Carie Adam, Rios-Doria Jonathan, Costich Tara, Burke Brian, Slama Richard, Skaff Habib, Sill Kevin
Intezyne, Inc, 3720 Spectrum Boulevard Suite 104, Tampa, FL 33612, USA.
J Drug Deliv. 2011;2011:869027. doi: 10.1155/2011/869027. Epub 2011 Dec 6.
Polymer micelles are promising drug delivery vehicles for the delivery of anticancer agents to tumors. Often, anticancer drugs display potent cytotoxic effects towards cancer cells but are too hydrophobic to be administered in the clinic as a free drug. To address this problem, a polymer micelle was designed using a triblock copolymer (ITP-101) that enables hydrophobic drugs to be encapsulated. An SN-38 encapsulated micelle, IT-141, was prepared that exhibited potent in vitro cytotoxicity against a wide array of cancer cell lines. In a mouse model, pharmacokinetic analysis revealed that IT-141 had a much longer circulation time, plasma exposure, and tumor exposure compared to irinotecan. IT-141 was also superior to irinotecan in terms of antitumor activity, exhibiting greater tumor inhibition in HT-29 and HCT116 colorectal cancer xenograft models at half the dose of irinotecan. The antitumor effect of IT-141 was dose-dependent and caused complete growth inhibition and tumor regression at well-tolerated doses. Varying the specific concentration of SN-38 within the IT-141 micelle had no detectible effect on this antitumor activity, indicating no differences in activity between different IT-141 formulations. In summary, IT-141 is a potent micelle-based chemotherapy that holds promise for the treatment of colorectal cancer.
聚合物胶束是将抗癌药物递送至肿瘤的有前景的药物递送载体。通常，抗癌药物对癌细胞显示出强大的细胞毒性作用，但疏水性太强，无法作为游离药物在临床上给药。为了解决这个问题，使用一种三嵌段共聚物（ITP-101）设计了一种聚合物胶束，该共聚物能够包裹疏水性药物。制备了一种包裹SN-38的胶束IT-141，它对多种癌细胞系表现出强大的体外细胞毒性。在小鼠模型中，药代动力学分析表明，与伊立替康相比，IT-141的循环时间、血浆暴露量和肿瘤暴露量长得多。在抗肿瘤活性方面，IT-141也优于伊立替康，在HT-29和HCT116结直肠癌异种移植模型中，以伊立替康一半的剂量表现出更大的肿瘤抑制作用。IT-141的抗肿瘤作用呈剂量依赖性，在耐受性良好的剂量下可导致完全生长抑制和肿瘤消退。改变IT-141胶束内SN-38的特定浓度对这种抗肿瘤活性没有可检测到的影响，表明不同IT-141制剂之间的活性没有差异。总之，IT-141是一种强大的基于胶束的化疗药物，有望用于治疗结直肠癌。
