School of Chemical and Biomedical Engineering , Nanyang Technological University , Singapore 637457.
Department of Oncology , Johns Hopkins Singapore , Singapore 308433.
Mol Pharm. 2019 Sep 3;16(9):3873-3886. doi: 10.1021/acs.molpharmaceut.9b00493. Epub 2019 Aug 7.
Acetyltanshinone IIA (ATA), synthesized in our group exhibiting good anti-breast cancer effects, is expected to replace the commonly used anti-ER+ breast cancer (breast cancer cells overexpressing the estrogen receptor) drug tamoxifen. To promote the clinical progress of ATA, polyethylene glycol (PEG)-modified liposomes were used to encapsulate ATA along with improving its bioavailability and in vivo anticancer efficiency. The resulting liposomal ATA exhibited a spherical shape with an average size of 188.5 nm. In vitro evaluations showed that liposomal ATA retained the anti-breast cancer efficacy of ATA while exerting much less cytotoxicity toward noncancerous cells. Significantly, pharmacokinetics analysis showed that the AUC of liposomal ATA was 59 times higher than that of free ATA, demonstrating increased bioavailability of ATA. Preclinical experiments demonstrated that liposomal ATA reduced the growth of ER-positive human breast tumor xenografts by 73% in nude mice, and the liposomal ATA exhibited a much lower level of toxicity than that of free ATA with respect to zebrafish larval mortality, body formation, and heart function during development. Moreover, 7-day and 21-day tissue toxicity levels were determined in mice by intravenous administration of a maximum dosage of liposomal ATA (120 mg/kg). The results showed no obvious tissue damage in major organs, including the heart, liver, spleen, kidney, and brain. In summary, we have developed a clinical formulation of liposomal ATA with the high bioavailability and potent efficacy for the treatment of ER-positive breast cancer.
乙酰丹参酮 IIA（ATA）是本课题组合成的一种具有良好抗乳腺癌作用的化合物，有望替代临床上常用的抗雌激素受体阳性（乳腺癌细胞过度表达雌激素受体）药物他莫昔芬。为了促进 ATA 的临床转化，我们采用聚乙二醇（PEG）修饰的脂质体包裹 ATA，以提高其生物利用度和体内抗肿瘤效果。所得的脂质体 ATA 呈球形，平均粒径为 188.5nm。体外评价结果表明，脂质体 ATA 保留了 ATA 的抗乳腺癌活性，同时对正常细胞的细胞毒性显著降低。药代动力学分析表明，脂质体 ATA 的 AUC 是游离 ATA 的 59 倍，表明 ATA 的生物利用度增加。临床前实验表明，脂质体 ATA 可使荷瘤裸鼠的 ER 阳性人乳腺癌肿瘤生长减少 73%，且脂质体 ATA 对斑马鱼幼鱼的死亡率、身体形成和心脏功能的毒性均低于游离 ATA。此外，通过静脉注射最大剂量的脂质体 ATA（120mg/kg）在小鼠中进行了 7 天和 21 天的组织毒性研究。结果表明，在主要器官（包括心、肝、脾、肾和脑）中未观察到明显的组织损伤。综上所述，我们开发了一种具有高生物利用度和高效抗肿瘤活性的临床用脂质体 ATA 制剂，可用于治疗 ER 阳性乳腺癌。
