Zhidong Liu

Design and evaluation of baicalin-containing in situ pH-triggered gelling system for sustained ophthalmic drug delivery

Baicalin has been reported to have anti-inflammatory and anti-cataract effects on eye tissues, but it has a low bioavailability partly due to its poor stability of baicalin, the special anatomic structure and efficient protective mechanism of eyes. The aim of this study was to investigate the correlation between the stability of baicalin and in situ pH-triggered gelling system. Carbopol(®) 974P (0.3%, w/v) was used as the gelling agent combined with hydroxypropylmethylcellulose E4M (0.6%, w/v) which acted as a viscosity enhancing agent. In vitro and in vivo evaluations were performed using several techniques, namely confocal scanning light microscopy analysis, rheometry, Gamma scintigraphic technique and microdialysis method. The rheological behavior showed a significant enhancement in gel strength under physiological conditions, and the formulation provided sustained release of the drug over an 8-h period. In elimination studies, the radioactivity of formulation was always higher than that of the control solution. Additionally, the AUC and C(max) values were 6.1-fold and 3.6-fold higher than those of the control solution, respectively. The results demonstrated that an in situ pH-triggered gelling system have better ability to keep baicalin stable and retain drug release than marketed baicalin eye drops to enhance the ocular bioavailability.

Effect of Baicalin-loaded PEGylated cationic solid lipid nanoparticles modified by OX26 antibody on regulating the levels of baicalin and amino acids during cerebral ischemia–reperfusion in rats

Baicalin has many pharmacological activities, including neuroprotective function against ischemia and neurodegeneration. In our previous study, we found that Baicalin-loaded PEGylated cationic solid lipid nanoparticles modified by OX26 antibody (OX26-PEG-CSLN) might be a promising carrier to deliver drugs across the blood-brain barrier for the treatment of brain diseases. So, the aim of this present study was to further elucidate the mechanisms of OX26-PEG-CSLN cerebral ischemia protection by monitoring the changes of extracellular amino acids. In addition, we investigated the effect of OX26-PEG-CSLN on the excitotoxic neuronal injury as well as the pharmacokinetic profiles of baicalin in cerebrospinal fluid during ischemia-reperfusion period. The cerebrospinal fluid was collected by a microdialysis technique and divided into two parts - one part for pharmacokinetic study of baicalin using LC-MS/MS method and the other for pharmacodynamic study which was done by pre- column derivatization of the amino acids and analysis using a high-performance liquid chromatography with fluorescence detector (HPLC-FLD). The pharmacokinetic study showed that the AUC value of OX26-PEG-CSLN was 5.69-fold higher than that of the baicalin solution (Sol) (P<0.05) and the Cmax value of OX26-PEG-CSLN was 6.84-fold higher than that of the Sol (P<0.05). Moreover, the extracellular levels of glutamate (Glu), aspartic acid (Asp), glycine (Gly), taurine (Tau) and γ-aminobutyric acid (GABA) were measured for monitoring the imbalance of amino acids caused by ischemia and reperfusion. The excitotoxic index (EI) was also calculated for evaluating the imbalance between excitatory amino acid and inhibitory amino acid. The pharmacodynamic study showed that OX26-PEG-CSLN had stronger effect than Sol in reducing the content of aspartic, glutamic acid and increasing the concentrations of glycine, taurine and γ-aminobutyric acid during ischemia-reperfusion period. In conclusion, OX26-PEG-CSLN improved uptake of baicalin across the BBB into the brain, and elevated bioavailability of baicalin in cerebral spinal fluid of rats under the cerebral ischemia-reperfusion injury. OX26-PEG-CSLN had much higher protection effect against cerebral ischemia injury than Sol by relieving the excitotoxic neuronal injury via regulating amino acid levels in cerebral spinal fluid.

Comparison of systemic absorption between ofloxacin ophthalmic in situ gels and ofloxacin conventional ophthalmic solutions administration to rabbit eyes by HPLC–MS/MS

In recent years, many pharmaceutical scientists have focused on developing the in situ gel-forming systems to overcome the poor bioavailability and therapeutic response exhibited by conventional ophthalmic solutions due to rapid pre-corneal elimination of the drug. The present work was to compare the systemic absorptions of ophthalmic ofloxacin in situ gel with the conventional ofloxacin eye drop after topical instillation to rabbit eyes by HPLC-MS/MS method and also determine the relative contribution of the nasal and the conjunctival mucosae to systemic ofloxacin absorption following topical instillation. The systemic AUC, Cmax, Tmax and Ke for ophthalmic in situ gel and ophthalmic solution after ocular instillation were 202.63±118.85 and 202.25±57.74 ng mL(-1) h, 54.22±28.31 and 48.4±25.97 ng mL(-1), 1.08±0.20 and 1.25±0.88 h, 0.0576±0.0207 and 0.0388±0.0248, respectively. And the values for the ratios of the AUC of anterior chamber of rabbit eye to blood plasma, AUCac/AUCpl, for ofloxacin conventional eye drop and in situ gel were 0.25 and 0.52, respectively. Statistic results showed that there was no significant difference in systemic absorption between the test groups and the reference groups (P>0.05) as both formulations have an AUCsa/AUCpl of 0.35. Therefore, the ophthalmic in situ gel may not decrease the drugs systemic absorption when administered in an equivalent dose as ophthalmic solutions into the rabbit eyes.

