Formulation of injectable glycyrrhizic acid-hydroxycamptothecin micelles as new generation of DNA topoisomerase I inhibitor for enhanced antitumor activity

Cai, Jieying; Luo, Shiwen; Lv, Xueli; Deng, Yingguang; Huang, Huaping; Zhao, Boxin; Zhang, Qing; Li, Guofeng

doi:10.1016/j.ijpharm.2019.118693

Cited by 26 publications

(13 citation statements)

References 59 publications

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“…HepG2 and Huh7 of human HCC cell lines were supplied by the Cell Bank of the Chinese Academy of Sciences (Shanghai, China) [ 39 ]. The DMEM medium (Invitrogen, Carlsbad, CA, USA) supplemented with 10% FBS (Invitrogen, Carlsbad, CA, USA) and 1% penicillin/streptomycin (Invitrogen, Carlsbad, CA, USA) were employed for cell culture at 37 °C in a humidified incubator (5% CO 2 ).…”

Section: Methodsmentioning

confidence: 99%

4-Hydroxyderricin Promotes Apoptosis and Cell Cycle Arrest through Regulating PI3K/AKT/mTOR Pathway in Hepatocellular Cells

Gao

Jiang

et al. 2021

Foods

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4-hydroxyderricin (4-HD), as a natural flavonoid compound derived from Angelica keiskei, has largely unknown inhibition and mechanisms on liver cancer. Herein, we investigated the inhibitory effects of 4-HD on hepatocellular carcinoma (HCC) cells and clarified the potential mechanisms by exploring apoptosis and cell cycle arrest mediated via the PI3K/AKT/mTOR signaling pathway. Our results show that 4-HD treatment dramatically decreased the survival rate and activities of HepG2 and Huh7 cells. The protein expressions of apoptosis-related genes significantly increased, while those related to the cell cycle were decreased by 4-HD. 4-HD also down-regulated PI3K, p-PI3K, p-AKT, and p-mTOR protein expression. Moreover, PI3K inhibitor (LY294002) enhanced the promoting effect of 4-HD on apoptosis and cell cycle arrest in HCC cells. Consequently, we demonstrate that 4-HD can suppress the proliferation of HCC cells by promoting the PI3K/AKT/mTOR signaling pathway mediated apoptosis and cell cycle arrest.

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Section: Methodsmentioning

confidence: 99%

4-Hydroxyderricin Promotes Apoptosis and Cell Cycle Arrest through Regulating PI3K/AKT/mTOR Pathway in Hepatocellular Cells

Gao

Jiang

et al. 2021

Foods

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“…In this work, we developed a novel BBR-loaded complex formulation by using GL as a carrier, which has been found in our previous work to improve the solubility of paclitaxel (Yang et al, 2015), podophyllotoxin (Wang et al, 2016), and hydroxycamtothecin (Cai et al, 2019). We found this BBR-GL complex enhanced the solubility of BBR by over 100-fold in PBS (pH = 7.4).…”

Section: Discussionmentioning

confidence: 81%

“…Pharmacologically, GL is frequently used as a supplement or solubilizer coadministrated with hydrophobic drugs to improve their efficacy and reduce toxicity (Lu et al, 2018;Zhang et al, 2018). In our previous study, GL has been proved to be used as a drug carrier of some sparingly soluble drugs such as paclitaxel (Yang et al, 2015), podophyllotoxin (Wang et al, 2016), and hydroxycamtothecin (Cai et al, 2019). All these studies showed GL had strong solubilization capability to some sparingly soluble compounds.…”

Section: Introductionmentioning

confidence: 95%

“…The drug powder of BBR and BBR-GL was excessively added in a 5 ml tube with solvent. They were shaken in a shaking incubator at 25 °C for 48 h to achieve solubility equilibrium (dos Santos et al, 2011;Cai et al, 2019). The samples of BBR and BBR-GL complex in PBS with different pHs (2, 4, 6, 7.4) were tested and then filtered through 0.45-μm filters.…”

Section: Solubility Studiesmentioning

confidence: 99%

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A Novel Berberine–Glycyrrhizic Acid Complex Formulation Enhanced the Prevention Effect to Doxorubicin-Induced Cardiotoxicity by Pharmacokinetic Modulation of Berberine in Rats

