Preparation of Polyethylene Glycol-Ginsenoside Rh1 and Rh2 Conjugates and Their Efficacy against Lung Cancer and Inflammation

Abstract

Low solubility and tumor-targeted delivery of ginsenosides to avoid off-target cytotoxicity are challenges for clinical trials. In the present study, we report on a methodology for the synthesis of polyethylene glycol (PEG)-ginsenoside conjugates through a hydrolysable ester bond using the hydrophilic polymer polyethylene glycol with the hydrophobic ginsenosides Rh1 and Rh2 to enhance water solubility and passive targeted delivery. The resulting conjugates were characterized by 1H nuclear magnetic resonance (1H NMR) and Fourier-transform infrared spectroscopy (FT-IR). 1H NMR revealed that the C-6 and C-3 sugar hydroxyl groups of Rh1 and Rh2 were esterified. The conjugates showed spherical shapes that were monitored by field-emission transmission electron microscopy (FE-TEM), and the average sizes of the particles were 62 ± 5.72 nm and 134 ± 8.75 nm for PEG-Rh1and PEG-Rh2, respectively (measured using a particle size analyzer). Owing to the hydrophilic enhancing properties of PEG, PEG-Rh1 and PEG-Rh2 solubility was greatly enhanced compared to Rh1 and Rh2 alone. The release rates of Rh1 and Rh2 were increased in lower pH conditions (pH 5.0), that for pathophysiological sites as well as for intracellular endosomes and lysosomes, compared to normal-cell pH conditions (pH 7.4). In vitro cytotoxicity assays showed that the PEG-Rh1conjugates had greater anticancer activity in a human non-small cell lung cancer cell line (A549) compared to Rh1 alone, whereas PEG-Rh2 showed lower cytotoxicity in lung cancer cells. On the other hand, both PEG-Rh1 and PEG-Rh2 showed non-cytotoxicity in a nondiseased murine macrophage cell line (RAW 264.7) compared to free Rh1 and Rh2, but PEG-Rh2 exhibited increased efficacy against inflammation by greatly inhibiting nitric oxide production. Thus, the overall conclusion of our study is that PEG conjugation promotes the properties of Rh1 for anticancer and Rh2 for inflammation treatments. Depends on the disease models, they could be potential drug candidates for further studies.

A rechargeable drug delivery system based on pNIPAM hydrogel for the local release of curcumin

“…As an example, it can prevent drug digestion in the wound area with acidic pH or inside organs with basic pH such as the intestine. 53 The curcumin water solubility has been previously reported as 0.6 μg/ml, 54 and the solubility in PBS is showed 9 μg/ml in the current study. The cumulative amount released of curcumin from Cur/PEG-10/pNIPAM in our study was 24.275 ± 1.262 μg/ml during the first hour while it continued to the maximum cumulative amount released of 33.163 ± 0.319 μg/ml by 1 week.…”

Ginsenoside Rh1 Induces MCF-7 Cell Apoptosis and Autophagic Cell Death through ROS-Mediated Akt Signaling

“…For instance, the IC 50 value of Rh1 in P388 cells was 37 µM [ 31 ]. Meanwhile, Rh1 inhibited approximately 30% of the cell viability of A549 cells at 100 µM [ 23 ] and suppressed approximately 25% of the cell viability of HeLa cells at 40 µM [ 32 ]. However, whether this compound can inhibit BC has not yet been reported.…”

“…Among them, ginsenoside Rh1 (Rh1) has been identified as a protopanaxatriol-type ginsenoside, which possesses anticancer activities in several cancer cell lines, such as human lung carcinoma, human cervix uterine adenocarcinoma, colorectal cancer cells, and malignant glioma cells [ 19 , 21 , 22 ]. Rh1 has been found to significantly induce cytotoxicity in human lung cancer cells from 100 µM [ 23 ], inhibit colorectal cancer cell proliferation from 50 µM [ 21 ], and suppress malignant glioma cell invasion at 300 µM [ 22 ]. However, the anticancer effect of Rh1 on BC cells and the underlying mechanisms remain to be elucidated.…”

(20S)G-Rh2 Inhibits NF-κB Regulated Epithelial-Mesenchymal Transition by Targeting Annexin A2

“…(20S)G-Rh2 has been proven efficiently inducing growth arrest and apoptosis [44][45][46][47]. Moreover, in-vivo study indicates that (20S)G-Rh2 inhibits tumor growth by inhibiting tumor associated angiogenesis and enhancing anti-tumor immunological response [48][49][50].…”

“…(20S)G-Rh2 failed to interact with Anxa2-K301A ( Figure 5A); p50-Anxa2-K301A interaction and NF-κB activation were surprisingly enhanced under (20S)G-Rh2 treatment (Figure 5B,C). Functioning as a multi-targeted chemical, (20S)G-Rh2 induced various cellular stress and NF-κB stayed inactive under the targeted inhibition [28,[44][45][46][47][48][49][50]. This status was reversed when Anxa2 mutant maintained the activation property regardless of (20S)G-Rh2 and stress related NF-κB activation was generated.…”