Bromelain-immobilized and lactobionic acid-modified chitosan nanoparticles for enhanced drug penetration in tumor tissues

Tumor extracellular matrix (ECM) still remains a major barrier that hinders the diffusion of drug in tumor parenchyma. We design a lactobionic acid (LA) and bromelain dual-functional nanoparticles as doxorubicin carriers. LA can increase the nanoparticles' tumor-targeting ability, while bromelain can enhance the permeation of nanoparticles in tumor parenchyma due to the hydrolytic activity to ECM. The chemical structures of these modified macromolecules were characterized by H-1 NMR, FT-IR and UV spectrum. Drug-loaded nanoparticles as final drug formulations were observed in terms of size, zeta potential and micromorphology. Monolayer cells and three-dimensional cell spheroids were used to investigate the influence of LA and bromelain on the nanoparticles' cellular uptake, cytotoxicity, accumulation and penetration. In vivo drug distribution and antitumor activity results demonstrated that bromelain increased nanoparticles penetration and diffusion ability in tumor area upon the digestion of ECM, leading to higher drug concentration in tumor area and superior antitumor effect. (C) 2018 Elsevier B.V. All rights reserved.