Xiaoye Yang

The design of pH-sensitive chitosan-based formulations for gastrointestinal delivery

Chitosan, a nontoxic and biocompatible polysaccharide, has been widely explored for the gastrointestinal delivery of drugs, proteins, peptides and genes for different therapeutic purposes. Because a pH gradient exists in the gastrointestinal tract, chitosan-based formulations in response to specific pH conditions, such as the low pH in the stomach and a high pH in the intestine, have been developed as a general strategy for disease diagnosis and therapy. Tailored pH-responsive drug release in the gastrointestinal tract can be achieved with various chitosan-based formulations such as nanoparticles, microspheres, hydrogels and nanocomposites. This review focuses on the most recent development of chitosan-based pH-sensitive formulations for gastrointestinal delivery, covering various types of chitosan-based formulations, their pH-responsive mechanisms and biomedical applications.

Advanced nanocarriers based on heparin and its derivatives for cancer management.

To obtain a satisfying anticancer effect, rationally designed nanocarriers are intensively studied. In this field, heparin and its derivatives have been widely attempted recently as potential component of nanocarriers due to their unique biological and physiochemical features, especially the anticancer activity. This review focuses on state-of-the-art nanocarriers with heparin/heparin derivatives as backbone or coating material. At the beginning, the unique advantages of heparin used in cancer nanotechnology are discussed. After that, different strategies of heparin chemical modification are reviewed, laying the foundation of developing various nanocarriers. Then a systematic summary of diverse nanoparticles with heparin as component is exhibited, involving heparin-drug conjugate, polymeric nanoparticles, nanogels, polyelectrolyte complex nanoparticles, and heparin-coated organic and inorganic nanoparticles. The application of these nanoparticles in various novel cancer therapy (containing targeted therapy, magnetic therapy, photodynamic therapy, and gene therapy) will be highlighted. Finally, future challenges and opportunities of heparin-based biomaterials in cancer nanotechnology are discussed.

The synthesis, self-assembling, and biocompatibility of a novel O-carboxymethyl chitosan cholate decorated with glycyrrhetinic acid.

O-carboxymethyl chitosan (OCMC) was firstly decorated with cholic acid (CA) to acquire an amphiphilic polymer under alkaline condition. Then glycyrrhetinic acid (GA) was conjugated to the polymer via a succinate linker and finally treated with NaCO3 solution to obtain new conjugates for potential liver targeted delivery. These conjugates formed uniform aggregates with low critical aggregation concentrations (0.028-0.079 mg/mL) in PBS. The average diameter of cholic acid modified carboxymethyl chitosan (CMCA) aggregates (110-257 nm) decreased with the increase of CA substitution degree and became slightly larger after GA modification. Negative zeta potential (-15 mV) of GA decorated CMCA (GA-CMCA) revealed that the formation of negatively charged shells and spherical morphology was observed under transmission electron microscopy. Furthermore, hemolysis test, in vitro cytotoxicity assay and cellular uptake study all demonstrated the safety and feasibility of these conjugates as a promising carrier for liver targeted drug delivery.

Hyaluronic acid-quercetin conjugate micelles: synthesis, characterization, in vitro and in vivo evaluation.

A tumor cell-targeted prodrug was developed for quercetin, using hyaluronic acid as polymeric carrier. Hyaluronic acid-quercetin (HA-QT) bioconjugates were synthesized by linking the hydroxy of quercetin via a succinate ester to adipic dihydrazide-modified hyaluronic acid. The mirco-morphology demonstrated that the prepared prodrug could form self-assembled micelles possessing spherical shape, 172.1 nm average diameter and -20.30 mV surface potential. The HA-QT micelles exhibited significant sustained and pH-dependent drug release behaviors without dramatic initial burst. Compared to free quercetin solution, the HA-QT micelles were found a 4 times increase in cytotoxicity on MCF-7 cells (CD44-overexpressing cell lines), while weak enhancement in inhibitory activity was observed towards L929 cells (CD44 deficient cell lines). Promisingly, 20.1-fold increase in the half-life and 4.9-fold increase in the area-under-the-curve (AUC) of quercetin were achieved for the HA-QT micelles compared with the parent drug. In addition, the HA-QT micelles also showed excellent inhibition effect on tumor growth in H22 tumor-bearing mice. Hemolytic toxicity and vein irritation assay further suggested that the HA-QT micelles were a safe and potent drug delivery system for targeted antitumor therapy.

