Intracellular trafficking and cellular uptake mechanism of mPEG-PLGA-PLL and mPEG-PLGA-PLL-Gal nanoparticles for targeted delivery to hepatomas.

Abstract

The lysosomal escape of nanoparticles is crucial to enhancing their delivery and therapeutic efficiency. Here, we report the cellular uptake mechanism, lysosomal escape, and organelle morphology effect of monomethoxy (polyethylene glycol)-poly (D,L-lactide-co-glycolide)-poly (L-lysine) (mPEG-PLGA-PLL, PEAL) and 4-O-beta-D-Galactopyranosyl-D-gluconic acid (Gal)-modified PEAL (PEAL-Gal) for intracellular delivery to HepG2, Huh7, and PLC hepatoma cells. These results indicate that PEAL is taken up by clathrin-mediated endocytosis of HepG2, Huh7 and PLC cells. For PEAL-Gal, sialic acid receptor-mediated endocytosis and clathrin-mediated endocytosis are the primary uptake pathways in HepG2 cells, respectively, whereas PEAL-Gal is internalized by sag vesicle- and clathrin-mediated endocytosis in Huh7 cells. In the case of PLC cells, clathrin-mediated endocytosis and sialic acid receptor play a primary role in the uptake of PEAL-Gal. TEM results verify that PEAL and PEAL-Gal lead to a different influence on organelle morphology of HepG2, Huh7 and PLC cells. In addition, the results of intracellular distribution reveal that PEAL and PEAL-Gal are less entrapped in the lysosomes of HepG2 and Huh7 cells, demonstrating that they effectively escape from lysosomes and contribute to enhance the efficiency of intracellular delivery and tumor therapy. In vivo tumor targeting image results demonstrate that PEAL-Gal specifically delivers Rhodamine B (Rb) to the tumor tissue of mice with HepG2, Huh7, and PLC hepatomas and remains at a high concentration in tumor tissue until 48 h, properties that will greatly contribute to enhanced antitumor efficiency.

• Authors: Peifeng Liu, Yanming Sun, Qi Wang, Ying Sun, He Li, Yourong Duan
• Journal: Biomaterials (Biomaterials) Vol. 35 Issue 2 Pg. 760-70 (Jan 2014) ISSN: 1878-5905 [Electronic] Netherlands
• PMID: 24148242 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Crown Copyright © 2013. Published by Elsevier Ltd. All rights reserved.

Chemical References

• Clathrin
• Drug Carriers
• Polyesters
• Rhodamines
• monomethoxy (polyethylene glycol)-poly(lactide-co-glycolide)-poly(lysine)
• Polylysine
• Polyethylene Glycols
• N-Acetylneuraminic Acid
• rhodamine B

Topics

• Animals
• Carcinoma, Hepatocellular (drug therapy)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Clathrin (metabolism)
• Drug Carriers
• Endocytosis (drug effects)
• Female
• Hep G2 Cells
• Humans
• Liver Neoplasms (drug therapy)
• Mice
• Mice, Inbred BALB C
• N-Acetylneuraminic Acid (metabolism)
• Nanoparticles (chemistry)
• Polyesters (pharmacokinetics)
• Polyethylene Glycols (pharmacokinetics)
• Polylysine (analogs & derivatives, pharmacokinetics)
• Rhodamines (pharmacology)