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Stealth, biocompatible monoolein-based lyotropic liquid crystalline nanoparticles for enhanced aloe-emodin delivery to breast cancer cells: in vitro and in vivo studies

View Article: PubMed Central - PubMed

ABSTRACT

Recently, research has progressively highlighted on clues from conventional use of herbal medicines to introduce new anticancer drugs. Aloe-emodin (AE) is a herbal drug with promising anticancer activity. Nevertheless, its clinical utility is handicapped by its low solubility. For the first time, this study aims to the fabrication of surface-functionalized polyethylene glycol liquid crystalline nanoparticles (PEG-LCNPs) of AE to enhance its water solubility and enable its anticancer use. Developed AE-PEG-LCNPs were optimized via particle size and zeta potential measurements. Phase behavior, solid state characteristics, hemocompatibility, and serum stability of LCNPs were assessed. Sterile formulations were developed using various sterilization technologies. Furthermore, the potential of the formulations was investigated using cell culture, pharmacokinetics, biodistribution, and toxicity studies. AE-PEG-LCNPs showed particle size of 190 nm and zeta potential of −49.9, and PEGylation approach reduced the monoolein hemolytic tendency to 3% and increased the serum stability of the nanoparticles. Sterilization of liquid and lyophilized AE-PEG-LCNPs via autoclaving and γ-radiations, respectively, insignificantly affected the physicochemical properties of the nanoparticles. Half maximal inhibitory concentration of AE-PEG-LCNPs was 3.6-fold lower than free AE after 48 hours and their cellular uptake was threefold higher than free AE after 24-hour incubation. AE-PEG-LCNPs presented 5.4-fold increase in t1/2 compared with free AE. Biodistribution and toxicity studies showed reduced AE-PEG-LCNP uptake by reticuloendothelial system organs and good safety profile. PEGylated LCNPs could serve as a promising nanocarrier for efficient delivery of AE to cancerous cells.

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(A) Plasma concentration of free AE, AE-LCNPs (F6), and AE-PEG-LCNPs (F13) following IP administration of a single dose of 7.5 mg/kg in healthy rats (mean ± SD, n=6), P<0.05. (B) Mean organ levels of free AE, AE-LCNPs, and AE-PEG LCNPs at 1 hour after IP administration of a single dose of 7.5 mg/kg in healthy rats. Each point represents mean ± SD, n=6, P<0.05.Abbreviations: AE, aloe-emodin; IP, intraperitoneal; LCNPs, liquid crystalline nanoparticles; PEG, polyethylene glycol; SD, standard deviation.
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f7-ijn-11-4799: (A) Plasma concentration of free AE, AE-LCNPs (F6), and AE-PEG-LCNPs (F13) following IP administration of a single dose of 7.5 mg/kg in healthy rats (mean ± SD, n=6), P<0.05. (B) Mean organ levels of free AE, AE-LCNPs, and AE-PEG LCNPs at 1 hour after IP administration of a single dose of 7.5 mg/kg in healthy rats. Each point represents mean ± SD, n=6, P<0.05.Abbreviations: AE, aloe-emodin; IP, intraperitoneal; LCNPs, liquid crystalline nanoparticles; PEG, polyethylene glycol; SD, standard deviation.

Mentions: Pharmacokinetic and tissue biodistribution studies were carried out to investigate the effect of naked LCNPs and PEGylated one on the in vivo behavior of AE in rats. AE formulations were administered intraperitoneally at a dose of 7.5 mg/kg. Non-compartmental model was selected for pharmacokinetic analysis due to its simplicity. All pharmacokinetic parameters are calculated and listed in Table 5. As shown in Figure 7A, after IP administration of free AE, plasma concentration increased rapidly to reach maximum concentration (Cmax) of 1.24±0.54 µg/mL, then declined rapidly within 30 minutes with mean residence time of 40 minutes. It was clearly observed that both LCNP dispersion and its PEGylated form significantly enhanced the bioavailability of AE in plasma evidenced by 2.1- and 5.4-fold higher AUC0→∞ compared with free AE. Notably, AE was still detectable in plasma until 8 hours in contrast to free AE and non-PEGylated AE-LCNPs that were quickly removed from the blood circulation after administration and cannot be detected after 1 hour. Clearly, the AE-PEG-LCNPs showed marked delay in blood CL with (t1/2) 6.7-fold increase compared with non-PEGylated LCNPs. The mean CL value of free AE was 2.2- and 5.5-fold greater than AE-LCNPs and AE-PEG-LCNPs, respectively. The increased AUC and half-life of AE-PEG-LCNPs confirmed the stealth properties imparted by PEG chains that prevent RES capture of the nanoparticles and delay their CL.


