Department of Biomedical Science and BK21 PLUS Centre for Creative Biomedical Scientists, Chonnam National University Medical School, Gwangju 61469, Korea.
Department of Polymer Science and Engineering, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon 34134, Korea.
Molecules. 2019 Mar 2;24(5):885. doi: 10.3390/molecules24050885.
Biodegradable polymers have been developed for the targeted delivery of therapeutics to tumors. However, tumor targeting and imaging are usually limited by systemic clearance and non-specific adsorption. In this study, we used poly(amino acid) derivatives, such as poly(succinimide), to synthesize a nanomicelle-forming poly(hydroxyethylaspartamide) (PHEA, P) modified sequentially with octadecylamine, polyethylene glycol (PEG, P), and glycine (G) to design PHEA-PEG-glycine (PPG) nanoparticles (NPs). These PPG NPs were further tethered to cyclic Arg-Gly-Asp (cRGD) sequences for formulating tumor-targeting PPG-cRGD NPs, and then loaded with IR-780 dye (PPG-cRGD-IR-780) for visualizing tumor homing. cRGD cloaked in PPG NPs could bind specifically to both tumor endothelium and cancer cells overexpressing αβ₃ integrins. PPG-cRGD NPs exhibited enhanced physiological stability, cellular viability, and targeted intracellular uptake in cancer cells. In addition, PPG-cRGD NPs offered enhanced systemic circulation, leading to preferential tumor targeting and prolonged fluorescence tumor imaging for nearly 30 days. Nevertheless, non-targeted formulations demonstrated premature systemic clearance with short-term tumor imaging. Histochemical analysis showed no damage to normal organs, reaffirming the biocompatibility of PHEA polymers. Overall, our results indicated that PPG-cRGD NPs, which were manipulated to obtain optimal particle size and surface charge, and were complemented with tumor targeting, could improve the targeted and theranostic potential of therapeutic delivery.
可生物降解聚合物已被开发用于将治疗剂靶向递送至肿瘤。然而，肿瘤靶向和成像通常受到全身清除率和非特异性吸附的限制。在本研究中，我们使用聚（氨基酸）衍生物，如聚琥珀酰亚胺，合成了一种纳米胶束形成的聚（羟乙基天冬酰胺）（PHEA，P），其顺序用十八胺、聚乙二醇（PEG，P）和甘氨酸（G）进行修饰，以设计 PHEA-PEG-甘氨酸（PPG）纳米颗粒（NPs）。这些 PPG NPs 进一步与环状 Arg-Gly-Asp（cRGD）序列连接，用于构建肿瘤靶向 PPG-cRGD NPs，然后负载 IR-780 染料（PPG-cRGD-IR-780）用于可视化肿瘤归巢。隐藏在 PPG NPs 中的 cRGD 可以特异性结合肿瘤内皮细胞和过度表达 αβ₃整合素的癌细胞。PPG-cRGD NPs 表现出增强的生理稳定性、细胞活力和在癌细胞中的靶向细胞内摄取。此外，PPG-cRGD NPs 提供了增强的系统循环，导致优先的肿瘤靶向和近 30 天的延长荧光肿瘤成像。然而，非靶向制剂表现出过早的全身清除，导致短期肿瘤成像。组织化学分析显示正常器官没有损伤，再次证实了 PHEA 聚合物的生物相容性。总体而言，我们的结果表明，经过优化粒径和表面电荷处理并补充肿瘤靶向的 PPG-cRGD NPs 可以提高治疗剂递送的靶向和治疗潜力。
