Chilkoti Ashutosh, Dreher Matthew R, Meyer Dan E, Raucher Drazen
Department of Biomedical Engineering, Box 90281, Duke University, Durham, NC 27708-0281, USA.
Adv Drug Deliv Rev. 2002 Sep 13;54(5):613-30. doi: 10.1016/s0169-409x(02)00041-8.
This review article summarizes recent results on the development of macromolecular carriers for thermal targeting of therapeutics to solid tumors. This approach employs thermally responsive polymers in conjunction with targeted heating of the tumor. The two thermally responsive polymers that are discussed in this article, poly(N-isopropylacrylamide-co-acrylamide) (poly(NIPAAm)) and an artificial elastin-like polypeptide (ELP), were designed to exhibit a soluble-insoluble lower critical solution transition in response to increased temperature slightly above 37 degrees C. In vivo fluorescent videomicroscopy and radiolabel distribution studies of ELP delivery to human tumors implanted in nude mice demonstrated that hyperthermic targeting of the thermally responsive ELP for 1 h provides a approximately two-fold increase in tumor localization compared to the same polypeptide without hyperthermia. Similar results were also obtained for poly(NIPAAm) though the extent of accumulation was somewhat lesser than observed for the ELP. The endocytotic uptake of a thermally responsive ELP was also observed to be significantly enhanced by the thermally triggered phase transition of the polypeptide in cell culture for three different tumor cell lines. Preliminary cytotoxicity studies of an ELP-doxorubicin conjugate indicate that the ELP-doxorubicin conjugate has near equivalent cytotoxicity as free doxorubicin in a cell culture assay.
这篇综述文章总结了用于将治疗药物热靶向至实体瘤的大分子载体的最新研究成果。该方法采用热敏聚合物并结合肿瘤的靶向加热。本文讨论的两种热敏聚合物，聚（N-异丙基丙烯酰胺-共-丙烯酰胺）（聚（NIPAAm））和一种人工弹性蛋白样多肽（ELP），被设计成在略高于37摄氏度的温度升高时表现出可溶-不溶的下临界溶液转变。对植入裸鼠体内的人肿瘤进行ELP递送的体内荧光视频显微镜和放射性标记分布研究表明，与未进行热疗的相同多肽相比，对热敏ELP进行1小时的热靶向可使肿瘤定位增加约两倍。聚（NIPAAm）也得到了类似的结果，尽管积累程度略低于ELP。在三种不同的肿瘤细胞系的细胞培养中，还观察到热敏ELP的内吞摄取因多肽的热触发相变而显著增强。对ELP-阿霉素缀合物的初步细胞毒性研究表明，在细胞培养试验中，ELP-阿霉素缀合物具有与游离阿霉素几乎相当的细胞毒性。
