Dataset Information

Ginsenoside Rg3 micelles mitigate doxorubicin-induced cardiotoxicity and enhance its anticancer efficacy.

ABSTRACT: Doxorubicin (DOX) is one of the most effective chemotherapy agents used in the treatment of hematological and solid tumors, however, it causes dose-related cardiotoxicity that may lead to heart failure in patients. One of the major reasons was increased reactive oxygen species (ROS) production. Ginsenoside Rg3 (Rg3), was powerful free radical scavengers and possessed cardioprotective effects. Nevertheless, Rg3 has low aqueous solubility and oral bioavailability, limiting its effects. Herein, we encapsulated Rg3 through spontaneous self-assembly of Pluronic F127 to improve its solubility and oral bioavailability. Moreover, co-administering Rg3 in Pluronic F127 micelles with doxorubicin can mitigate the cardiotoxicity, with ameliorating mitochondrial and metabolic function, improving calcium handling, and decreasing ROS production. In addition, it can improve the anticancer efficacy of doxorubicin. Therefore, our study provides a rational strategy for further developing a potentially viable adjunct-supportive treatment for reducing toxicity and increasing efficiency on chemotherapy.

SUBMITTER: Li L

PROVIDER: S-EPMC8241051 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Ginsenoside Rg3 micelles mitigate doxorubicin-induced cardiotoxicity and enhance its anticancer efficacy.

Li Lan L Ni Jingyu J Li Min M Chen Jingrui J Han Lifeng L Zhu Yan Y Kong Deling D Mao Jingyuan J Wang Yi Y Zhang Boli B Zhu Meifeng M Gao Xiumei X Fan Guanwei G

Drug delivery 20171101 1

Doxorubicin (DOX) is one of the most effective chemotherapy agents used in the treatment of hematological and solid tumors, however, it causes dose-related cardiotoxicity that may lead to heart failure in patients. One of the major reasons was increased reactive oxygen species (ROS) production. Ginsenoside Rg3 (Rg3), was powerful free radical scavengers and possessed cardioprotective effects. Nevertheless, Rg3 has low aqueous solubility and oral bioavailability, limiting its effects. Herein, we ...[more]

PMID: 29063791

Similar Datasets

Project description:The molecular architecture of pH-responsive amphiphilic block copolymers, their self-assembly behavior to form nanoparticles (NPs), and doxorubicin (DOX)-loading technique govern the extent of DOX-induced cardiotoxicity. We observed that the choice of pH-sensitive tertiary amines, surface charge, and DOX-loading techniques within the self-assembled NPs strongly influence the release and stimulation of DOX-induced cardiotoxicity in primary cardiomyocytes. However, covalent conjugation of DOX to a pH-sensitive nanocarrier through a "conditionally unstable amide" linkage (PCPY-cDOX; PC = polycarbonate and PY = 2-pyrrolidine-1-yl-ethyl-amine) significantly reduced the cardiotoxicity of DOX in cardiomyocytes as compared to noncovalently encapsulated DOX NPs (PCPY-eDOX). When these formulations were tested for drug release in serum-containing media, the PCPY-cDOX systems showed prolonged control over drug release (for ∼72 h) at acidic pH compared to DOX-encapsulated nanocarriers, as expected. We found that DOX-encapsulated nanoformulations triggered cardiotoxicity in primary cardiomyocytes more acutely, while conjugated systems such as PCPY-cDOX prevented cardiotoxicity by disabling the nuclear entry of the drug. Using 2D and 3D (spheroid) cultures of an ER + breast cancer cell line (MCF-7) and a triple-negative breast cancer cell line (MDA-MB-231), we unravel that, similar to encapsulated systems (PCPY-eDOX-type) as reported earlier, the PCPY-cDOX system suppresses cellular proliferation in both cell lines and enhances trafficking through 3D spheroids of MDA-MB-231 cells. Collectively, our studies indicate that PCPY-cDOX is less cardiotoxic as compared to noncovalently encapsulated variants without compromising the chemotherapeutic properties of the drug. Thus, our studies suggest that the appropriate selection of the nanocarrier for DOX delivery may prove fruitful in shifting the balance between low cardiotoxicity and triggering the chemotherapeutic potency of DOX.

Project description:Hepatocellular carcinoma (HCC) is the 2nd leading cause of cancer-related deaths every year globally. The most common form of treatment, hepatic arterial infusion (HAI), involves the direct injection of doxorubicin (DOX) into the hepatic artery. It is plagued with limited therapeutic efficacy and the occurrence of severe toxicities (e.g. cardiotoxicity). We aim to improve the therapeutic index of DOX delivered via HAI by loading the drug onto generation 5 (G5) poly(amidoamine) (PAMAM) dendrimers targeted to hepatic cancer cells via N-acetylgalactosamine (NAcGal) ligands. DOX is attached to the surface of G5 molecules via two different enzyme-sensitive linkages, L3 or L4, to achieve controllable drug release inside hepatic cancer cells. We previously reported on P1 and P2 particles that resulted from the combination of NAcGal-targeting with L3- or L4-DOX linkages, respectively, and showed controllable DOX release and toxicity towards hepatic cancer cells comparable to free DOX. In this study, we demonstrate that while the intratumoral delivery of free DOX (1 mg/kg) into HCC-bearing nod scid gamma (NSG) mice achieves a 2.5-fold inhibition of tumor growth compared to the saline group over 30 days, P1 and P2 particles delivered at the same DOX dosage achieve a 5.1- and 4.4-fold inhibition, respectively. Incubation of the particles with human induced pluripotent stem cell derived cardiomyocytes (hiPSC CMs) showed no effect on monolayer viability, apoptosis induction, or CM electrophysiology, contrary to the effect of free DOX. Moreover, magnetic resonance imaging revealed that P1- and P2-treated mice maintained cardiac function after intraperitoneal administration of DOX at 1 mg/kg for 21 days, unlike the free DOX group at an equivalent dosage, confirming that P1/P2 can avoid DOX-induced cardiotoxicity. Taken together, these results highlight the ability of P1/P2 particles to improve the therapeutic index of DOX and offer a replacement therapy for clinical HCC treatment.

Dataset Information

Ginsenoside Rg3 micelles mitigate doxorubicin-induced cardiotoxicity and enhance its anticancer efficacy.

Publications

Ginsenoside Rg3 micelles mitigate doxorubicin-induced cardiotoxicity and enhance its anticancer efficacy.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets