Preparation of ginsenoside compound-K mixed micelles with improved retention and antitumor efficacy

Abstract

IntroductionGinsenoside compound K (CK) has effects on cell-cycle regulation, tumor growth inhibition, and apoptosis induction. However, it has limited applications in clinical settings because of its low solubility and poor absorption.MethodsTo overcome these limitations, we aimed to develop a mixed micellar system composed of phosphatidylcholine (PC) and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine polyethylene glycol 2000 (DSPE PEG 2000; DP). CK encapsulated in PC/DP mixed micelles had enhanced solubility, permeability, and retention effects.ResultsCompared to free CK, the CK PC/DP micellar system exhibited improved anticancer effects in vitro, including cell-cycle arrest, apoptosis, and anti-invasion in human lung carcinoma A549 cells. The significant proapoptotic effect was reflected by increased chromosomal condensation, annexin V/propidium iodide staining, and related protein expression. In vitro cellular uptake and optical mouse imaging in vivo suggested that the improved antitumor effect was caused primarily by enhanced uptake and tumor targeting. Furthermore, an in vivo antitumor efficacy study indicated that the CK mixed micelles significantly inhibited tumor growth, thereby decreasing tumor volume at the end of the experiment as compared with that in the control mice. Histological analysis confirmed the antitumor effect with low toxicity.ConclusionThe PC/DP micellar system was an effective drug delivery system for CK in tumor therapy.

Ginsenoside Compound K: Insights into Recent Studies on Pharmacokinetics and Health-Promoting Activities

“…Likewise, CK ascorbyl palmitate (AP)/TPGS micelles enhanced solubility of CK and significantly inhibited P-gp-mediated efflux [ 37 ]. Similarly, the micellar system based on phosphatidylcholine (PC) and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine polyethylene glycol 2000 (DP) showed improved solubility and continued release of CK [ 38 ]. The water solubility of the CK nanoparticles (NPs)/bovine serum albumin (BSA) and CK, was compared, and BSA was found to augment the water solubility of CK.…”

“… K/γ-CyD and K/β-CyD K/γ-CyD at different ratios 1:1 and 1:3 and K/β-CyD at 1:1 Improved solubility at lower concentrations (<0.03 M) compared to higher (<0.06 M) ↑bioavailability ↑dissolution rate compared to CK and K/β-CyD Higher dissolution rate in 1:1 ratio compared to 1:3 [ 21 ] GCKT-liposomes Phospholipid and TPGS (7:3 ratio) ↑High CK loading capacity and solubility GCK EE% was of above 98.4 ± 2.3% Sustained discharge of GCK from GCKT-liposomes compared to GCK solution (in PBS) [ 33 ] CK-M PEG-PCL/TPGS mixed micelles at different ratios of 3:0. 3:1, 3:2, 3:3 ↑drug EE% in CK-M (94.6 ± 1.4) than CK-P (62.5 ± 1.6; PEG-PCL micelles) ↑CK concentration (107.3-times) in micelles (CK-M) than free CK ↑solubility of CK with higher TPGS [ 36 ] CK-AP/TPGS micelles AP/TPGS mixed micelles ↑solubility from 35.2 ± 4.3 to 1,463.2 ± 153.3 µg/mL of CK EE% = 91.3 ± 5.2% Inhibited P-gp mediated efflux [ 37 ] CK PC/DP micellar system CK, DP, and PC at ratios of 5:12:18 ↑water solubility (~66-fold) and long drug retention time [ 38 ] BSA-CK NPs BSA ↑water solubility [ 39 ] DCY51T-AuCKNps AuNPs synthesized using Lactobacillus kimchicus Drug loading efficiency-11.03% [ 40 ] …”

“…Meanwhile, CK-M also displayed an improved tumor inhibitory effect in vivo [ 36 ]. The anti-lung cancer effects (in vitro and in vivo) of CK AP/TPGS mixed micelles [ 37 ] and CK PC/DP micellar system [ 38 ] have also been documented. Moreover, using in vitro models, BSA-CK NPs showed more significant cytotoxic effects in the liver carcinoma (HepG2), skin cell line (HaCaT), A549 cells, and colon cancer cell line (HT29) compared to monomer CK.…”

Pharmacokinetics and Intestinal Metabolism of Compound K in Rats and Mice

“…Moreover, the compound K plasma concentrations increased or maintained at 2-4 h after sharply decreasing in the 0-2 h period, and then showed a slow decrease over the 4-48 h time period in both rats and mice ( Figure 7A,B). This pattern could be attributable to the continuous reabsorption of compound K. The lipophilicity (LogP value 3.85 for compound K; 5.53 for PPD) and moderate permeability (0.5-2 × 10 −6 cm/s for compound K; 1.15 × 10 −6 cm/s for PPD) of compound K and PPD in Caco-2 cells also support the possibility of compound K and PPD reabsorption [3,7,14,15].…”

“…Collectively, the proposed enterohepatic circulation of compound K and PPD ( Figure 10) could explain how compound K shows efficacy in vivo despite its fast and exclusive biliary excretion. The distribution of compound K into the liver could be a possible link to the hepatoprotective effect of compound K. However, the therapeutic use of compound K in other tissues and the oral administration of compound K and PPD may be limited because of poor aqueous solubility (33 µg/mL for compound K; <50 ng/mL for PPD) and P-gp-mediated efflux [4,14,15]. The use of nanocrystals for PPD formulation improved oral bioavailability and brain delivery [15].…”