasher, J. Brantley;Forrest, M. Laird;Li, Benyi
雄激素去除沿着早期发现和手术的结合使得前列腺癌在初始阶段高度可治疗。然而，由于去势抵抗性进展，这种癌症仍然是美国男性癌症死亡的第二大原因，这表明迫切需要新的治疗药物来治疗这种威胁生命的疾病。磷脂酰肌醇3-激酶p110β是一种主要的细胞信号分子，已被确定为前列腺癌进展的关键因素。在最近的一份报告中，我们建立了一种基于纳米胶束的策略，通过将纳米胶束表面与针对所有临床前列腺癌中存在的前列腺膜特异性抗原（PSMA）的RNA适体结合，将p110β特异性抑制剂TGX 221递送至前列腺癌细胞。在这项研究中，我们测试了这种纳米胶束TGX 221在小鼠异种移植模型中的体内抗肿瘤作用。前列腺癌细胞系LAPC-4、LNCaP、C4-2和22 RV 1用于在裸鼠中建立皮下异种移植瘤。将来自异种移植肿瘤标本的石蜡切片用于免疫组织化学测定以检测AKT磷酸化、细胞增殖标记物Ki 67和PCNA以及BrdU掺入。进行定量PCR测定以确定PSA基因在异种移植肿瘤中的表达。尽管与溶剂对照相比，未缀合的TGX 221的全身递送显著降低了裸鼠中的异种移植物肿瘤生长，但纳米胶束TGX 221缀合物完全阻断了源自多种前列腺癌细胞系的异种移植物的肿瘤生长。进一步的分析显示，与接受未缀合的TGX 221处理的异种移植肿瘤相比，接受纳米胶束TGX 221的异种移植肿瘤中的AKT磷酸化和细胞增殖指数显著降低。大体观察或器官组织切片显微镜下观察未见明显副作用。这些数据有力地表明，前列腺癌细胞靶向纳米胶束TGX 221是一种有效的前列腺癌抗癌剂。
Combination of androgen ablation along with early detection and surgery has made prostate cancer highly treatable at the initial stage. However, this cancer remains the second leading cause of cancer death among American men due to castration-resistant progression, suggesting that novel therapeutic agents are urgently needed for this life-threaten condition. Phosphatidylinositol 3-kinase p110β is a major cellular signaling molecule and has been identified as a critical factor in prostate cancer progression. In a recent report, we established a nanomicelle-based strategy to deliver p110β-specific inhibitor TGX221 to prostate cancer cells by conjugating the surface of nanomicelles with a RNA aptamer against prostate membrane specific antigen (PSMA) present in all clinical prostate cancers. In this study, we tested this nanomicellar TGX221 for its in vivo anti-tumor effect in mouse xenograft models. Prostate cancer cell lines LAPC-4, LNCaP, C4-2 and 22RV1 were used to establish subcutaneous xenograft tumors in nude mice. Paraffin sections from xenograft tumor specimens were used in immunohistochemistry assays to detect AKT phosphorylation, cell proliferation marker Ki67 and PCNA, as well as BrdU incorporation. Quantitative PCR assay was conducted to determine PSA gene expression in xenograft tumors. Although systemic delivery of unconjugated TGX221 significantly reduced xenograft tumor growth in nude mice compared to solvent control, the nanomicellar TGX221 conjugates completely blocked tumor growth of xenografts derived from multiple prostate cancer cell lines. Further analyses revealed that AKT phosphorylation and cell proliferation indexes were dramatically reduced in xenograft tumors received nanomicellar TGX221 compared to xenograft tumors received unconjugated TGX221 treatment. There was no noticeable side effect by gross observation or at microscopic level of organ tissue section. These data strongly suggest that prostate cancer cell-targeted nanomicellar TGX221 is an effective anti-cancer agent for prostate cancer.
登录
查看更多内容
影响因子：
17.1
作者：
Khisamutdinov, Emil F.;Jasinski, Daniel L.;Guo, Peixuan
通讯作者：
Guo, Peixuan
影响因子：
2.6
作者：
Kinoshita, Y;Kuratsukuri, K;Haas, GP
通讯作者：
Haas, GP
影响因子：
2.8
作者：
Liu, Jianjun;Youn, Hyewon;Yang, Jun;Du, Ningchao;Liu, Jihong;Liu, Hongwei;Li, Benyi
通讯作者：
Li, Benyi
影响因子：
28.2
作者：
Klempner SJ;Myers AP;Cantley LC
通讯作者：
Cantley LC
影响因子：
50.3
作者：
Carver BS;Chapinski C;Wongvipat J;Hieronymus H;Chen Y;Chandarlapaty S;Arora VK;Le C;Koutcher J;Scher H;Scardino PT;Rosen N;Sawyers CL
通讯作者：
Sawyers CL