Preparation, characterization, and in vitro/vivo studies of oleanolic acid-loaded lactoferrin nanoparticles

Abstract

Oleanolic acid (OA), a pentacyclic triterpene, is used to safely and economically treat hepatopathy. However, OA, a Biopharmaceutics Classification System IV category drug, has low bioavailability owing to low solubility (<1 μg/mL) and biomembrane permeability. We developed a novel OA nanoparticle (OA-NP)-loaded lactoferrin (Lf) nanodelivery system with enhanced in vitro OA dissolution and improved oral absorption and bioavailability. The OA-NPs were prepared using NP albumin-bound technology and characterized using dynamic light scattering, scanning electron microscopy, X-ray powder diffraction, differential scanning calorimetry, and in vitro dissolution test. The in vivo pharmacokinetics was investigated in Sprague Dawley rats using liquid chromatography-tandem mass spectrometry. OA-NPs (OA:Lf =1:6, w/w%) exhibited spherical morphology, 202.2±8.3 nm particle size, +(27.1±0.32) mV ζ potential, 92.59%±3.24% encapsulation efficiency, and desirable in vitro release profiles. An effective in vivo bioavailability (340.59%) was achieved compared to the free drug following oral administration to rats. The Lf novel nanodelivery vehicle enhanced the dissolution rate, intestinal absorption, and bioavailability of OA. These results demonstrate that Lf NPs are a new strategy for improving oral absorption and bioavailability of poorly soluble and poorly absorbed drugs.

Lactoferrin, a unique molecule with diverse therapeutical and nanotechnological applications

“…An emulsion is formed by homogenization and sonication, then final formulation could be obtained by removing remaining organic solvent [ 75 ]. Preparation of optimized drug-loaded protein nanoparticles by this method was found to be greatly dependent on the ratio between the drug and the utilized protein, pH of the preparation, power and duration of homogenization [ 79 ]. Regarding thermal denaturation method, it starts with a heating step at 70–80 °C for 15–20 min in an oil bath to denature the protein, followed by dropwise addition of drug solution and finally leaving this mixture to cool under continuous stirring at room temperature to allow formation of drug-loaded LF nanoparticles [ 87 , 94 ].…”

“…Furthermore, oral administration of GA-loaded nanoparticles resulted in enhanced anti-tumor effect in S180 tumor-bearing mice in comparison to intravenous injection of arginine-conjugated GA, which indicates that LF nanoparticles could increase the oral absorption of hydrophobic drugs, while minimizing the toxicities associated with their intravenous injection [ 78 ]. Similarly, LF nanoparticles encapsulating oleanolic acid (OA) were prepared by NAB technology [ 79 ]. OA is a pentacyclic triterpenoid which is abundant in the plant kingdom [ 80 ].…”

“…In addition, interaction between LF and OA was found to cause a decrease in the surface tension of the drug, which resulted in the production of nanoparticles with good wettability associated with improved drug aqueous solubility. Oral administration of OA-loaded LF nanoparticles in Sprague Dawley rats resulted in significant enhancement in the bioavailability and pharmacokinetic profile of OA in comparison to its free form, which might be attributed to increased intestinal absorption and cellular uptake of prepared LF nanoparticles ( Table 2 ) [ 79 ].…”

“… [ 78 ] Oleanolic acid Oral Improved pharmacokinetic profile and intestinal absorption resulted in enhanced bioavailability in Sprague Dawley rats. [ 79 ] …”

Lactoferrin, a multi-functional glycoprotein: Active therapeutic, drug nanocarrier & targeting ligand

“… [ 104 ] Lf NPs Nab technology Oleanolic acid Improved bioavailability Increased dissolution and enhanced oral absorption of OA. [ 105 ] Lf-Drug conjugate Carbodiimide coupling CUR Colorectal cancer Lower IC 50 of NPs (0.5 μg/ml) against HCT116 cells than free curcumin (3.3 μg/ml) after 48 h. [ 112 ] Lf-Drug conjugate Carbodiimide coupling DOX Prostate cancer Orally Fe-bLf-DOX inhibited tumor growth, prolonged survival, reduced DOX toxicity. [ 77 ] Lf-Drug conjugate Free-radical graft copolymerization EGCG CA Gallic acid Antioxidant Higher antioxidant activity of Lf-polyphenol conjugates than control Lf in both ABTS scavenging and reducing power assays.…”