Preparation, Characterization, and In Vitro/In Vivo Evaluation of 3-O-ß-D-Galactosylated Resveratrol-Loaded Polydopamine Nanoparticles.

3-O-ß-D-galactosylated resveratrol (Gal-Res) was synthesized from resveratrol (Res) and 3-O-ß-D-galactose (Gal) in our previous study. In order to improve the pH sensitivity and bioavailability of Gal-Res, Gal-Res nanoparticles (Gal-Res NPs) were prepared using polydopamine (PDA) as a drug carrier. The drug loading (DL %) and entrapment efficiency (EE %) of Gal-Res NPs were 46.80% and 88.06%. The average particle size, polydispersity index (PDI), and Zeta potential of Gal-Res NPs were 179.38 ± 2.83 nm, 0.129 ± 0.013, and - 28.05 ± 0.36 mV, respectively. The transmission electron microscope (TEM) showed that Gal-Res NPs had uniform spherical morphology. Compared with the fast release of raw Gal-Res, the in vitro release of Gal-Res NPs was slow and pH-sensitive. The results of the blood vessel irritation and hemolysis test demonstrated that Gal-Res NPs had good hemocompatibility. The pharmacokinetics study in rats showed that area under the curve of plasma drug concentration time (AUC0→600) and half-life (t1/2) of Gal-Res NPs were enhanced 1.82-fold and 2.19-fold higher than those of raw Gal-Res. The in vivo biodistribution results showed that Gal-Res NPs were more distributed in liver tissue than Gal-Res. Gal-Res NPs with high bioavailability and liver accumulation were hopeful drug delivery systems (DDS) to treat liver diseases.

Oral Delivery of Gambogenic Acid by Functional Polydopamine Nanoparticles for Targeted Tumor Therapy.

To enhance the water solubility, oral bioavailability, and tumor targeting of gambogenic acid (GNA), polydopamine nanoparticles (PDA NPs) were prepared to encapsulate and stabilize GNA surface modified by folic acid (FA) and then coated with sodium alginate (GNA@PDA-FA SA NPs) to achieve an antitumor effect by oral administration. GNA@PDA-FA SA NPs exhibited in vitro pH-sensitive release behavior. In vitro cell studies manifested that GNA@PDA-FA NPs had higher cytotoxicity to 4T1 cells compared with raw GNA (IC50 = 2.58 µM vs 7.57 µM). After being modified with FA, GNA@PDA-FA NPs were taken up easily by 4T1 cells. In vivo studies demonstrated that the area under the curve (AUC0→∞) of the plasma drug concentration-time of GNA@PDA-FA SA NPs was 2.97-fold higher than that of raw GNA, along with improving drug distribution in the liver, lung, and kidney tissues. In vivo anti-tumor experiments, GNA@PDA-FA SA NPs significantly inhibited the growth of breast tumors in the 4T1 xenograft breast cancer model via oral administration without obvious toxicity on major organs. Our studies indicated that the GNA@PDA-FA SA NPs modified with FA and coated with SA were a promising drug delivery system for targeting tumor therapy via oral administration.

In vitro/in vivo evaluation of pH-sensitive Gambogenic acid loaded Zein nanoparticles with polydopamine coating.

As one of the active pharmaceutical ingredients in Gamboge, Gambogenic acid (GNA) has shown diverse anti-tumor activities. To reduce the vascular irritation of GNA and improve its water solubility, tumor targeting, and bioavailability, GNA loaded Zein nanoparticles (GNA@Zein NPs) was further coated by polydopamine (PDA) to develop GNA@Zein-PDA NPs by anti-solvent precipitation and surface modification. The results showed that particle size and Zeta potential of GNA@Zein-PDA NPs were about 310 nm and -40.8 mV with core-shell morphology confirmed by TEM. GNA@Zein-PDA NPs increased the water solubility of GNA by more than 700 times and showed pH-sensitive release behavior in PBS with pH 6.86. In vitro cytotoxicity tests showed that GNA@Zein-PDA NPs had higher inhibitory activity on HepG2 cells than free GNA, and their IC50 were 1.59 µg/mL and 9.89 µg/mL, respectively. Additionally, the hemolysis and vascular irritation assay showed that GNA@Zein-PDA NPs had good cytocompatibility and reduced the irritation of GNA to blood vessels. Moreover, the in vivo pharmacokinetic experiments exhibited that the Cmax and AUC0-t of GNA@Zein-PDA NPs were significantly improved approximately by 2.09-fold and 3.48-fold over that of GNA, respectively. In conclusion, GNA@Zein-PDA NPs solve many defects of GNA and provide a tumor-targeting drug delivery for GNA.

