MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou 310027, China.
Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Institute of Functional Nano & Soft Materials (FUNSOM), Soochow University, Suzhou 215123, Jiangsu, China.
J Colloid Interface Sci. 2017 Dec 1;507:217-224. doi: 10.1016/j.jcis.2017.07.047. Epub 2017 Jul 17.
Development of gemcitabine (GEM) nanocarriers as theranostic agents for pancreatic cancer chemotherapy has received extensive attention in recent years. A novel enzyme-sensitive albumin-based GEM delivery nanoplatform was developed in this research by simple conjugation of GEM to human serum albumin (HSA) via cathepsin B cleavable peptide GFLG and then complexing with near-infrared (NIR) dye IR780, forming a HSA-GEM/IR780 complex. The successful preparation of HSA-GEM/IR780 complex was confirmed by Matrix-Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry (MALDI-TOF-MS), UV-vis-NIR absorption spectra and fluorescent emission spectra. The in vivo performance of HSA-GEM/IR780 complex was carried out on BxPC-3 pancreatic tumor xenografted mice. As revealed by in vivo NIR imaging, HSA-GEM/IR780 exhibited enhanced accumulation and long-term retention in tumor tissues compared to free IR780. Meanwhile, compared to free GEM, the deamination of GEM nanovectors into inactive 2',2'-difluorodeoxyuridine (dFdU) can be greatly suppressed, while the concentration of the activated form of GEM (gemcitabine triphosphate, dFdCTP) was significantly increased in tumor tissue, thus exhibiting superior tumor inhibition activity with minimal side effects.
近年来，将吉西他滨（GEM）纳米载体开发为用于胰腺癌化疗的治疗药物引起了广泛关注。本研究通过将 GEM 通过组织蛋白酶 B 可切割肽 GFLG 简单缀合到人血清白蛋白（HSA）上来制备新型酶敏感的基于白蛋白的 GEM 递药纳米平台，然后与近红外（NIR）染料 IR780 复合，形成 HSA-GEM/IR780 复合物。通过基质辅助激光解吸/电离飞行时间质谱（MALDI-TOF-MS）、紫外-可见-近红外吸收光谱和荧光发射光谱证实了 HSA-GEM/IR780 复合物的成功制备。在 BxPC-3 胰腺肿瘤异种移植小鼠上进行了 HSA-GEM/IR780 复合物的体内性能研究。体内近红外成像显示，与游离 IR780 相比，HSA-GEM/IR780 在肿瘤组织中具有增强的积累和长期保留。同时，与游离 GEM 相比，GEM 纳米载体脱氨为无活性的 2',2'-二氟脱氧尿苷（dFdU）的情况可以得到极大抑制，而在肿瘤组织中 GEM 的活化形式（吉西他滨三磷酸，dFdCTP）的浓度显著增加，从而表现出优异的肿瘤抑制活性和最小的副作用。
