Geng Tao, Zhao Xia, Ma Meng, Zhu Gang, Yin Ling
Department of Pharmacy, the Affiliated Hospital of Taishan Medical University, Tai'an, 271000, China.
Department of Pharmacy, Shandong Qianfoshan Hospital, Jinan, 250000, China.
Nanoscale Res Lett. 2017 Dec;12(1):437. doi: 10.1186/s11671-017-2206-6. Epub 2017 Jun 30.
Human serum albumin (HSA) is an intrinsic protein and important carrier that transports endogenous as well as exogenous substances across cell membranes. Herein, we have designed and prepared resveratrol (RV)-loaded HSA nanoparticles conjugating RGD (arginine-glycine-aspartate) via a polyethylene glycol (PEG) "bridge" (HRP-RGD NPs) for highly effective targeted pancreatic tumor therapy. HRP-RGD NPs possess an average size of 120 ± 2.6 nm with a narrow distribution, a homodisperse spherical shape, a RV encapsulation efficiency of 62.5 ± 4.21%, and a maximum RV release ratio of 58.4.2 ± 2.8% at pH 5.0 and 37 °C. In vitro biocompatibility of RV is improved after coating with HSA and PEG. Confocal fluorescence images show that HRP-RGD NPs have the highest cellular uptake ratio of 47.3 ± 4.6% compared to HRP NPs and HRP-RGD NPs with free RGD blocking, attributing to an RGD-mediated effect. A cell counting kit-8 (CCK-8) assay indicates that HRP-RGD NPs without RV (HP-RGD NPs) have nearly no cytotoxicity, but HRP-RGD NPs are significantly more cytotoxic to PANC-1 cells compared to free RV and HRP NPs in a concentration dependent manner, showing apoptotic morphology. Furthermore, with a formulated PEG and HSA coating, HRP-RGD NPs prolong the blood circulation of RV, increasing approximately 5.43-fold (t). After intravenous injection into tumor-bearing mice, the content of HRP-RGD NPs in tumor tissue was proven to be approximately 3.01- and 8.1-fold higher than that of HRP NPs and free RV, respectively. Based on these results, HRP-RGD NPs were used in an in vivo anti-cancer study and demonstrated the best tumor growth suppression effect of all tested drugs with no relapse, high in vivo biocompatibility, and no significant systemic toxicity over 35 days treatment. These results demonstrate that HRP-RGD NPs with prolonged blood circulation and improved biocompatibility have high anti-cancer effects with promising future applications in cancer therapy.
人血清白蛋白（HSA）是一种内在蛋白和重要载体，可将内源性和外源性物质转运穿过细胞膜。在此，我们设计并制备了通过聚乙二醇（PEG）“桥”连接RGD（精氨酸-甘氨酸-天冬氨酸）的负载白藜芦醇（RV）的HSA纳米颗粒（HRP-RGD NPs），用于高效靶向胰腺肿瘤治疗。HRP-RGD NPs的平均尺寸为120±2.6nm，分布窄，呈均匀分散的球形，RV包封率为62.5±4.21%，在pH 5.0和37℃下最大RV释放率为58.4±2.8%。用HSA和PEG包被后，RV的体外生物相容性得到改善。共聚焦荧光图像显示，与HRP NPs和游离RGD阻断的HRP-RGD NPs相比，HRP-RGD NPs的细胞摄取率最高，为47.3±4.6%，这归因于RGD介导的效应。细胞计数试剂盒-8（CCK-8）分析表明，不含RV的HRP-RGD NPs（HP-RGD NPs）几乎没有细胞毒性，但与游离RV和HRP NPs相比，HRP-RGD NPs对PANC-1细胞具有显著更高的细胞毒性，且呈浓度依赖性，表现出凋亡形态。此外，如果采用配方化的PEG和HSA包被，HRP-RGD NPs可延长RV的血液循环时间，增加约5.43倍（t）。静脉注射到荷瘤小鼠体内后，肿瘤组织中HRP-RGD NPs的含量分别被证明比HRP NPs和游离RV高约3.01倍和8.1倍。基于这些结果，HRP-RGD NPs被用于体内抗癌研究，并在所有测试药物中显示出最佳的肿瘤生长抑制效果，无复发，体内生物相容性高，在35天的治疗中无明显全身毒性。这些结果表明，具有延长血液循环时间和改善生物相容性的HRP-RGD NPs具有很高的抗癌效果，在癌症治疗中具有广阔的应用前景。