Salvianolic acid B protects against myocardial damage caused by nanocarrier TiO 2 ; and synergistic anti-breast carcinoma effect with curcumin via codelivery system of folic acid-targeted and polyethylene glycol-modified TiO 2 nanoparticles

Targeted delivery by the folate ligand is an effective way to enhance an anti-breast carcinoma effect, due to its high affinity for the folate receptor, which is overexpressed in many tumor cells. In this study, we firstly synthesized a folic acid (FA)-targeted and polyethylene glycol (PEG)-modified TiO2 nanocarrier. Then, an FA-PEG-TiO2 nanoparticle (NP) codelivery system loaded with curcumin and salvianolic acid B were prepared by emulsion evaporation–solidification at low temperature. The obtained folate-targeted NPs (FA-NPs) showed more cytotoxicity on MCF7 cells and MDA-MB-231 cells than a nontargeted NP group. Apart from a synergistic anti-breast cancer effect with curcumin, salvianolic acid B protects the cardiovascular system from oxidative injury by the TiO2 nanocarrier. With coumarin 6 as a fluorescent probe to observe cellular uptake of NPs, the results of in vitro cellular uptake demonstrated FA-NPs exhibited higher cellular uptake and accumulation in MCF7 cells and MDA-MB-231 cells than nontargeted NPs. Then, in vivo biodistribution of NPs was further qualitatively and quantitatively confirmed by in vivo imaging. More importantly, the animal study further suggested that FA-NPs had significantly stronger antitumor effects via receptor-mediated targeted delivery. Consequently, FA-PEG-TiO2 NPs loaded with curcumin and salvianolic acid B could be a promising drug-delivery system to treat breast cancer.

Tumor-targeting delivery of herb-based drugs with cell-penetrating/tumor-targeting peptide-modified nanocarriers

Cancer has become one of the leading causes of mortality globally. The major challenges of conventional cancer therapy are the failure of most chemotherapeutic agents to accumulate selectively in tumor cells and their severe systemic side effects. In the past three decades, a number of drug delivery approaches have been discovered to overwhelm the obstacles. Among these, nanocarriers have gained much attention for their excellent and efficient drug delivery systems to improve specific tissue/organ/cell targeting. In order to enhance targeting efficiency further and reduce limitations of nanocarriers, nanoparticle surfaces are functionalized with different ligands. Several kinds of ligand-modified nanomedicines have been reported. Cell-penetrating peptides (CPPs) are promising ligands, attracting the attention of researchers due to their efficiency to transport bioactive molecules intracellularly. However, their lack of specificity and in vivo degradation led to the development of newer types of CPP. Currently, activable CPP and tumor-targeting peptide (TTP)-modified nanocarriers have shown dramatically superior cellular specific uptake, cytotoxicity, and tumor growth inhibition. In this review, we discuss recent advances in tumor-targeting strategies using CPPs and their limitations in tumor delivery systems. Special emphasis is given to activable CPPs and TTPs. Finally, we address the application of CPPs and/or TTPs in the delivery of plant-derived chemotherapeutic agents.

Cell penetrating peptides functionalized gambogic acid-nanostructured lipid carrier for cancer treatment

Abstract Tumor-targeted delivery is considered a crucial component of current anticancer drug development and is the best approach to increase the efficacy and reduce the toxicity. Nanomedicine, particularly ligand-based nanoparticles have shown a great potential for active targeting of tumor. Cell penetrating peptide is one of the promising ligands in a targeted cancer therapy. In this study, the gambogic acid-loaded nanostructured lipid carrier (GA-NLC) was modified with two kinds of cell penetrating peptides (cRGD and RGERPPR). The GA-NLC was prepared by emulsification and solvent evaporation method and coupled with cRGD, RGERPPR, and combination cRGD and RGERPPR to form GA-NLC-cRGD, GA-NLC-RGE, and GA-NLC-cRGD/RGE, respectively. The formulations were characterized by their particle size and morphology, zeta potential, encapsulation efficiency, and differential scanning calorimetry. In vitro cytotoxicity and cellular uptake study of the formulations were performed against breast cancer cell (MDA-MB-231). Furthermore, in vivo biodistribution and antitumor activity of the formulations were determined by in vivo imaging and in tumor-bearing nude mice, respectively. The result of in vitro cytotoxicity study showed that GA-NLC-RGE exhibited a significantly higher cytotoxicity on MDA-MB-231 as compared with GA-NLC and GA-Sol. Similarly, RGE-Cou-6-NLC showed remarkably higher uptake by the cells than other NLCs over the incubation period. The in vivo imaging study has demonstrated that among the formulations, the RGE-decorated DiR-NLC were more accumulated in the tumor site. The in vivo antitumor activity revealed that RGE-GA-NLC inhibits the tumor growth more efficiently than other formulations. In conclusion, RGERPPR has a potential as an effective carrier in targeting drug delivery of anticancer agents.