Polymer-drug conjugates: recent progress on administration routes

Introduction: Polymer-drug conjugates are an important part of polymer therapeutics. Recently, they have been used as an appealing platform for drug delivery. As a delivery vector, the route of administration performs a serious impact on the accessibility of drug molecules to their respective target site and therapeutic index. Furthermore, the physicochemical and biological properties of conjugates also correlate distinctly with the route of administration. Areas covered: This article reviews the recent advances of polymer-drug conjugates as drug delivery systems through parenteral, enteral and topical routes. In particular, it mainly focuses on the classical and emerging routes such as injection, oral, transdermal, pulmonary and ocular routes using polymer-drug conjugates as delivery systems. Expert opinion: Although polymer-conjugated drug delivery systems reported so far face severe shortcoming of being incomplete methodology and limited routes for administration (mostly concentrated in injection), some polymer carriers like poly(amidoamine) and hyaluronic acid still offer an appealing platform to deliver drug. Acquiring the particular characteristics of each polymer carrier, exploiting novel biodegradable polymer, expanding classical drug administration ways by emerging routes and developing a rational and systematic methodology to design administration routes will be the promising directions.

Design of chitosan-based nanoformulations for efficient intracellular release of active compounds

The use of chitosan-based nanocarriers to transport active compounds gained an increasing attention in drug delivery. Intracellular delivery, with efficient intracellular release, become an important design considerations in chitosan based nanoformlations. Internal stimuli-responsive nanoformulations are designed to release active compounds after internalization based on certain internal stimuli like pH, redox potential and enzymes. Futhermore, nondestructive pathways may provide a nondigestive compartment for active compounds transport, which can protect the encapsulated agents from possible lysosomal degradation, thereby realizing release agents safely. This review gives a brief overview about the chitosan-based nanoformulations for efficient intracellular cargo release, including internal stimuli-responsive nanoformulations and nondestructive pathways based nanoformulations: design strategies and applications. The present problems and a possible future perspective related them are also discussed.

Tumor targeting strategies for chitosan-based nanoparticles

Currently, targeted nanoparticles (NPs) are rapidly being developed to overcome various bottlenecks of antitumor agents, such as poor solubility in aqueous solution, poor pharmacokinetics, a lack of selectivity and undesirable side effects in healthy tissues. In recent years, chitosan, a cationic polysaccharide, has been widely explored for the targeted delivery of antitumor agents due to its unique physicochemical and biological properties, such as biocompatibility, biodegradability, mucoadhesive feature, absorption enhancement and active functional groups for chemical modifications. This article reviews the recent developments in various target-specific nanoparticles based on chitosan and its derivatives, including passive, active and stimuli-sensitive targeting strategies. In addition, the target mechanisms and the key efficacy factors are illuminated.

Redox-sensitive self-assembled nanoparticles based on alpha-tocopherol succinate-modified heparin for intracellular delivery of paclitaxel

