Mehata Abhishesh Kumar, Singh Virendra, Singh Nitesh, Mandal Abhijit, Dash Debabrata, Koch Biplob, Muthu Madaswamy S
Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology, (BHU), Varanasi 221005, Uttar Pradesh, India.
Cancer Biology Laboratory, Department of Zoology Institute of Science, (BHU), Varanasi 221005, Uttar Pradesh, India.
ACS Appl Mater Interfaces. 2023 Jul 26;15(29):34343-34359. doi: 10.1021/acsami.3c03184. Epub 2023 Jul 11.
Breast cancer is the leading cause of death among women globally. Approximately 80% of all breast cancers diagnosed are overexpressed with estrogen receptors (ERs). In this study, we have developed an estrone (Egen)-grafted chitosan-based polymeric nanocarrier for the targeted delivery of palbociclib (PLB) to breast cancer. The nanoparticles (NPs) were prepared by solvent evaporation using the ionic gelation method and characterized for particle size, zeta potential, polydispersity, surface morphology, surface chemistry, drug entrapment efficiency, cytotoxicity assay, cellular uptake, and apoptosis study. The developed PLB-CS NPs and PLB-CS-g-Egen NPs had a particle size of 116.3 ± 1.53 nm and 141.6 ± 1.97 nm, respectively. The zeta potential of PLB-CS NPs and PLB-CS-g-Egen NPs was found to be 18.70 ± 0.416 mV and 12.45 ± 0.574 mV, respectively. The morphological analysis demonstrated that all NPs were spherical in shape and had a smooth surface. An cytotoxicity assay was performed in estrogen receptor (ER)-expressing MCF7 cells and T47D cells, which suggested that targeted NPs were 57.34- and 30.32-fold more cytotoxic compared to the pure PLB, respectively. Additionally, cell cycle analysis confirmed that cell cycle progression from the G1 into S phase was blocked more efficiently by targeted NPs compared to nontargeted NPs and PLB in MCF7 cells. pharmacokinetic studies demonstrated that entrapment of the PLB in the NPs improved the half-life and bioavailability by ∼2-3-fold. Further, ultrasound and photoacoustic imaging of DMBA induced breast cancer in the Sprague-Dawley (SD) rat showed that targeted NPs completely vanished breast tumor, reduced hypoxic tumor volume, and suppressed tumor angiogenesis more efficiently compared to the nontargeted NPs and free PLB. Further, hemocompatibility and histopathology studies suggested that NPs were biocompatible and safe for clinical use.
乳腺癌是全球女性死亡的主要原因。所有确诊的乳腺癌中，约80%雌激素受体（ERs）呈过表达状态。在本研究中，我们制备了一种接枝有雌酮（Egen）的壳聚糖基聚合物纳米载体，用于将哌柏西利（PLB）靶向递送至乳腺癌部位。纳米颗粒（NPs）采用离子凝胶法通过溶剂蒸发制备，并对其粒径、zeta电位、多分散性、表面形态、表面化学性质、药物包封率、细胞毒性测定、细胞摄取和凋亡研究进行了表征。所制备的PLB-CS NPs和PLB-CS-g-Egen NPs的粒径分别为116.3±1.53 nm和141.6±1.97 nm。PLB-CS NPs和PLB-CS-g-Egen NPs的zeta电位分别为18.70±0.416 mV和12.45±0.574 mV。形态分析表明，所有纳米颗粒均呈球形且表面光滑。在表达雌激素受体（ER）的MCF7细胞和T47D细胞中进行了细胞毒性测定，结果表明，与纯PLB相比，靶向纳米颗粒的细胞毒性分别高57.34倍和30.32倍。此外，细胞周期分析证实，与非靶向纳米颗粒和PLB相比，靶向纳米颗粒在MCF7细胞中更有效地阻断了从G1期到S期的细胞周期进程。药代动力学研究表明，PLB包封在纳米颗粒中可使半衰期和生物利用度提高约2至3倍。此外，对Sprague-Dawley（SD）大鼠二甲基苯并蒽（DMBA）诱导的乳腺癌进行的超声和光声成像显示，与非靶向纳米颗粒和游离PLB相比，靶向纳米颗粒能更有效地完全消除乳腺肿瘤、减少缺氧肿瘤体积并抑制肿瘤血管生成。此外，血液相容性和组织病理学研究表明，纳米颗粒具有生物相容性且临床使用安全。
