Enhanced Reactive Oxygen Species Generation by Mitochondria Targeting of Anticancer Drug To Overcome Tumor Multidrug Resistance.

Abstract

As a major clinical tumor chemotherapeutic burden, multidrug resistance (MDR) is often a result of up-regulation of P-glycoprotein (P-gp), which strongly enhances anticancer drug efflux. The excess mitochondrial reactive oxygen species (ROS) could not only inhibit the function of P-gp through insufficient adenosine triphosphate supply but also cause apoptosis in MDR cells. Here, we designed a mitochondria targeting nanoparticulate system (GNPs-P-Dox-GA) for overcoming MDR through enhanced ROS generation, where increased cellular uptake as well as mitochondria accumulation were both realized by glycyrrhetinic acid (GA). First, doxorubicin was conjugated with GA (GA-Dox) and then grafted onto a N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer backbone via hydrazone bond (P-Dox-GA). The obtained P-Dox-GA was subsequently attached to the surface of gelatin nanoparticles (GNPs). As gelatin is a substrate of tumor extracellular metal matrix protease-2 (MMP2), GNPs-P-Dox-GA nanoparticles could be degraded and release small size P-Dox-GA to facilitate tumor tissue penetration. After P-Dox-GA internalized by tumor cells under GA mediation, Dox-GA detached from HPMA copolymer through hydrolysis of hydrazone bond and then efficiently delivered to mitochondria. Compared to non-GA modified carriers, GNPs-P-Dox-GA exhibited increased cellular uptake nearly 4-fold and mitochondria distribution 8.8-fold, and increased ROS production level nearly 3-fold, significantly decreased efflux rate (55% compared with Dox group) in drug resistant HepG2/ADR cells, and then led to improved in vitro antitumor efficiency in HepG2/ADR cells (IC50 only 19.5% of unmodified ones) as well as exciting in vivo antitumor efficiency on HepG2/ADR heterotopic tumor nude mice (1.75-fold higher tumor growth inhibition rate than free drug).

• Authors: Yuanyuan Liu, Zhou Zhou, Xi Lin, Xiaofeng Xiong, Rui Zhou, Minglu Zhou, Yuan Huang
• Journal: Biomacromolecules (Biomacromolecules) Vol. 20 Issue 10 Pg. 3755-3766 (10 14 2019) ISSN: 1526-4602 [Electronic] United States
• PMID: 31465208 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Hydrazones
• Methacrylates
• Nanoconjugates
• Reactive Oxygen Species
• Doxorubicin
• Gelatin
• Matrix Metalloproteinase 2
• Glycyrrhetinic Acid
• hydroxypropyl methacrylate

Topics

• Animals
• Antineoplastic Agents (administration & dosage, pharmacokinetics, pharmacology, therapeutic use)
• Doxorubicin (administration & dosage, pharmacokinetics, pharmacology, therapeutic use)
• Drug Resistance, Neoplasm
• Gelatin (chemistry)
• Glycyrrhetinic Acid (chemistry)
• Hep G2 Cells
• Humans
• Hydrazones (chemistry)
• Lysosomes (metabolism)
• Male
• Matrix Metalloproteinase 2 (metabolism)
• Methacrylates (chemistry)
• Mice
• Mice, Inbred BALB C
• Mitochondria (drug effects, metabolism)
• Nanoconjugates (chemistry)
• Nanoparticles (chemistry)
• Neoplasms, Experimental (drug therapy)
• Reactive Oxygen Species (metabolism)
• Tissue Distribution