To remedy the problems riddled in cancer chemotherapy, such as poor solubility, low selectivity, and insufficient intra-cellular release of drugs, novel heparin-based redox-sensitive polymeric nanoparticles were developed. The amphiphilic polymer, heparin-alpha-tocopherol succinate (Hep-cys-TOS) was synthesized by grafting hydrophobic TOS to heparin using cystamine as the redox-sensitive linker, which could self-assemble into nanoparticles in phosphate buffer saline (PBS) with low critical aggregation concentration (CAC) values ranging from 0.026 to 0.093mg/mL. Paclitaxel (PTX)-loaded Hep-cys-TOS nanoparticles were prepared via a dialysis method, exhibiting a high drug-loading efficiency of 18.99%. Physicochemical properties of the optimized formulation were characterized by dynamic light scattering (DLS), transmission electron microscope (TEM) and differential scanning calorimetry (DSC). Subsequently, the redox-sensitivity of Hep-cys-TOS nanoparticles was confirmed by the changes in size distribution, morphology and appearance after dithiothreitol (DTT) treatment. Besides, the in vitro release of PTX from Hep-cys-TOS nanoparticles also exhibited a redox-triggered profile. Also, the uptake behavior and pathways of coumarin 6-loaded Hep-cys-TOS nanoparticles were investigated, suggesting the nanoparticles could be taken into MCF-7 cells in energy-dependent, caveolae-mediated and cholesterol-dependent endocytosis manners. Later, MTT assays of different PTX-free and PTX-loaded formulations revealed the desirable safety of PTX-free nanoparticles and the enhanced anti-cancer activity of PTX-loaded Hep-cys-TOS nanoparticles (IC50=0.79μg/mL). Apoptosis study indicated the redox-sensitive formulation could induce more apoptosis of MCF-7 cells than insensitive one (55.2% vs. 41.7%), showing the importance of intracellular burst release of PTX. Subsequently, the hemolytic toxicity confirmed the safety of the nanoparticles for intravenous administration. The results indicated the developed redox-sensitive nanoparticles were promising as intracellular drug delivery vehicles for cancer treatment.

In vitro and in vivo study of Baicalin-loaded mixed micelles for oral delivery.

Abstract The aim of this work was to research the potential functions and the mechanism of absorption of the baicalin (BC)-loaded micelle system that contained Pluronic P123 copolymer (P123) and sodium taurocholate (ST) as carrier materials via oral delivery. Based on the numerous advantages of oral administration, such as cost-effectiveness, flexible and accommodated dosing regimen, and improved compliance for patients, the ST-P123-MMs system would be evaluated as oral delivery vehicle of BC. In this study, X-ray powder diffractometer analysis confirmed the phase change of BC after being incorporated in mixed micelles. The release study in simulated gastric fluid/simulated intestinal fluid exhibited that BC-loaded ST-P123-MMs presented a sustained drug release behavior. Compared with coumarin-6 solution, higher cellar uptake efficiency was achieved for coumarin-6 loaded ST-P123-MMs towards Caco-2 cell lines. The in situ perfusion test in rat indicated that the absorption of BC-loaded ST-P123-MMs in intestinal tract was stronger than BC solution. After oral administration, the Cmax and AUC of BC-loaded ST-P123-MMs were 1.77 times and 1.54 times as high as those of BC suspension in rat, respectively. Promisingly, the formulated BC exhibited a prolonged circulation time with the oral bioavailability increased to 1.54-fold compared with the control group. These results all suggested that P123 and ST mixed micelles could serve as a promising approach to oral administration of BC.

Curcumin-loaded mixed micelles: preparation, optimization, physicochemical properties and cytotoxicity in vitro

Abstract Although curcumin (CUR) can inhibit proliferation and induce apoptosis of tumors, the poor water solubility restricted its clinical application. The aim of this study was to improve the aqueous solubility of CUR and make more favorable changes to bioactivity by preparing curcumin-loaded phospholipid-sodium deoxycholate-mixed micelles (CUR-PC-SDC-MMs). CUR-PC-SDC-MMs were prepared by the thin-film dispersion method. Based on the results of single factor exploration, the preparation technology was optimized using the central composite design-response surface methodology with drug loading and entrapment efficiency (EE%) as indicators. The images of transmission electron microscopy showed that the optimized CUR-PC-SDC-MMs were spherical and well dispersed. The average size of the mixed micelles was 66.5 nm, the zeta potential was about −26.96 mV and critical micelle concentration was 0.0087 g/l. CUR was encapsulated in PC-SDC-MMs with loading capacity of 13.12%, EE% of 87.58%, and the solubility of CUR in water was 3.14 mg/ml. The release results in vitro showed that the mixed micelles presented sustained release behavior compared to the propylene glycol solution of CUR. The IC50 values of CUR-loaded micelles and free drug in human breast carcinoma cell lines were 4.10 μg/ml and 6.93 µg/ml, respectively. It could be concluded from the above results that the CUR-PC-SDC-MMs system might serve as a promising nanocarrier to improve the solubility and bioactivity of CUR.