Preparation of a Self-Assembled Rhein–Doxorubicin Nanogel Targeting Mitochondria and Investigation on Its Antihepatoma Activity

Abstract

Mitochondria are involved in the regulation of apoptosis, making them a promising target for the development of new anticancer drugs. Doxorubicin (DOX), a chemotherapeutic drug, can induce reactive oxygen species (ROS)-mediated apoptosis, improving its anticancer effects. Herein, Rhein, an active ingredient in rhubarb, with the capability of self-assembly and mitochondrial targeting, was used in conjunction with DOX to form efficient nanomaterials (Rhein–DOX nanogel) capable of sustained drug release. It was self-assembled with a hydrogen bond, π–π stacking interactions, and hydrophobic interactions as the main driving force, and its loading efficiency was up to 100%. Based on its self-assembly characteristics, we evaluated the mechanism of this material to target mitochondria, induce ROS production, and promote apoptosis. The IC50 of the Rhein–DOX nanogel (3.74 μM) was only 46.3% of that of DOX (11.89 μM), and the tumor inhibition rate of the Rhein–DOX nanogel was 79.4% in vivo, 2.3 times that of DOX. This study not only addresses the disadvantages of high toxicity of DOX and low bioavailability of Rhein, when DOX and Rhein are combined for the treatment of hepatoma, but it also significantly improved the synergistic antihepatoma efficacy of Rhein and DOX, which provides a new idea for the development of long-term antihepatoma agents with low toxicity.

A New Strategy to Fight Metallodrug Resistance: Mitochondria‐Relevant Treatment through Mitophagy to Inhibit Metabolic Adaptations of Cancer Cells

“…Natural product rhein‐based ruthenium‐arene complex has been reported in our recent study, where rhein would facilitate the complex to localize in mitochondria and generate synthetic lethality behavior after conjugation to the Ru‐arene component in vivo [24] . Previous pharmacologic study indicated that rhein could target mitochondria via binding to a variety of molecules on the mitochondrial membrane and induce the pathological opening of the mitochondrial permeability transition pore (mPTP) [25, 26] . Inspired by this result, a novel rhein‐functionalized mitochondria‐targeting cyclometalated iridium(III) complex Ir‐Rhein (see Figure 1) was successfully synthesized in this work.…”

“…[24] Previous pharmacologic study indicated that rhein could target mitochondria via binding to a variety of molecules on the mitochondrial membrane and induce the pathological opening of the mitochondrial permeability transition pore (mPTP). [25,26] Inspired by this result, a novel rhein-functionalized mitochondria-targeting cyclometalated iridium(III) complex Ir-Rhein (see Figure 1) was successfully synthesized in this work. Compared with the rhein-free cyclometalated iridium-(III) complex Ir-NH 2 (33.6 % accumulation in mitochondria), the mitochondrial occupation of complex Ir-Rhein in the total cellular uptake was elevated to 71.3 %, which demonstrated the strong mitochondria-targeting capability of rhein.…”

In situ stimulus-responsive self-assembled nanomaterials for drug delivery and disease treatment

“…Tumor cell mitochondria are known to have higher levels of endogenous reactive oxygen species (ROS). 132 In the conjugate of the polymer and the cytotoxic peptide KLAK, the cleavage of the thioketal occurs under the trigger of ROS. This results in the destruction of the hydrophilic PEG and the breaking of the hydrophilic/hydrophobic balance.…”

ROS-Triggered Self-Assembled Nanoparticles Based on a Chemo-Sonodynamic Combinational Therapy Strategy for the Noninvasive Elimination of Hypoxic Tumors

“…Notably, a thioketal linkage was introduced to conjugate linoleic acid (LA) and gemcitabine into a GEM prodrug (LA-GEM). Second, LA-GEM and Rh were then self-assembled in water, together with the commercialized amphiphilic polymer DSPE-PEG 2k in the outer layer of nanoparticles, to enhance stability and long circulation of RP-NPs. , Based on the characteristics of the aforementioned materials, it could be speculatively assumed that the RP-NPs was a self-assembling system with hydrogen bonding, π–π stacking interactions, and hydrophobic interactions acting as the primary driving forces . Third, a HeLa tumor-bearing mice model was constructed.…”

“…51,52 Based on the characteristics of the aforementioned materials, it could be speculatively assumed that the RP-NPs was a self-assembling system with hydrogen bonding, π−π stacking interactions, and hydrophobic interactions acting as the primary driving forces. 53 Third, a HeLa tumor-bearing mice model was constructed. Upon US, the permeability of the tumor was increased, and the hypoxia state of the tumor was initially improved.…”