Key Laboratory of Modern Preparation of TCM, Ministry of Education, Jiangxi University of Traditional Chinese Medicine, Nanchang 330004, China.
State Key Laboratory of Innovative Drug and Efficient Energy-Saving Pharmaceutical Equipment, Jiangxi University of Traditional Chinese Medicine, Nanchang 330006, China.
Molecules. 2018 Nov 7;23(11):2906. doi: 10.3390/molecules23112906.
Combination chemotherapy is a common clinical practice in cancer treatment. Here, cyclic RGD (arginylglycylaspartic acid) peptide was introduced to the surface of lipid/calcium/phosphate (LCP) asymmetric lipid layer nanoparticles for the co-delivery of paclitaxel (PTX) and gemcitabine monophosphate (GMP) (P/G-NPs). The sphere-like morphology of P/G-NPs displays a well-distributed particle size, and high entrapment efficiency and drug loading for both PTX and GMP, with a positive zeta potential. P/G-NPs were stable for up to 15 days. The cellular uptake of these cyclic RGD-modified nanoparticles was significantly higher than that of unmodified nanoparticles over 2 h incubation. Compared with the combination of free PTX and GMP (P/G-Free), P/G-NPs exhibited a longer circulation lifetime and improved absorption for PTX and GMP. Polyethylene glycol was responsible for a higher plasma concentration and a decreased apparent volume of distribution (V). Nanoparticles enhanced the drug accumulation in tumors compared with other major organs after 24 h. P/G-NPs nearly halted tumor growth, with little evidence of general toxicity, whereas P/G-Free had only a modest inhibitory effect at 16 mg/kg of GMP and 2.0 mg/kg of PTX. Increased levels of apoptosis within tumors were detected in P/G-NPs group by approximately 43.6% (TUNEL assay). When compared with GMP NPs, PTX NPs, and P/G-Free, P/G-NPs decreased expression of B-cell lymphoma-2 and B-cell lymphoma-extra large proteins, and increased expression of cleaved poly-ADP-ribose polymerase-1. Calreticulin expression in tumors also increased upon the co-delivery of PTX and GMP. The antitumor effect of P/G-NPs is more powerful than P/G-Free, GMP NP, or PTX NP alone, without obvious toxicity.
联合化疗是癌症治疗中的一种常见临床实践。在这里，环状 RGD（精氨酰-甘氨酰-天冬氨酸）肽被引入脂质/钙/磷酸盐（LCP）不对称脂质层纳米粒子的表面，用于共递送紫杉醇（PTX）和单磷酸吉西他滨（GMP）（P/G-NPs）。P/G-NPs 的球型形态显示出均匀的粒径分布，以及对 PTX 和 GMP 均具有高包封效率和载药量，并带有正的 Zeta 电位。P/G-NPs 在长达 15 天内稳定。这些环状 RGD 修饰的纳米粒子的细胞摄取在 2 小时孵育期间明显高于未修饰的纳米粒子。与游离 PTX 和 GMP 的组合（P/G-Free）相比，P/G-NPs 表现出更长的循环寿命和改善的 PTX 和 GMP 吸收。聚乙二醇负责更高的血浆浓度和降低的表观分布容积（V）。与其他主要器官相比，纳米粒子增强了肿瘤中的药物积累。与 P/G-Free 相比，P/G-NPs 几乎停止了肿瘤生长，且毒性较小，而 P/G-Free 在 16mg/kg GMP 和 2.0mg/kg PTX 时仅具有适度的抑制作用。在 P/G-NPs 组中，通过大约 43.6%（TUNEL 测定）检测到肿瘤中凋亡的增加。与 GMP NPs、PTX NPs 和 P/G-Free 相比，P/G-NPs 降低了 B 细胞淋巴瘤-2 和 B 细胞淋巴瘤-额外大蛋白的表达，并增加了裂解多聚 ADP-核糖聚合酶-1 的表达。在共递送 PTX 和 GMP 时，肿瘤中钙网蛋白的表达也增加。与 P/G-Free、GMP NP 或 PTX NP 单独相比，P/G-NPs 的抗肿瘤作用更强，而没有明显的毒性。
