Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College St., Toronto, Ontario, Canada.
Pharm Res. 2010 Nov;27(11):2343-55. doi: 10.1007/s11095-010-0068-z. Epub 2010 Mar 2.
Block copolymer micelles (BCMs) were functionalized with indium-111 and/or epidermal growth factor (EGF), which enabled investigation of the in vivo transport of passively and actively targeted BCMs. The integration of conventional and image-based techniques afforded novel quantitative means to achieve an in-depth insight into the fate of polymeric nanoparticles in vivo.
Pharmacokinetics and biodistribution studies were performed in athymic mice bearing human breast xenografts to evaluate the whole-body transport of NT-BCMs (non-targeted, EGF-) and T-BCMs (targeted, EGF+). The intratumoral distribution of BCMs was investigated using MicroSPECT/CT and autoradiographic imaging, complemented with quantitative MATLAB® analyses. Tumors were fractionated for quantifying intracellular uptake of BCMs via γ-counting.
The intratumoral distribution of NT-BCMs and T-BCMs were found to be heterogeneous, and positively correlated with tumor vascularization (r>0.68 ± 0.04). The enhanced in vivo cell uptake and cell membrane binding of T-BCMs were found to delay their clearance from tumors overexpressing EGFR, and therefore resulted in enhanced tumor accumulation for the T-BCMs in comparison to the NT-BCMs.
Adequate passive targeting is required in order to achieve effective active targeting. Tumor physiology has a significant impact on the transvascular and intratumoral transport of passively and actively targeted BCMs.
将嵌段共聚物胶束（BCMs）用铟-111 和/或表皮生长因子（EGF）功能化，从而能够研究被动和主动靶向 BCM 的体内转运。常规和基于图像的技术的结合为深入了解聚合物纳米粒子在体内的命运提供了新颖的定量方法。
在患有人类乳腺癌异种移植物的无胸腺小鼠中进行药代动力学和生物分布研究，以评估非靶向（无 EGF）和靶向（有 EGF）NT-BCMs 和 T-BCMs 的全身转运。使用 MicroSPECT/CT 和放射自显影成像研究 BCMs 的肿瘤内分布，并结合定量 MATLAB®分析进行补充。对肿瘤进行分割，通过γ计数定量测定 BCMs 的细胞内摄取。
发现 NT-BCMs 和 T-BCMs 的肿瘤内分布不均匀，与肿瘤血管生成呈正相关（r>0.68±0.04）。发现 T-BCMs 的体内细胞摄取和细胞膜结合增强会延迟其在 EGFR 过表达的肿瘤中的清除速度，因此与 NT-BCMs 相比，T-BCMs 在肿瘤中的积累增强。
为了实现有效的主动靶向，需要适当的被动靶向。肿瘤生理学对被动和主动靶向 BCM 的跨血管和肿瘤内转运有重大影响。