et al. 2022

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Developing a new drug delivery system is one of the useful approaches to overcome the limited use of berberine (BBR) to enhance its absorption and bioavailability. We prepared a novel berberine–glycyrrhizic acid (BBR–GL) complex formulation to increase the plasma concentration and bioavailability of BBR by improving BBR solubility and lowering the absorption barrier. The complex formulation with BBR and GL in the ratio 1:1 was developed through the self-assembly process and evaluated in vitro. Compared with BBR and BBR/GL physical mixture, the BBR–GL complex showed different characteristics by SEM, DSC, FT-IR, and PXRD measurement. In pharmacokinetic evaluation, the BBR–GL complex significantly increased the plasma concentration of BBR and the major metabolite berberrubine (BBB), with the AUC of BBR elevated to 4.43-folds, while the complex was safe as BBR. Furthermore, doxorubicin (DOX) was used to induce cardiotoxicity. Hematological study, histopathological examinations, electrocardiography (ECG), cardiac secretion measurement, and biochemical index analysis proved that the model of doxorubicin-induced cardiotoxicity (DIC) was conducted successfully. With the AUC of BBR increasing in the BBR–GL complex and the absorbed complex itself, the BBR–GL complex enhanced prevention effect to DIC and exhibited a significant prevention effect to attenuate heart damage. Our findings demonstrated that a novel BBR-loaded BBR–GL complex formulation could increase BBR plasma concentration. Improvement of BBR bioavailability by the BBR–GL complex could coordinate with GL to attenuate DIC. Concerning the safety of the drug delivery system at present, the BBR–GL complex could be a potential therapeutic formulation for the prevention of cardiac damage in the clinical application of doxorubicin.

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“…In our previous study, we demonstrated that hydroxycamptothecin (HCPT), a natural camptothecin compound found in Camptotheca acuminata, acts as a DNA topoisomerase I inhibitor to suppress cell overproliferation and induce apoptosis of fibroblasts, which remarkably prevents tendon adhesion after tendon injury [6]. However, the DNA synthesis inhibitory effect of HCPT could also lead to concerns about its toxicity to normally functioning mammalian cells [7]. Accordingly, direct clinical application of HCPT could give rise to severe symptoms such as myelosuppression, nausea, and diarrhea [8].…”

Section: Backgroudmentioning

confidence: 99%

Extracellular vesicles from hydroxycamptothecin primed umbilical cord stem cells enhance anti-adhesion potential for treatment of tendon injury

Yao

Xiong

et al. 2020

Stem Cell Res Ther

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Background Peritendinous fibrosis represents a fibrotic healing process that usually occurs after tendon injury or surgery. This worldwide challenge hampers the functional rehabilitation and the mobility of extremities. However, effective treatment is still lacking at present. The aim of our study was to explore the effect of extracellular vesicles derived from hydroxycamptothecin primed human umbilical cord stem cells (HCPT-EVs) on post-traumatic tendon adhesion. Methods Extracellular vesicles derived from unprimed human umbilical cord mesenchymal stem cells (Unprimed EVs) or HCPT-EVs were isolated and characterized. A rat model of Achilles tendon injury was used to confirm the anti-adhesion effect of HCPT-EVs and compared with that of Unprimed EVs in vivo. In vitro, the inhibitory effects of HCPT-EVs on fibroblast proliferation, viability, and myofibroblast differentiation upon TGF-β1 stimulation were compared with the effects of Unprimed EVs. For mechanistic analysis, the expression of endoplasmic reticulum stress (ERS)-associated proteins was examined among the effector cargos of HCPT-EVs and Unprimed EVs. The ERS antagonist salubrinal was used to determine the ERS dependence of the anti-adhesion effects of HCPT-EVs. Results There were no obvious differences between Unprimed EVs and HCPT-EVs in terms of morphology, particle size, characteristic protein expression, and cellular uptake. HCPT-EVs exhibited a fortified anti-adhesion effect after Achilles tendon injury compared with Unprimed EVs. Fibroblast proliferation and viability and myofibroblast differentiation were all inhibited by HCPT-EVs. These properties were superior for HCPT-EVs relative to Unprimed EVs. Mechanistically, HCPT-EVs contained more ERS-associated protein than Unprimed EVs and activated the ERS pathway in fibroblast to counteract myofibroblast differentiation. Conclusion This study demonstrates that HCPT-EVs show high anti-adhesion potential for the treatment of tendon injury by provoking ERS in fibroblasts. HCPT-EVs represent a promising strategy for clinical use in treating adhesion-related diseases.

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Formulation of injectable glycyrrhizic acid-hydroxycamptothecin micelles as new generation of DNA topoisomerase I inhibitor for enhanced antitumor activity

Cited by 26 publications

References 59 publications

4-Hydroxyderricin Promotes Apoptosis and Cell Cycle Arrest through Regulating PI3K/AKT/mTOR Pathway in Hepatocellular Cells

4-Hydroxyderricin Promotes Apoptosis and Cell Cycle Arrest through Regulating PI3K/AKT/mTOR Pathway in Hepatocellular Cells

A Novel Berberine–Glycyrrhizic Acid Complex Formulation Enhanced the Prevention Effect to Doxorubicin-Induced Cardiotoxicity by Pharmacokinetic Modulation of Berberine in Rats

Extracellular vesicles from hydroxycamptothecin primed umbilical cord stem cells enhance anti-adhesion potential for treatment of tendon injury

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