Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11432, USA.
Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11432, USA.
Eur J Pharm Sci. 2019 May 15;133:145-159. doi: 10.1016/j.ejps.2019.03.026. Epub 2019 Apr 1.
Non-small cell lung cancer is a major sub-type of lung cancer that is associated with a poor diagnosis resulting in poor therapy for the disorder. In order to achieve a better prognosis, innovative multi-functional systems need to be developed which will aide in diagnosis as well as therapy for the disorder. One such multi-functional delivery system fabricated is Quantum Dots (QDs). QDs are photo-luminescent inorganic nanoparticles utilized for tumor detection, preclinically. Erlotinib hydrochloride, a tyrosine kinase inhibitor, is a first-generation drug developed to treat NSCLC. Its active metabolite, Desmethyl Erlotinib (OSI-420), exhibits similar anticancer activity as erlotinib. OSI-420 was conjugated to QDs to fabricate a delivery system and was then characterized by FT-IR, H NMR, UV-VIS, particle size, zeta potential, fluorescence spectroscopy and TEM. Drug loading was estimated using UV-VIS spectroscopy (52.2 ± 7.5%). A concentration-dependent release of OSI-420 was achieved using esterase enzymes, which was further confirmed using LC-MS. A cellular uptake study revealed the internalization potential of QDs and QD-OSI 420. A cellular recovery study was performed to confirm the internalization potential. Cell viability studies revealed that QD-OSI 420 conjugates had significantly better efficacy than pure drugs in all tested cell lines. QD conjugated OSI-420 demonstrated an IC of 2.5 μM in erlotinib-resistant A549 cell lines, where erlotinib or OSI-420 alone could not exhibit 60% inhibition when evaluated up to 20 μM. Similar cytotoxic enhancement of erlotinib was seen with QD-OSI 420 in other NSCLC cell lines as well. These results were strengthened by 3D-SCC model of A549 which revealed that QD-OSI 420 was significantly better in reducing in-vitro 3D tumor volume, as compared to pure drugs. This study, being one of its kind, explores the feasibility of conjugating OSI-420 with QDs as an alternative to traditional anti-cancer therapy, by improving intracellular drug delivery.
非小细胞肺癌是肺癌的主要亚型之一，由于诊断不佳，导致该疾病的治疗效果不佳。为了获得更好的预后，需要开发创新的多功能系统，以辅助该疾病的诊断和治疗。一种这样的多功能递药系统是量子点（Quantum Dots，QDs）。QDs 是光致发光的无机纳米粒子，用于肿瘤检测，在临床前研究中得到了应用。盐酸厄洛替尼是一种酪氨酸激酶抑制剂，是开发用于治疗非小细胞肺癌的第一代药物。其活性代谢物，去甲基厄洛替尼（Desmethyl Erlotinib，OSI-420），表现出与厄洛替尼相似的抗癌活性。将 OSI-420 与 QDs 偶联制成递药系统，并通过傅里叶变换红外光谱（FT-IR）、核磁共振氢谱（1H NMR）、紫外可见分光光度法（UV-VIS）、粒径、Zeta 电位、荧光光谱和透射电子显微镜（TEM）进行了表征。使用紫外可见分光光度法（UV-VIS）估算了药物负载量（52.2 ± 7.5%）。使用酯酶酶实现了 OSI-420 的浓度依赖性释放，并用 LC-MS 进一步证实。细胞摄取研究揭示了 QDs 和 QD-OSI 420 的内化潜力。进行了细胞回收研究以确认内化潜力。细胞活力研究表明，QD-OSI 420 缀合物在所有测试的细胞系中的疗效明显优于纯药物。QD 偶联的 OSI-420 在厄洛替尼耐药的 A549 细胞系中的 IC 为 2.5 μM，而单独使用厄洛替尼或 OSI-420 时，在评估高达 20 μM 时，无法达到 60%的抑制率。QD-OSI 420 在其他非小细胞肺癌细胞系中也表现出类似的厄洛替尼细胞毒性增强作用。A549 的 3D-SCC 模型的研究结果加强了这些结果，该模型表明，与纯药物相比，QD-OSI 420 能更有效地减少体外 3D 肿瘤体积。这项研究是此类研究中的首例，通过改善细胞内药物递送，探索了将 OSI-420 与 QDs 偶联作为传统抗癌疗法替代物的可行性。
