Zhang Yu, Xiao Chunsheng, Ding Jianxun, Li Mingqiang, Chen Xin, Tang Zhaohui, Zhuang Xiuli, Chen Xuesi
Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, People's Republic of China.
Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, People's Republic of China; Graduate University of Chinese Academy of Sciences, Beijing 100039, People's Republic of China.
Acta Biomater. 2016 Aug;40:243-253. doi: 10.1016/j.actbio.2016.04.007. Epub 2016 Apr 7.
The linear, Y-shaped, and linear-dendritic block copolymers of methoxy poly(ethylene glycol)-block-polyamidoamine-block-poly(l-glutamic acid) (MPEG-b-PAMAM-b-PGA) with one, two, four, and eight PGA arms but similar MPEG/PGA weight ratios (W/W) (named as P1PA, P2PA, P4PA and P8PA, respectively) were synthesized and comparatively investigated for doxorubicin hydrochloride (DOX) delivery. All the obtained block copolymers were highly biocompatible and could efficiently load DOX into nanoparticles (NPs) through electrostatic interaction. The NPs formed by linear (P1PA) or Y-shaped (P2PA) block copolymers and DOX were spherically shaped with smaller sizes, while the NPs formed from linear-dendritic block copolymers (P4PA and P8PA) were irregular in shape and larger in size. The P1PA/DOX and P2PA/DOX NPs exhibited better DOX protection and slower DOX release profile. However, cell cytotoxicity assays indicated that all the DOX-loaded NPs exhibited similar cytotoxicities with free DOX, indicating effective DOX release after cellular uptake. The NPs from linear and Y-shaped block copolymers greatly extended the blood circulation time, and displayed more accumulation in tumor site and less accumulation in the liver and kidney compared with the linear-dendritic counterparts. In addition, the P1PA/DOX and P2PA/DOX NPs also exhibited higher anti-tumor efficacy and less toxicity than the other DOX formulations. All these results indicated that the linear and Y-shaped MPEG-b-PAMAM-b-PGA block copolymers displayed better DOX delivery ability in anti-tumor treatment than the linear-dendritic copolymers.
Polymeric NPs derived from block copolymers have emerged as effective vehicles for drug delivery. However, the majority of the researches in this field have involved simple linear block copolymers and there are very few comparative studies on the self-assembly, in vitro, and in vivo drug delivery by the block copolymers with similar composition but different architectures. In this study, a series of linear, Y-shaped, and linear-dendritic polypeptide-based block copolymers were prepared and thoroughly investigated for DOX delivery. These block polymers loaded DOX into NPs with different sizes and morphologies, and exhibited different anti-tumor capabilities both in vitro and in vivo. The results indicated that the architecture of the block copolymers played an important role in their drug delivery behaviors.
合成了具有一个、两个、四个和八个聚谷氨酸（PGA）臂但甲氧基聚乙二醇-聚酰胺胺-聚（L-谷氨酸）（MPEG-b-PAMAM-b-PGA）重量比（W/W）相似的线性、Y形和线性-树枝状嵌段共聚物（分别命名为P1PA、P2PA、P4PA和P8PA），并对其用于盐酸多柔比星（DOX）递送进行了比较研究。所有获得的嵌段共聚物都具有高度生物相容性，并且可以通过静电相互作用将DOX有效地负载到纳米颗粒（NPs）中。由线性（P1PA）或Y形（P2PA）嵌段共聚物与DOX形成的NPs呈球形，尺寸较小，而由线性-树枝状嵌段共聚物（P4PA和P8PA）形成的NPs形状不规则且尺寸较大。P1PA/DOX和P2PA/DOX NPs表现出更好的DOX保护和更慢的DOX释放曲线。然而，细胞毒性试验表明，所有负载DOX的NPs与游离DOX表现出相似的细胞毒性，表明细胞摄取后DOX有效释放。与线性-树枝状对应物相比，来自线性和Y形嵌段共聚物的NPs大大延长了血液循环时间，并且在肿瘤部位的积累更多，在肝脏和肾脏中的积累更少。此外，P1PA/DOX和P2PA/DOX NPs也比其他DOX制剂表现出更高的抗肿瘤疗效和更低的毒性。所有这些结果表明，线性和Y形MPEG-b-PAMAM-b-PGA嵌段共聚物在抗肿瘤治疗中比线性-树枝状共聚物表现出更好的DOX递送能力。
源自嵌段共聚物的聚合物纳米颗粒已成为有效的药物递送载体。然而，该领域的大多数研究都涉及简单的线性嵌段共聚物，对于具有相似组成但不同结构的嵌段共聚物的自组装、体外和体内药物递送的比较研究非常少。在本研究中，制备了一系列线性、Y形和线性-树枝状多肽基嵌段共聚物，并对其DOX递送进行了深入研究。这些嵌段聚合物将DOX负载到具有不同尺寸和形态的NPs中，并且在体外和体内都表现出不同的抗肿瘤能力。结果表明，嵌段共聚物的结构在其药物递送行为中起着重要作用。
