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).

The role of reactive oxygen species in tumor treatment

“…4). 28 Although the chemophotodynamic therapy has a signicant synergistic effect on malignant tumors, currently available nanocarriers have limited capabilities in selective toxicity, drug release and tumor penetration. A poly ethylene glycol (PEG)stearylamine (C18) conjugate (PTS) self-assembled with ROSsensitive thioketal linker (TL), and was combined with the coloaded doxorubicin (DOX) and photosensitive decolorant A (PhA) to enhance the local chemophotodynamic therapy.…”

PEGylated Water‐Soluble Organic Nanoparticles with Chlorin Derivative for Biocompatible Photodynamic Therapy In Vitro and In Vivo

“…Most of the PSs in WSON‐PEG 3400 and WSON‐PEG 2000 were located in the cytoplasm of the tumour cells. In particular, WSON‐PEG 3400 and WSON‐PEG 2000 displayed a mitochondria‐targeted accumulation (orange‐colour in merged images) of PSs, inducing mitochondria‐mediated apoptosis to destroy the tumour cells [22,37,47–51] …”

Mitochondrial targeted strategies and their application for cancer and other diseases treatment

“…Since GA could generate hydrogen peroxide which led to the opening of mitochondrial permeability transition pore (MPTP) when Ca 2+ was also present, it might be capable of delivering drugs to IMS and matrix. Our group designed a GA-modified gelatin nanoparticle and it exhibited 4-fold higher cell internalization and 8.8-fold higher mitochondrial accumulation than GA unmodified nanoparticles in HepG2/ADR cells (details were introduced in next section) (Liu et al 2019). These results revealed that GA is a novel potentially active ligand for both hepatocellular carcinoma and mitochondria targeting.…”

“…Unfortunately, the positive charge of P-M-DOX restricted its application in vivo. Considering that, another smart mitochondrial targeted nanoparticle was (Zhou et al 2019) designed for better in vivo drug delivery (Liu et al 2019). As HPMA copolymer with a small size was capable of achieving deeper tumor penetration but its blood stability and tumor accumulation were unsatisfactory, HPMA copolymers modified degradable gelatin nanoparticles (GNPs) was developed as a size-switchable carrier to realize both long circulation and deep penetration.…”