Tethering of Chemotherapeutic Drug/Imaging Agent to Bile Acid-Phospholipid Increases the Efficacy and Bioavailability with Reduced Hepatotoxicity,Bioconjugate Chemistry

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Tethering of Chemotherapeutic Drug/Imaging Agent to Bile Acid-Phospholipid Increases the Efficacy and Bioavailability with Reduced Hepatotoxicity
Bioconjugate Chemistry ( IF 4.0 ) Pub Date : 2017-11-09 00:00:00 , DOI: 10.1021/acs.bioconjchem.7b00564
Vedagopuram Sreekanth _{1,

2} , Nihal Medatwal _{1,

2} , Sandeep Kumar _{1,

2} , Sanjay Pal _{1,

3} , Malyla Vamshikrishna ₁ , Animesh Kar ₁ , Priyanshu Bhargava ₁ , Aaliya Naaz ₁ , Nitin Kumar ₄ , Sagar Sengupta ₄ , Avinash Bajaj ₁

Affiliation

Weakly basic drugs display poor solubility and tend to precipitate in the stomach’s acidic environment causing reduced oral bioavailability. Tracing of these orally delivered therapeutic agents using molecular probes is challenged due to their poor absorption in the gastrointestinal tract (GIT). Therefore, we designed a gastric pH stable bile acid derived amphiphile where Tamoxifen (as a model anticancer drug) is conjugated to lithocholic acid derived phospholipid (LCA-Tam-PC). In vitro studies suggested the selective nature of LCA-Tam-PC for cancer cells over normal cells as compared to the parent drug. Fluorescent labeled version of the conjugate (LCA-Tam-NBD-PC) displayed an increased intracellular uptake compared to Tamoxifen. We then investigated the antitumor potential, toxicity, and median survival in 4T1 tumor bearing BALB/c mice upon LCA-Tam-PC treatment. Our studies confirmed a significant reduction in the tumor volume, tumor weight, and reduced hepatotoxicity with a significant increase in median survival on LCA-Tam-PC treatment as compared to the parent drug. Pharmacokinetic and biodistribution studies using LCA-Tam-NBD-PC witnessed the enhanced gut absorption, blood circulation, and tumor site accumulation of phospholipid–drug conjugate leading to improved antitumor activity. Therefore, our studies revealed that conjugation of chemotherapeutic/imaging agents to bile acid phospholipid can provide a new platform for oral delivery and tracing of chemotherapeutic drugs.

中文翻译：

化疗药物/成像剂与胆汁酸磷脂的束缚可提高功效和生物利用度，并具有降低的肝毒性

弱碱性药物显示出较差的溶解性，并倾向于在胃的酸性环境中沉淀，导致口服生物利用度降低。由于它们在胃肠道（GIT）中的吸收较差，因此使用分子探针追踪这些口服给药的治疗剂受到了挑战。因此，我们设计了一种胃pH稳定的胆汁酸衍生的两亲物，其中他莫昔芬（作为模型抗癌药）与石胆酸衍生的磷脂（LCA-Tam-PC）缀合。体外研究表明，与母体药物相比，LCA-Tam-PC对癌细胞的选择性高于正常细胞。与他莫昔芬相比，缀合物的荧光标记版本（LCA-Tam-NBD-PC）显示出更高的细胞内摄取。然后，我们研究了在LCA-Tam-PC处理后，携带4T1肿瘤的BALB / c小鼠的抗肿瘤潜力，毒性和中位生存期。我们的研究证实，与母体药物相比，LCA-Tam-PC治疗的中位生存期显着增加，肿瘤体积，肿瘤重量和肝毒性显着降低。使用LCA-Tam-NBD-PC进行的药代动力学和生物分布研究表明，肠溶磷脂，药物结合物增强了肠道吸收，血液循环和肿瘤部位蓄积，从而提高了抗肿瘤活性。所以，

更新日期：2017-11-09

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