Stealth, biocompatible monoolein-based lyotropic liquid crystalline nanoparticles for enhanced aloe-emodin delivery to breast cancer cells: in vitro and in vivo studies
(A) Plasma concentration of free AE, AE-LCNPs (F6), and AE-PEG-LCNPs (F13) following IP administration of a single dose of 7.5 mg/kg in healthy rats (mean ± SD, n=6), P<0.05. (B) Mean organ levels of free AE, AE-LCNPs, and AE-PEG LCNPs at 1 hour after IP administration of a single dose of 7.5 mg/kg in healthy rats. Each point represents mean ± SD, n=6, P<0.05.Abbreviations: AE, aloe-emodin; IP, intraperitoneal; LCNPs, liquid crystalline nanoparticles; PEG, polyethylene glycol; SD, standard deviation.
© Copyright Policy
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC5036603&req=5

f7-ijn-11-4799: (A) Plasma concentration of free AE, AE-LCNPs (F6), and AE-PEG-LCNPs (F13) following IP administration of a single dose of 7.5 mg/kg in healthy rats (mean ± SD, n=6), P<0.05. (B) Mean organ levels of free AE, AE-LCNPs, and AE-PEG LCNPs at 1 hour after IP administration of a single dose of 7.5 mg/kg in healthy rats. Each point represents mean ± SD, n=6, P<0.05.Abbreviations: AE, aloe-emodin; IP, intraperitoneal; LCNPs, liquid crystalline nanoparticles; PEG, polyethylene glycol; SD, standard deviation.
Mentions: Pharmacokinetic and tissue biodistribution studies were carried out to investigate the effect of naked LCNPs and PEGylated one on the in vivo behavior of AE in rats. AE formulations were administered intraperitoneally at a dose of 7.5 mg/kg. Non-compartmental model was selected for pharmacokinetic analysis due to its simplicity. All pharmacokinetic parameters are calculated and listed in Table 5. As shown in Figure 7A, after IP administration of free AE, plasma concentration increased rapidly to reach maximum concentration (Cmax) of 1.24±0.54 µg/mL, then declined rapidly within 30 minutes with mean residence time of 40 minutes. It was clearly observed that both LCNP dispersion and its PEGylated form significantly enhanced the bioavailability of AE in plasma evidenced by 2.1- and 5.4-fold higher AUC0→∞ compared with free AE. Notably, AE was still detectable in plasma until 8 hours in contrast to free AE and non-PEGylated AE-LCNPs that were quickly removed from the blood circulation after administration and cannot be detected after 1 hour. Clearly, the AE-PEG-LCNPs showed marked delay in blood CL with (t1/2) 6.7-fold increase compared with non-PEGylated LCNPs. The mean CL value of free AE was 2.2- and 5.5-fold greater than AE-LCNPs and AE-PEG-LCNPs, respectively. The increased AUC and half-life of AE-PEG-LCNPs confirmed the stealth properties imparted by PEG chains that prevent RES capture of the nanoparticles and delay their CL.

View Article: PubMed Central - PubMed

ABSTRACT

Recently, research has progressively highlighted on clues from conventional use of herbal medicines to introduce new anticancer drugs. Aloe-emodin (AE) is a herbal drug with promising anticancer activity. Nevertheless, its clinical utility is handicapped by its low solubility. For the first time, this study aims to the fabrication of surface-functionalized polyethylene glycol liquid crystalline nanoparticles (PEG-LCNPs) of AE to enhance its water solubility and enable its anticancer use. Developed AE-PEG-LCNPs were optimized via particle size and zeta potential measurements. Phase behavior, solid state characteristics, hemocompatibility, and serum stability of LCNPs were assessed. Sterile formulations were developed using various sterilization technologies. Furthermore, the potential of the formulations was investigated using cell culture, pharmacokinetics, biodistribution, and toxicity studies. AE-PEG-LCNPs showed particle size of 190 nm and zeta potential of &minus;49.9, and PEGylation approach reduced the monoolein hemolytic tendency to 3% and increased the serum stability of the nanoparticles. Sterilization of liquid and lyophilized AE-PEG-LCNPs via autoclaving and &gamma;-radiations, respectively, insignificantly affected the physicochemical properties of the nanoparticles. Half maximal inhibitory concentration of AE-PEG-LCNPs was 3.6-fold lower than free AE after 48 hours and their cellular uptake was threefold higher than free AE after 24-hour incubation. AE-PEG-LCNPs presented 5.4-fold increase in t1/2 compared with free AE. Biodistribution and toxicity studies showed reduced AE-PEG-LCNP uptake by reticuloendothelial system organs and good safety profile. PEGylated LCNPs could serve as a promising nanocarrier for efficient delivery of AE to cancerous cells.

No MeSH data available.


Related in: MedlinePlus