a Department of Pharmaceutics , Poona College of Pharmacy, Bharati Vidyapeeth Deemed University , Pune , India.
b Department of Pharmaceutics , Dr. D. Y. Patil College of Pharmacy , Pune , India.
Artif Cells Nanomed Biotechnol. 2018;46(sup1):347-361. doi: 10.1080/21691401.2018.1423991. Epub 2018 Jan 15.
The natural flavonoid fisetin (FS) has shown anticancer properties but its in-vivo administration remains challenging due to its poor aqueous solubility. The aim of the study was to develop FS loaded pluronic127 (PF)-folic acid (FA) conjugated micelles (FS-PF-FA) by the way of increasing solubility, bioavailability and active targetability of FS shall increase its therapeutic efficacy. FA-conjugated PF was prepared by carbodiimide crosslinker chemistry. FS-PF-FA micelles were prepared by thin-film hydration method and evaluated in comparison with free FS and FS loaded PF micelles (FS-PF). The smooth surfaces with spherical in shape of FS-PF-PF micelles displayed smaller in size (103.2 ± 6.1 nm), good encapsulation efficiency (82.50 ± 1.78%), zeta potential (-26.7 ± 0.44 mV) and sustained FS release. Bioavailability of FS from FS-PF-PF micelles was increased by 6-fold with long circulation time, slower plasma elimination and no sign of tissue toxicity as compared to free FS. Further, the FS-PF-FA micelles demonstrated active targeting effect on folate overexpressed human breast cancer MCF-7 cells. The concentration of the drug needed for growth inhibition of 50% of cells in a designed time period (GI50) was 14.3 ± 1.2 µg/ml for FS while it was greatly decreased to 9.8 ± 0.78 µg/ml, i.e. a 31.46% decrease for the FS-PF. Furthermore, the GI50 value for FS-PF-FA was 4.9 ± 0.4 µg/ml, i.e. a 65.737% decrease compared to FS and 50% decrease compare to FS-PF. The results indicate that the FS-PF-FA micelles have the potential to be applied for targeting anticancer drug delivery.
天然类黄酮非瑟酮 (FS) 具有抗癌特性，但由于其水溶性差，其体内给药仍具有挑战性。本研究旨在通过增加 FS 的溶解度、生物利用度和主动靶向性来开发负载 FS 的 Pluronic127 (PF)-叶酸 (FA) 缀合物胶束 (FS-PF-FA)，以提高其治疗效果。通过碳二亚胺交联剂化学法制备 FA 缀合的 PF。通过薄膜水化法制备 FS-PF-FA 胶束，并与游离 FS 和负载 FS 的 PF 胶束 (FS-PF) 进行比较评估。FS-PF-PF 胶束表面光滑，呈球形，粒径较小（103.2±6.1nm），包封效率高（82.50±1.78%），Zeta 电位（-26.7±0.44mV），FS 释放缓慢。与游离 FS 相比，FS-PF-PF 胶束中的 FS 生物利用度提高了 6 倍，具有更长的循环时间、较慢的血浆消除和无组织毒性迹象。此外，FS-PF-FA 胶束对叶酸过表达的人乳腺癌 MCF-7 细胞表现出主动靶向作用。在设计的时间段内使 50%细胞生长抑制所需的药物浓度（GI50），FS 为 14.3±1.2μg/ml，而 FS-PF 则大大降低至 9.8±0.78μg/ml，即 31.46%的降低。此外，FS-PF-FA 的 GI50 值为 4.9±0.4μg/ml，即与 FS 相比降低了 65.737%，与 FS-PF 相比降低了 50%。结果表明，FS-PF-FA 胶束具有作为靶向抗癌药物递送的潜力。
