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.
Highlights
According to a World Health Organization report, lung cancer (1.76 million deaths) is the leading cause of cancer mortality in humans [1], beating out colorectal (862,000 deaths), stomach (783,000 deaths), liver (782,000 deaths), and breast (627,000 deaths) cancer
Polyethylene glycol (PEG) is a water-soluble, nontoxic polymer that has been approved by the Food and Drug Administration (FDA) as “Generally Regarded as Safe (GRAS)”, and it is used in targeted delivery [10,11,12]
We found that polyethylene glycol (PEG)-Rh1 exhibited high cytotoxicity ginsenosides Rh1 and Rh2 were purchased from the Lab of Hanbangbio, Kyung Hee University, compared to Rh1 at 100 μM (Figure 5C)
Summary
According to a World Health Organization report (https://www.who.int/news-room/fact-sheets/detail/cancer), lung cancer (1.76 million deaths) is the leading cause of cancer mortality in humans [1], beating out colorectal (862,000 deaths), stomach (783,000 deaths), liver (782,000 deaths), and breast (627,000 deaths) cancer. Pitfalls exist in the physiochemical properties of cancer drugs, including poor aqueous solubility, a short half-life in the body, low bioavailability, and target-specific cytotoxicity in the cancer microenvironment [3,4] These factors lead to poor antitumor effects, systemic toxicity, and other side effects in patients and reduce the quality of life and clinical applications. To surmount these issues, numerous water-soluble polymers with good biocompatible and biodegradable properties have been applied as carriers for the delivery of these anticancer drugs, and they have exhibited various advantages [5,6,7,8,9]. PEG has been reported to improve the solubility of drugs [14], increase the circulation time of drugs in the bloodstream by preventing them from reticuloendothelial clearance, enhance accumulation in tumor tissues through an enhanced permeation and retention (EPR) effect, induce a stimuli-responsive release of the conjugated drugs into the tumor microenvironment by reducing the cytotoxicity in the normal tissues, improve the half-life of drugs in the body compared to free drugs, and prevent the degradation of drugs by intestinal enzymes [13,15,16,17,18,19,20,21,22,23]
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