Nair Hareesh B, Huffman Steven, Veerapaneni Poornachand, Kirma Nameer B, Binkley Peter, Perla Rao P, Evans Dean B, Tekmal Rajeshwar R
Department of Obstetrics and Gynecology and Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, TX 78229, USA.
J Nanosci Nanotechnol. 2011 May;11(5):3789-99. doi: 10.1166/jnn.2011.3871.
Letrozole is a potent aromatase inhibitor and superior to other defined selective estrogen receptor modulators such as tamoxifen in treating hormone-responsive postmenopausal breast cancer patients. Patients who receive this drug may become insensitive to the effects of estrogen deprivation induced by letrozole. Letrozole has known side effects on bone metabolism due to systemic ablation of estrogen production. The purpose of this study was to examine the therapeutic efficacy of hyaluronic acid-bound letrozole nanoparticles (HA-Letr-NPs) in restoring sensitivity to letrozole-resistant (LTLT-Ca) cells. To target letrozole to LTLT-Ca cells, hyaluronic acid-bound letrozole nanoparticles were prepared by nanoprecipitation using biodegradable PLGA-PEG co-polymer. Binding specificity of HA to CD44 on the cell surface was analyzed in vitro using FITC-CD44 Ab and CD44 siRNA by flow cytometry. Effects on in vitro cytotoxicity and aromatase enzymatic activity of HA-Letr-NPs were performed in MCF-7 breast cancer cells, MCF-7 cells over-expressing aromatase (MCF-7/Aro), and LTLT-Ca cells resistant to letrozole. Preclinical efficacy of HA-Letr-NPs was examined in mice using LTLT-Ca xenograft tumors. HA-Letr-NPs were restricted to a maximum size of 100 nm. The in vitro drug release assay showed that the highest released concentration of letrozole occurred after 23 hours at 37 degrees C in phosphate-buffered saline. HA-Letr-NPs on MCF-7/Aro and LTLT-Ca cells showed an IC50 of 2 microM and 5 microM, respectively. HA-Letr-NPs were more efficacious in inhibiting tumor growth, reducing in vitro cellular and in vivo tumor aromatase enzyme activity more than the corresponding Letr-NPs or letrozole. HA-Letr-NPs restored and maintained a prolonged sensitivity and targeted delivery of letrozole in letrozole-resistant tumors in vivo.
来曲唑是一种强效芳香化酶抑制剂，在治疗激素反应性绝经后乳腺癌患者方面优于其他已明确的选择性雌激素受体调节剂，如他莫昔芬。接受这种药物的患者可能会对来曲唑诱导的雌激素剥夺效应变得不敏感。由于雌激素生成的全身消除，来曲唑对骨代谢有已知的副作用。本研究的目的是检查透明质酸结合来曲唑纳米颗粒（HA-Letr-NPs）在恢复对来曲唑耐药（LTLT-Ca）细胞敏感性方面的治疗效果。为了将来曲唑靶向LTLT-Ca细胞，使用可生物降解的PLGA-PEG共聚物通过纳米沉淀法制备了透明质酸结合来曲唑纳米颗粒。使用FITC-CD44抗体和CD44 siRNA通过流式细胞术在体外分析HA与细胞表面CD44的结合特异性。在MCF-7乳腺癌细胞、过表达芳香化酶的MCF-7细胞（MCF-7/Aro）和对来曲唑耐药的LTLT-Ca细胞中进行了HA-Letr-NPs对体外细胞毒性和芳香化酶活性的影响实验。使用LTLT-Ca异种移植肿瘤在小鼠中检查了HA-Letr-NPs的临床前疗效。HA-Letr-NPs的最大尺寸限制为100纳米。体外药物释放试验表明，在37℃的磷酸盐缓冲盐水中，来曲唑在23小时后释放浓度最高。HA-Letr-NPs对MCF-7/Aro和LTLT-Ca细胞的IC50分别为2 microM和5 microM。HA-Letr-NPs在抑制肿瘤生长、降低体外细胞和体内肿瘤芳香化酶活性方面比相应的Letr-NPs或来曲唑更有效。HA-Letr-NPs在体内恢复并维持了对来曲唑耐药肿瘤中延长的敏感性和来曲唑的靶向递送。
