Convenient preparation of charge-adaptive chitosan nanomedicines for extended blood circulation and accelerated endosomal escape

Zhang, YP (Zhang, Yapei)^[ 1 ] ; Li, YY (Li, Yingying)^[ 1 ] ; Ma, JL (Ma, Jinlong)^[ 1 ] ; Wang, XY (Wang, Xinyu)^[ 1 ] ; Yuan, Z (Yuan, Zhi)^[ 1,2 ] ; Wang, W (Wang, Wei)^[ 1 ]

NANO RESEARCH, 2018, 11(8): 4278-4292

DOI: 10.1007/s12274-018-2014-z

 WOS:000440733100028

Abstract

A major impediment in the development of chitosan nanoparticles (CTS NPs) as effective drug delivery vesicles is their rapid clearance from blood and endosome entrapment. To overcome these problems, a convenient and promising template system was developed by decorating poly(methacrylic acid) (PMAA) to the surface of 10-hydroxy camptothecin (HCPT)-loaded CTS NPs (HCPT-CTS/PMAA NPs). The results show that the presence of negatively charged PMAA significantly elongated the blood circulation time of HCPT-CTS NPs from 12 to 24 h, and reduced the blood clearance (Cl) from 30.57 to 6.72 mL/h in vivo. The calculated area under curve (AUC(0-24h)) and terminal elimination half-life (t(1/2)) of HCPT-CTS/PMAA NPs were 4.37-fold and 2.48-fold compared with those of HCPT-CTS NPs. Furthermore, the positively charged HCPT-CTS/PMAA NPs triggered by tumor acidic microenvironment (pH 6.5) result in a 453-fold higher cellular uptake than the negatively charged counterparts at pH 7.4. Additionally, HCPT-CTS/PMAA NPs have the ability to escape endosomal entrapment via "proton sponge effect" after incubation with HepG2 cells for 3 h at pH 6.5. Taken together, these findings open up a convenient, low-cost, but effective way to prepare HCPT-CTS/PMAA NPs as a candidate for developing vectors with enhanced long blood circulation and endosomal escape ability in future clinical experiments.