The Blood Clearance Kinetics and Pathway of Polymeric Micelles in Cancer Drug Delivery

作者：Xuanrong Sun, Guowei Wang, Hao Zhang, Shiqi Hu, Xin Liu, Jianbin Tang, Youqing Shen · 发表于：ACS Nano · 年份：2018 · DOI：10.1021/acsnano.8b02830 · 被引用次数：249 · 研究领域：Nanoparticle-Based Drug Delivery、Surfactants and Colloidal Systems、Hydrogels: synthesis, properties, applications

Polymer micelles are one of the most investigated nanocarriers for drug delivery; many have entered clinical trials and some are in clinic use, but their delivery systems have not yet shown the expected high therapeutic efficacy in clinics. Further understanding their in vivo behaviors, particularly how quickly and by what mechanism polymer micelles are cleared ( i. e., via micelles or unimers) once injected, is key to solving this dilemma. Herein, we hope to answer these questions for the clinically relevant polyethylene glycol- block-poly(ε-caprolactone) (PEG-PCL) and PEG- block-poly(d,l-lactide) (PEG-PDLLA) micelles. A small fraction of the hydrophobic chain ends was conjugated with a pair of fluorescence resonance energy transfer (FRET) dyes, Cy5 and Cy5.5, and used to fabricate FRET micelles whose FRET efficiency was correlated to the percentage of polymer chains in the micelles, the micelle degree. In vitro, serum proteins induced PEG-PCL micelle dissociation to some extent; mouse serum or blood surprisingly did not induce micelle dissociation but once with shear applied by a microfluidic channel caused most PEG-PCL micelles dissociated. After intravenous administration in mice, the PEG-PCL or PEG-PDLLA micelles were quickly sequestered into the liver as unimers, and the micelle degree in the blood quickly decreased to about 20%. The FRET-imaging experiments showed that in blood vessels the micelles quickly dissociated into unimers, which were found associated with albu...