Ursolic Acid Nanocrystals for Dissolution Rate and Bioavailability Enhancement: Influence of Different Particle Size

BACKGROUND Ursolic acid (UA), a natural pentacyclic triterpenoid, has been reported to possess a variety of pharmacological activities, but the poor oral bioavailability of UA owing to the poor aqueous solubility and membrane permeability limits the further clinical application. OBJECTIVE The purpose of the present study was to develop UA nanocrystals and microcrystals employing high pressure homogenization (HPH) and to evaluate their effects on UA oral bioavailability. METHOD The crystalline morphology of UA nanocrystals and microcrystals prepared by HPH was observed by scanning electron microscopy and the crystalline state was characterized by differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD). The dissolution rate of UA nanocrystals in different pH conditions was tested. Oral bioavailability of UA nanocrystals and microcrystals comparing with UA coarse suspension was evaluated in SD rats after 50 mg·kg-1 administration. RESULTS UA nanocrystals and microcrystals, the size of which ranged between 291.7 nm and 1299.3 nm were obtained. The results of DSC and PXRD revealed a degree of crystalline-amorphous transformation during HPH preparation. A significant increase was observed in the dissolution rate of UA nanocrystals. The relative bioavailability of UA nanocrystals and microcrystals exhibited 2.56 and 1.40-fold enhancement than that of UA coarse suspension, respectively, along with an increased peak concentration and a prolonged retention. CONCLUSION The nanosized UA crystal is a viable and efficient approach to improve the oral bioavailability of UA.

Increasing Efficacy and Reducing Systemic Absorption of Brimonidine Tartrate Ophthalmic Gels in Rabbits

Abstract Systemic absorption of ocularly administered Brimonidine Tartrate has been reported to give rise to several side-effects. Hence, it has become crucial to develop a delivery system that could increase efficacy and reduce systemic absorption. Therefore, the present work aims to develop Brimonidine Tartrate gels with different concentrations (0.05%, 0.1%, and 0.2% w/v, respectively) using Carbopol 974 P and HPMC E4M, and compare the therapeutic efficacy and systemic absorption with that of eye drop (0.2%, w/v) by UPLC-MS/MS. The result of histological analysis did not show any morphological or structural changes after the administration of formulations. In vitro residence time studies demonstrated that the gels exhibited a better precorneal residence time as compared with the eye drop. The gels with lower concentrations of the drug (0.05% and 0.1%, w/v) could significantly decrease intraocular pressure (IOP) in both normal and water-loaded rabbits as compared to the eye drop. Finally, the values of the ratio of AUC(0→∞) in comparison to eye drop showed the gels with lower concentrations of Brimonidine Tartrate could decrease the systemic absorption. From the result, it can be concluded the 0.1% ophthalmic gel has a potential to improve therapeutic efficacy and reduce the potential toxicity caused by systemic absorption.

Research progress of in-situ gelling ophthalmic drug delivery system

Blindness and vision impairment are the most devastating global health problems resulting in a substantial economic and social burden. Delivery of drug to particular parts of the anterior or posterior segment has been a major challenge due to various protective barriers and elimination mechanisms associated with the unique anatomical and physiological nature of the ocular system. Drug administration to the eye by conventional delivery systems results in poor ocular bioavailability (<5%). The designing of a novel approach for a safe, simple, and effective ocular drug delivery is a major concern and requires innovative strategies to combat the problem. Over the past decades, several novel approaches involving different strategies have been developed to improve the ocular delivery system. Among these, the ophthalmic in-situ gel has attained a great attention over the past few years. This review discussed and summarized the recent and the promising research progress of in-situ gelling in ocular drug delivery system.

A strategy to improve the oral availability of baicalein: The baicalein-theophylline cocrystal

Baicalein (BE) is a flavonoid compound derived from the roots of Scutellaria baicalensis. It has widely been used as anti-oxidant, anti-virus, anti-bacteria, anti-inflammatory and anti-allergic therapies. Due to its poor water solubility (16.82 μg/ml), the therapeutic effectiveness and oral bioavailability of Baicalein are highly limited. The purpose of this study was to investigate the possibility of baicalein-theophylline (BE-TH) cocrystals to achieve the simultaneous enhancement in dissolution and oral bioavailability of BE. The cocrystal had the new characteristic of scanning electron microscopy, differential scanning calorimetry thermograms and X-ray powder diffraction. Compared with coarse powder of BE, BE-TH cocrystals had significantly improved the solubility of BE. The dissolution test showed that the BE-TH cocrystals demonstrated 2.2-fold and 7.1-fold higher rate of dissolution than that of BE coarse powder in HCl (pH = 1.2) and phosphate buffer (PBS, pH = 6.8), respectively. Moreover, the cocrystals exhibited a 5.86-fold higher area under the curve in rats after the oral administration. This investigation enriched the present understanding of cocrystals on their behavior in vitro and in vivo, and built the groundwork for future development of BE as a promising compound into efficacious drug products.