Nanoparticle Delivery of Artesunate Enhances the Anti-tumor Efficiency by Activating Mitochondria-Mediated Cell Apoptosis

Li, Rui; Yu, Xiwei; Su, Chang; Shi, Yijie; Zhao, Liang

doi:10.1186/s11671-017-2169-7

Cited by 31 publications

(21 citation statements)

References 28 publications

(18 reference statements)

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“…Lysosomes contain high levels of redox-active iron and iron-catalyzed lysosomal ROS production leads to mitochondrial outer membrane permeabilization and apoptosis in response to specific stimuli [23] . It is consistent with many studies [24] , [25] , [26] that ART treatment leads to mitochondrial ROS accumulation, disruption of mitochondrial membrane potential and induction of the intrinsic mitochondrial apoptosis. However, it remains unknown whether these damaged mitochondria could be degraded through mitophagy.…”

Section: Introductionsupporting

confidence: 92%

Artesunate-induced mitophagy alters cellular redox status

et al. 2018

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Artesunate (ART) is a prominent anti-malarial with significant anti-cancer properties. Our previous studies showed that ART enhances lysosomal function and ferritin degradation, which was necessary for its anti-cancer properties. ART targeting to mitochondria also significantly improved its efficacy, but the effect of ART on mitophagy, an important cellular pathway that facilitates the removal of damaged mitochondria, remains unknown. Here, we first observed that ART mainly localizes in the mitochondria and its probe labeling revealed that it binds to a large number of mitochondrial proteins and causes mitochondrial fission. Second, we found that ART treatment leads to autophagy induction and the decrease of mitochondrial proteins. When autophagy is inhibited, the decrease of mitochondrial proteins could be reversed, indicating that the degradation of mitochondrial proteins is through mitophagy. Third, our results showed that ART treatment stabilizes the full-length form of PTEN induced putative kinase 1 (PINK1) on the mitochondria and activates the PINK1-dependent pathway. This in turn leads to the recruitment of Parkin, sequestosome 1 (SQSTM1), ubiquitin and microtubule-associated proteins 1A/1B light chain 3 (LC3) to the mitochondria and culminates in mitophagy. When PINK1 is knocked down, ART-induced mitophagy is markedly suppressed. Finally, we investigated the effect of mitophagy by ART on mitochondrial functions and found that knockdown of PINK1 alters the cellular redox status in ART-treated cells, which is accompanied with a significant decrease in glutathione (GSH) and increase in mitochondrial reactive oxidative species (mROS) and cellular lactate levels. Additionally, knockdown of PINK1 leads to a significant increase of mitochondrial depolarization and more cell apoptosis by ART, suggesting that mitophagy protects from ART-induced cell death. Taken together, our findings reveal the molecular mechanism that ART induces cytoprotective mitophagy through the PINK1-dependent pathway, suggesting that mitophagy inhibition could enhance the anti-cancer activity of ART.

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Section: Introductionsupporting

confidence: 92%

Artesunate-induced mitophagy alters cellular redox status

et al. 2018

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“…A variety of nanotechnology has been developed in the past years to improve the solubility and bioavailability of ART. [23][24][25][26] ART loaded liposomes were reported with glioma targeting capabilities with enhanced toxicity towards glioma U87 cells. 27 Jin et al reported artesunate nanoliposomes, prepared with cholesterol and an appropriate amount of lecithin via thin film hydration method, showing stronger antitumor effect on HepG2 cells than that of free artesunate.…”

Section: Introductionmentioning

confidence: 99%

<p>pH-Responsive Artesunate Polymer Prodrugs with Enhanced Ablation Effect on Rodent Xenograft Colon Cancer</p>

Hao

Xie

et al. 2020

IJN

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In this study, pH-sensitive poly(2-ethyl-2-oxazoline)-poly(lactic acid)-poly(βamino ester) (PEOz-PLA-PBAE) triblock copolymers were synthesized and were conjugated with an antimalaria drug artesunate (ART), for inhibition of a colon cancer xenograft model. Methods: The as-prepared polymer prodrugs are tended to self-assemble into polymeric micelles in aqueous milieu, with PEOz segment as hydrophilic shell and PLA-PBAE segment as hydrophobic core. Results: The pH sensitivity of the as-prepared copolymers was confirmed by acid-base titration with pKb values around 6.5. The drug-conjugated polymer micelles showed high stability for at least 96 h in PBS and 37°C, respectively. The as-prepared copolymer prodrugs showed high drug loading content, with 9.57%±1.24% of drug loading for PEOz-PLA-PBAE-ART4. The conjugated ART could be released in a sustained and pH-dependent manner, with 92% of released drug at pH 6.0 and 57% of drug released at pH 7.4, respectively. In addition, in vitro experiments showed higher inhibitory effect of the prodrugs on rodent CT-26 cells than that of free ART. Animal studies also demonstrated the enhanced inhibitory efficacy of PEOz-PLA-PBAE-ART2 micelles on the growth of rodent xenograft tumor. Conclusion: The pH-responsive artesunate polymer prodrugs are promising candidates for colon cancer adjuvant therapy.

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“…Albumin NPs were also applied for AS encapsulation. The comparison with free AS, the nanosystems presented cytotoxicity and significant apoptotic effects indicating activated mitochondrial-mediated cell apoptosis [31]. Herein, PNs indicate their potential to encapsulate ART and its derivatives and the use in cancer and protozoal diseases with high therapeutic efficacy (Table 1).…”

Section: Polymeric Nanoparticlesmentioning

confidence: 92%

Progress in nano-drug delivery of artemisinin and its derivatives: towards to use in immunomodulatory approaches

Charlie-Silva

Fraceto

Melo

2018

Artificial Cells, Nanomedicine, and Biotechnology

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In recent years, artemisinin (ART) and its derivatives have highlighted according to their effects on highly aggressive cancers, as well as treatment of malaria and leishmaniasis, besides presenting antiinflammatory and antibacterial activity. It has also been shown that ART compounds have the ability to modulate the immune response by regulating cell proliferation and cytokine release. These effects may be beneficial and improve the treatment of cancer and parasitic diseases by increasing therapeutic success, but it has some pharmacological limitations such as low bioavailability, short half-life and limited tissue access. Nanotechnology has been explored during the last decades, notably in the design of drug carrier systems which includes polymeric, lipid and inorganic nanoparticles, cyclodextrins inclusion complexes, liposomes, carbon nanotubes, among others. These nanostructured drug delivery systems bring benefits both increased therapeutic efficacy and reduced toxicity. This review article aims to give an overview of the current progress in nanostructured drug carriers used for encapsulation of ART and its derivatives yielding examples of successful outcomes. The data collection suggests future applications of ART and derivatives encapsulated in nano delivery systems in clinical trials and prospects for use of ART loaded nanosystems in immunomodulatory responses.

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Nanoparticle Delivery of Artesunate Enhances the Anti-tumor Efficiency by Activating Mitochondria-Mediated Cell Apoptosis

Cited by 31 publications

References 28 publications

Artesunate-induced mitophagy alters cellular redox status

Artesunate-induced mitophagy alters cellular redox status

<p>pH-Responsive Artesunate Polymer Prodrugs with Enhanced Ablation Effect on Rodent Xenograft Colon Cancer</p>

Progress in nano-drug delivery of artemisinin and its derivatives: towards to use in immunomodulatory approaches

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