Preparation, characterization and preliminary pharmacokinetic study of pH-sensitive Hydroxyapatite/Zein nano-drug delivery system for doxorubicin hydrochloride.

OBJECTIVES: Zein nanoparticles (Zein NPs) were used as a hydroxyapatite (HA) biomineralization template to generate HA/Zein NPs. Doxorubicin hydrochloride (DOX) was loaded on HA/Zein NPs (HA/Zein-DOX NPs) to improve its pH-sensitive release, bioavailability and decrease cardiotoxicity. METHODS: HA/Zein-DOX NPs were prepared by phase separation and biomimetic mineralization method. Particle size, polydispersity index (PDI), Zeta potential, transmission electron microscope, X-ray diffraction and Fourier-transform infrared spectroscopy of HA/Zein-DOX NPs were characterized. The nanoparticles were then evaluated in vitro and in vivo. KEY FINDINGS: The small PDI and high Zeta potential demonstrated that HA/Zein-DOX NPs were a stable and homogeneous dispersed system and that HA was mineralized on Zein-DOX NPs. HA/Zein-DOX NPs showed pH-sensitive release. Compared with free DOX, HA/Zein-DOX NPs increased cellular uptake which caused 7 times higher in-vitro cytotoxicity in 4T1 cells. Pharmacokinetic experiments indicated the t1/2ß and AUC0- t of HA/Zein-DOX NPs were 2.73- and 3.12-fold higher than those of DOX solution, respectively. Tissue distribution exhibited HA/Zein-DOX NPs reduced heart toxicity with lower heart targeting efficiency (18.58%) than that of DOX solution (37.62%). CONCLUSION: In this study, HA/Zein-DOX NPs represented an antitumour drug delivery system for DOX in clinical tumour therapy with improved bioavailability and decreased cardiotoxicity.

Preparation, preliminary pharmacokinetics and brain tissue distribution of Tanshinone IIA and Tetramethylpyrazine composite nanoemulsions.

Objective: Tanshinone IIA (TSN) and Tetramethylpyrazine (TMP) were combined in a composite, oil-in-water nanoemulsions (TSN/TMP O/W NEs) was prepared to prolong in vitro and vivo circulation time, and enhance the bioavailability of TSN. Material and methods: Physicochemical characterization of TSN/TMP O/W NEs was characterized systematically. The in vitro dissolution and in vivo pharmacokinetic experiments of TSN/TMP O/W NEs were also evaluated. Result: A formulation was optimized, yielding a 32.5 nm average particle size, an encapsulation efficiency of over 95 %, and were spherical in shape as shown by TEM. TSN/TMP O/W NEs were shown to extend the release and availability in vitro compared to raw compounds. In pharmacokinetic study, the AUC0→∞ and t1/2 of the TSN/TMP O/W NEs were 481.50 mg/L*min and 346.39 min higher than TSN solution, respectively. Brain tissue concentration of TSN was enhanced with TSN/TMP O/W NEs over raw TSN and even TSN O/W NEs. Conclusions: Therefore, nanoemulsions are an effective carrier to increase encapsulation efficiency of drugs, improve bioavailability and brain penetration for TSN - which is further enhanced by pairing with the co-delivery of TMP, providing a promising drug delivery.

Self-assembled micelles based on gambogenic acid-phospholipid complex for sustained-release drug delivery.

