Department of Obstetrics and Gynecology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, PR China; Shanghai Key Laboratory of Gynecologic Oncology, Shanghai 200127, PR China.
Biomaterials. 2014 Jan;35(3):983-92. doi: 10.1016/j.biomaterials.2013.09.062. Epub 2013 Oct 28.
Good biocompatibility, specific tumor targeting, effective drug loading capacity and persistence in the circulation in vivo are imperative prerequisites for the antitumor efficiency of nanoparticles and their further clinical application. In this study, APRPG (Ala-Pro-Arg-Pro-Gly) peptide-modified poly (ethylene glycol)-poly (lactic acid) (PEG-PLA) nanoparticles (NP-APRPG) encapsulating inhibitors of angiogenesis (TNP-470) (TNP-470-NP-APRPG) were fabricated. TNP-470-NP-APRPG was designed to feature maleimide-PEG-PLA and mPEG-PLA as carrier materials, the APRPG peptide for targeting angiogenesis, PEG for prolonging circulation in vivo and PLA for loading TNP-470. TNP-470-NP-APRPG was confirmed to be approximately 130 nm in size with negative ζ-potential (-14.3 mV), narrow distribution (PDI = 0.27) and spherical morphology according to dynamic light scattering (DLS) and transmission electron microscopy (TEM) analyses. In addition, X-ray photoelectron spectra (XPS) analyses confirmed 7.73% APRPG grafting on the TNP-470-NP. In vitro, TNP-470-NP-APRPG exhibited effective inhibition of proliferation, migration and tube formation in human umbilical vein endothelial cells (HUVECs). Similar findings were observed for the retardation of tumor growth in SKOV3 ovarian cancer-bearing mice, suggesting the significant inhibition of angiogenesis and antitumor efficiency of TNP-470-NP-APRPG. Moreover, no obvious toxic drug responses were observed. Further evidence obtained from the immunohistochemical examination demonstrated that the tumor growth inhibition was closely correlated with the high rate of apoptosis among endothelial cells and the effective blockade of endothelial cell proliferation. These results demonstrate that NP-APRPG is a promising carrier for delivering TNP-470 to treat ovarian cancer and that this approach has the potential to achieve broad tumor coverage in the clinic.
良好的生物相容性、特异性肿瘤靶向、有效的药物载药量和在体内循环中的持久性是纳米粒子抗肿瘤效率及其进一步临床应用的必要前提。在本研究中，制备了 APRPG（丙氨酰-脯氨酰-精氨酰-脯氨酰-甘氨酸）肽修饰的聚乙二醇-聚乳酸（PEG-PLA）纳米粒子（NP-APRPG）包封的血管生成抑制剂（TNP-470）（TNP-470-NP-APRPG）。TNP-470-NP-APRPG 设计为以马来酰亚胺-PEG-PLA 和 mPEG-PLA 为载体材料，APRPG 肽为靶向血管生成，PEG 为延长体内循环，PLA 为载 TNP-470。根据动态光散射（DLS）和透射电子显微镜（TEM）分析，TNP-470-NP-APRPG 被证实为约 130nm 大小，带负 ζ-电位（-14.3 mV），分布较窄（PDI=0.27），呈球形形态。此外，X 射线光电子能谱（XPS）分析证实 TNP-470-NP 上接枝了 7.73%的 APRPG。体外实验表明，TNP-470-NP-APRPG 能有效抑制人脐静脉内皮细胞（HUVEC）的增殖、迁移和管形成。在 SKOV3 卵巢癌荷瘤小鼠中，也观察到肿瘤生长的延迟，提示 TNP-470-NP-APRPG 对血管生成和抗肿瘤效率有显著抑制作用。此外，没有观察到明显的毒副作用。免疫组织化学检查进一步证实，肿瘤生长抑制与内皮细胞高凋亡率和内皮细胞增殖的有效阻断密切相关。这些结果表明，NP-APRPG 是一种很有前途的载体，可将 TNP-470 递送至治疗卵巢癌，并且这种方法有可能在临床上实现广泛的肿瘤覆盖。
