PO.CH01.04 · 化学
盐酸小檗胺纳米药物通过诱导凋亡增强结直肠癌抗肿瘤疗效
Enhanced antitumor efficacy of berbamine dihydrochloride nanomedicine via apoptosis induction in colorectal cancer
该海报暂无可下载的资料
AACR 官方页面
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：盐酸小檗胺（BBM）是一种天然的双苄基异喹啉生物碱，具有广泛的抗肿瘤活性。然而，其临床转化受到非特异性组织分布、生物利用度差和剂量限制性毒性的阻碍。牛血清白蛋白（BSA）纳米颗粒因其生物相容性、低免疫原性和固有的肿瘤靶向能力，是一种理想的药物递送平台。本研究旨在开发负载BBM的BSA纳米颗粒（BBM-BSA-NPs），以增强针对结直肠癌（CRC）的药物靶向和抗肿瘤疗效。
方法：制备并表征了BBM-BSA-NPs。通过CCK-8试验评估了对CRC细胞系（CT26、HT29）和其他癌细胞系（AGS、CAOV3、HepG2）的体外细胞毒性。通过比较对癌细胞与正常293细胞的作用来评估选择性。通过流式细胞术测量凋亡诱导。在小鼠CT26肿瘤模型中研究了体内抗肿瘤疗效和全身安全性。
结果：与天然BBM相比，BBM-BSA-NPs以浓度和时间依赖的方式显著增加了对CT26和HT29细胞的细胞毒性（P < 0.05）。该制剂对癌细胞表现出选择性毒性，对HepG2细胞的抑制作用显著更强（P < 0.05），而在24 h和48 h对正常293细胞的影响极小。值得注意的是，BBM-BSA-NPs有效诱导了CT26细胞的形态学改变和凋亡，在所有测试浓度下的凋亡率均显著超过天然BBM（P < 0.05）。在体内，BBM-BSA-NP治疗使肿瘤体积（279.19 ± 46.75 mm³）和重量（0.13 ± 0.04 g）显著降低，明显优于天然BBM（456.75 ± 54.64 mm³；0.29 ± 0.04 g；P < 0.05）。未观察到体重或全身毒性的显著变化，证实了该治疗的安全性。空白BSA-NPs未显示抗肿瘤活性，证实疗效和安全性获益归因于该纳米制剂。
结论：我们成功开发了一种新型BBM-BSA纳米颗粒系统，可显著增强BBM对结直肠癌的选择性细胞毒性和凋亡诱导，同时改善其体内治疗疗效。本研究为利用白蛋白纳米颗粒将BBM重新用作CRC强效且安全的治疗药物提供了令人信服的依据。
查看英文原文 English abstract
Background: Berbamine dihydrochloride (BBM), a natural bisbenzylisoquinoline alkaloid, exhibits broad antitumor activity. However, its clinical translation is hampered by nonspecific tissue distribution, poor bioavailability, and dose-limiting toxicity. Bovine serum albumin (BSA) nanoparticles represent an ideal drug delivery platform because of their biocompatibility, low immunogenicity, and inherent tumor-targeting capability. This study aimed to develop BBM-loaded BSA nanoparticles (BBM-BSA-NPs) to enhance drug targeting and antitumor efficacy against colorectal cancer (CRC).
Methods: BBM-BSA-NPs were prepared and characterized. In vitro cytotoxicity was assessed against CRC cell lines (CT26, HT29) and other cancer lines (AGS, CAOV3, HepG2) via CCK-8 assays. Selectivity was evaluated by comparing the effects on cancer cells with those on normal 293 cells. Apoptosis induction was measured by flow cytometry. In vivo antitumor efficacy and systemic safety were investigated in a murine CT26 tumor model.
Results: Compared with native BBM, BBM-BSA-NPs significantly increased the cytotoxicity to CT26 and HT29 cells in a concentration- and time-dependent manner (P < 0.05). The formulation showed selective toxicity toward cancer cells, with markedly greater inhibition in HepG2 cells (P < 0.05) and minimal effects on normal 293 cells at 24 h and 48 h. Notably, BBM-BSA-NPs effectively induced morphological changes and apoptosis in CT26 cells, with apoptosis rates significantly exceeding those of native BBM at all concentrations tested (P < 0.05). In vivo, BBM-BSA-NP treatment resulted in a remarkable reduction in tumor volume (279.19 ± 46.75 mm³) and weight (0.13 ± 0.04 g), significantly outperforming native BBM (456.75 ± 54.64 mm³; 0.29 ± 0.04 g; P < 0.05). No significant changes in body weight or systemic toxicity were observed, confirming the safety of the treatment. The blank BSA-NPs showed no antitumor activity, confirming that the efficacy and safety benefits were attributable to the nanoformulation.
Conclusion: We successfully developed a novel BBM-BSA nanoparticle system that significantly enhances the selective cytotoxicity and apoptotic induction of BBM against colorectal cancer while improving its therapeutic efficacy in vivo. This study provides a compelling rationale for leveraging albumin nanoparticles to repurpose BBM as a potent and safe therapeutic agent for CRC.
利益披露 Disclosure
C. Zhang, None..
Q. Guan, None..
Z. Li, None.