Department of Chemistry, Amirkabir University of Technology, Tehran 1591634311, Iran.
Department of Medical Biotechnology, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran 1449614535, Iran.
ACS Appl Bio Mater. 2023 May 15;6(5):1806-1815. doi: 10.1021/acsabm.3c00041. Epub 2023 Apr 24.
An effective treatment for hormone-dependent breast cancer is chemotherapy using cytotoxic agents such as letrozole (LTZ). However, most anticancer drugs, including LTZ, are classified as class IV biopharmaceuticals, which are associated with low water solubility, poor bioavailability, and significant toxicity. As a result, developing a targeted delivery system for LTZ is critical for overcoming these challenges and limitations. Here, biodegradable LTZ-loaded nanocarriers were synthesized by solvent emulsification evaporation using nanomicelles prepared with dodecanol-polylactic acid-co-polyethylene glycol (DPLA-co-PEG). Furthermore, cancer cell-targeting folic acid (FA) was conjugated into the nanomicelles to achieve a more effective and safer cancer treatment. During our investigation, DPLA-co-PEG and DPLA-co-PEG-FA displayed a uniform and spherical morphology. The average diameters of DPLA-co-PEG and DPLA-co-PEG-FA nanomicelles were 86.5 and 241.3 nm, respectively. Our preliminary data suggest that both nanoformulations were cytocompatible, with ≥90% cell viability across all concentrations tested. In addition, the amphiphilic nature of the nanomicelles led to high drug loading and dispersion in water, resulting in the extended release of LTZ for up to 50 h. According to the Higuchi model, nanomicelles functionalized with FA have a greater potential for the controlled delivery of LTZ into target cells. This model was confirmed experimentally, as LTZ-containing DPLA-co-PEG-FA was significantly and specifically more cytotoxic (up to 90% cell death) toward MCF-7 cells, a hormone-dependent human breast cancer cell line, when compared to free LTZ and LTZ-containing DPLA-co-PEG. Furthermore, a half-maximal inhibitory concentration (IC50) of 87 ± 1 nM was achieved when MCF-7 cells were exposed to LTZ-containing DPLA-co-PEG-FA, whereas higher doses of 125 ± 2 and 100 ± 2 nM were required for free LTZ and LTZ-containing DPLA-co-PEG, respectively. Collectively, DPLA-co-PEG-FA represents a promising nanosized drug delivery system to target controllably the delivery of drugs such as chemotherapeutics.
一种有效的激素依赖性乳腺癌治疗方法是使用细胞毒性药物（如来曲唑）进行化疗。然而，大多数抗癌药物，包括来曲唑，都被归类为第四类生物制药，它们具有低水溶性、生物利用度差和显著毒性等特点。因此，开发来曲唑的靶向递送系统对于克服这些挑战和限制至关重要。在这里，使用通过溶剂乳化蒸发法制备的由十二醇-聚乳酸-共-聚乙二醇（DPLA-co-PEG）制成的纳米胶束来合成了可生物降解的载来曲唑纳米载体。此外，将癌细胞靶向叶酸（FA）偶联到纳米胶束中，以实现更有效和更安全的癌症治疗。在我们的研究中，DPLA-co-PEG 和 DPLA-co-PEG-FA 表现出均匀的球形形态。DPLA-co-PEG 和 DPLA-co-PEG-FA 纳米胶束的平均直径分别为 86.5nm 和 241.3nm。我们的初步数据表明，两种纳米制剂均具有细胞相容性，在所有测试浓度下细胞存活率均≥90%。此外，纳米胶束的两亲性导致药物在水中的高载药量和分散性，从而使来曲唑的释放时间延长至 50 小时。根据 Higuchi 模型，FA 功能化的纳米胶束具有将 LTZ 更有效地递送到靶细胞的潜力。实验证实了这一模型，因为与游离 LTZ 和载有 LTZ 的 DPLA-co-PEG 相比，含有 LTZ 的 DPLA-co-PEG-FA 对激素依赖性人乳腺癌细胞系 MCF-7 细胞的细胞毒性显著增强（高达 90%的细胞死亡）。此外，当 MCF-7 细胞暴露于含有 LTZ 的 DPLA-co-PEG-FA 时，达到半最大抑制浓度（IC50）为 87±1nM，而游离 LTZ 和载有 LTZ 的 DPLA-co-PEG 分别需要更高的剂量 125±2nM 和 100±2nM。总之，DPLA-co-PEG-FA 代表了一种有前途的纳米级药物递送系统，可用于靶向控制化疗等药物的递送。