Objective: To improve the water solubility and enhance the oral bioavailability of gambogenic acid (GNA). Methods: GNA-phospholipid complex (GNA-PLC) micelles were successfully prepared by anti-solvent method. Results: The encapsulation efficiency of GNA-PLC micelles can reach 99.33 % (w/w). The average particle size of the GNA-PLC micelles was 291.23 nm which was approximate agreed with the transmission electron microscopy (TEM). In vitro release profile showed the GNA-PLC and GNA-PLC micelles have significant sustained-release of GNA compared with crude GNA. Pharmacokinetic parameters indicated that the area under concentration-time curve (AUC0→t) of GNA in cases of GNA-PLC and GNA-PLC micelles are 2.04- and 3.92-fold higher than crude GNA, respectively. Conclusions: The better water solubility and higher bioavailability of GNA in GNA-PLC micelles with significant sustained-release of GNA endow the nanoparticle with great potential in GNA delivery system.

Preparation and preliminary pharmacokinetics study of GNA-loaded zein nanoparticles.

OBJECTIVES: Gambogenic acid (GNA), one of the main active ingredients isolated from Garcinia cambogia, has shown diverse antitumour activities. However, short biological half-life and low oral bioavailability severely limit its clinical application. Here, we developed GNA-loaded zein nanoparticles (GNA-ZN-NPs) based on phospholipid complex and zein nanoparticles to prolong the circulation time and enhance oral bioavailability of GNA. METHODS: The physicochemical properties of GNA-ZN-NP were characterized in details. The in vitro release profile, in vivo pharmacokinetic experiments and tissue distribution of GNA-ZN-NPs were also evaluated. KEY FINDINGS: The particle size, PDI and encapsulation efficiency of GNA-ZN-NPs were 102.90 nm, 0.027 and 76.35 ± 0.64%, respectively. The results of SEM, FTIR, DSC and XRD demonstrated that GNA-ZN-NPs were prepared successfully. The in vitro dissolution of GNA-ZN-NPs exhibited controlled release compared with raw GNA solution. The pharmacokinetic study showed that the AUC of GNA-ZN-NPs was significantly increased, and the t1/2 and MRT values of GNA-ZN-NPs were 3.21-fold and 2.19-fold higher than that of GNA solution. Tissue distribution results illustrated that GNA-ZN-NPs showed hepatic-targeting properties. CONCLUSION: GNA-ZN-NPs significantly enhanced the oral bioavailability and prolonged half-life of GNA, providing a promising oral drug delivery system to improve in vivo pharmacokinetic behaviour of GNA.

Synthesis, cytotoxicity and liver targeting of 3-O-ß-D-Galactosylated Resveratrol.

OBJECTIVES: Resveratrol (Res), a naturally occurring polyphenol, has shown pharmacological activities in treatment of liver diseases. However, the application of Res was limited by its poor bioavailability and liver targeting. Herein, 3-O-ß-D-Galactosylated Resveratrol (Gal-Res) was synthesized by structural modification of Res to enhance bioavailability and liver targeting. METHODS: The Gal-Res was characterized by IR, 1 H-NMR spectra and MS. The in vitro antitumour experiments, in vivo pharmacokinetics and biodistribution studies were evaluated. RESULTS: Gal-Res was successfully synthesized in our study. Compared to Res, Gal-Res resulted in enhanced cytotoxicity in HepG2 cells. After intravenous injection of normal SD rats, Gal-Res significantly improved the bioavailability of Res and the Cmax and AUC0-t of Gal-Res were 3.186 and 3.929 time than that of Res. In addition, in the study of liver targeting, the relative uptake rate (Re ) of Gal-Res in the liver (2.006) is the largest. The drug targeting efficiency (Te ; 38.924%) of Gal-Res was greater than that of Res. These showed that Gal-Res could significantly improve the distribution ability of Res in liver. CONCLUSIONS: On the whole, Gal-Res increased cellular uptake to HepG2 cells, bioavailability and liver targeting, providing its future clinical application in the treatment of liver diseases.