Improving Therapeutic Potential of Farnesylthiosalicylic Acid: Tumor Specific Delivery via Conjugation with Heptamethine Cyanine Dye.
Improving Therapeutic Potential of Farnesylthiosalicylic Acid: Tumor Specific Delivery via Conjugation with Heptamethine Cyanine Dye.
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DOI：
10.1021/acs.molpharmaceut.5b00906
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发表时间：
2017-01-03
影响因子：
4.9
通讯作者：
Pan D
中科院分区：
文献类型：
--
作者：
Guan Y;Zhang Y;Xiao L;Li J;Wang JP;Chordia MD;Liu ZQ;Chung LW;Yue W;Pan D
RAS和mTOR抑制剂S-反式-反式-法尼基硫代水杨酸（FTS）是具有中等效力的有前途的抗癌剂，目前正在进行作为化疗剂的临床试验。FTS已显示出其对多种癌症的潜力，包括内分泌抵抗性乳腺癌。然而，由于其高疏水性导致的较差的药代动力学特性是其在临床上持续发展的主要障碍。提高其治疗潜力的方法之一是通过开发靶向递送方法来提高其对癌症组织的生物利用度。在本研究中，FTS与癌症靶向七甲川花青染料5缀合以形成FTS-染料缀合物11。与母体FTS相比，在体外评估缀合物11针对癌细胞生长和mTOR抑制的肿瘤靶向性质的效率。用非侵入性近红外荧光（NIRF）成像证明了MCF 7异种移植物的活小鼠模型中11的癌症靶向。我们的研究结果清楚地表明，FTS的生物利用度确实得到了改善，如log P值和癌细胞摄取所示。FTS-染料缀合物11显示出比母体FTS（IC 50 = 16.8 ± 0.5 μM）更高的效力（IC 50 = 161.3 ± 1.8 μM），并且在较低浓度（12.5 μM）下抑制癌细胞中的mTOR活性。通过体内NIRF成像、器官分布和离体肿瘤组织学沿着细胞水平共聚焦显微镜观察，显示缀合物11在肿瘤中特异性积累。总之，FTS与癌症靶向七甲川花青染料的缀合改善了其药理学特征。
The RAS and mTOR inhibitor S-trans-trans-farnesylthiosalicylic acid (FTS) is a promising anticancer agent with moderate potency, currently undergoing clinical trials as a chemotherapeutic agent. FTS has displayed its potential against a variety of cancers including endocrine resistant breast cancer. However, the poor pharmacokinetics profile attributed to its high hydrophobicity is a major hindrance for its continued advancement in clinic. One of the ways to improve its therapeutic potential would be to enhance its bioavailability to cancer tissue by developing a method for targeted delivery. In the current study, FTS was conjugated with the cancer-targeting heptamethine cyanine dye 5 to form the FTS–dye conjugate 11. The efficiency of tumor targeting properties of conjugate 11 against cancer cell growth and mTOR inhibition was evaluated in vitro in comparison with parent FTS. Cancer targeting of 11 in a live mouse model of MCF7 xenografts was demonstrated with noninvasive, near-infrared fluorescence (NIRF) imaging. The results from our studies clearly suggest that the bioavailability of FTS is indeed improved as indicated by log P values and cancer cell uptake. The FTS–dye conjugate 11 displayed higher potency (IC50 = 16.8 ± 0.5 μM) than parent FTS (IC50 = ∼51.3 ± 1.8 μM) and inhibited mTOR activity in the cancer cells at a lower concentration (12.5 μM). The conjugate 11 was shown to be specifically accumulated in tumors as observed by in vivo NIRF imaging, organ distribution, and ex vivo tumor histology along with cellular level confocal microscopy. In conclusion, the conjugation of FTS with cancer-targeting heptamethine cyanine dye improved its pharmacological profile.
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影响因子：
37.3
作者：
Charette N;De Saeger C;Lannoy V;Horsmans Y;Leclercq I;Stärkel P
通讯作者：
Stärkel P
用于全身性抗癌药物和siRNA的全层纳米颗粒，用于潜在的三阴性乳腺癌治疗。
影响因子：
17.1
作者：
Deng, Zhou J.;Morton, Stephen W.;Ben-Akiva, Elana;Dreaden, Erik C.;Shopsowitz, Kevin E.;Hammond, Paula T.
通讯作者：
Hammond, Paula T.
影响因子：
3.9
作者：
Santen, RJ;Song, RX;Yue, W
通讯作者：
Yue, W
影响因子：
3.8
作者：
Banerjee, Nilasha;Miller, Naomi;Bendayan, Reina
通讯作者：
Bendayan, Reina
影响因子：
2.4
作者：
Chen, Chujian;Chan, Hing Man;Kubow, Stan
通讯作者：
Kubow, Stan