Hongliang Du

Polymer–drug conjugates: present state of play and future perspectives

Polymer conjugation is an efficient approach to improve therapeutic properties of drugs and biological agents. Since the first synthetic polymer-drug conjugate entered clinical trials in 1994, this technology has undergone notable development for the introduction and study of novel polymers and for the progress in the biological rationale for designing conjugates. Not surprisingly, new polymers, in addition to the best known polyethylene glycol, poly[N-(2-hydroxypropyl)methacrylamide], are continuously conjugated with drugs to achieve biodegradable, stimuli-sensitive and targeted systems in an attempt to prolong blood circulation times and enhance drug concentrations at the intended site of action. This overview focuses on bioconjugates of water-soluble polymers with low molecular weight drugs. Additionally, the most recent achievements in the polymer-drug conjugate field and several promising approaches for the future are discussed.

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.

Novel in situ gel systems based on P123/TPGS mixed micelles and gellan gum for ophthalmic delivery of curcumin.

Curcumin, a natural polyphenol compound, has been widely reported for diverse pharmacological effects and already been investigated for eye diseases. However, the water-insolubility of curcumin and the inherent penetration barriers in cornea make it difficult for curcumin to enter eye. This work aimed to develop ion-sensitive curcumin-loaded Pluronic P123 (P123)/D-a-tocopheryl polyethylene glycolsuccinate (TPGS) mixed micelle in situ gels (CUR-MM-ISGs) to prolong ocular retention time and improve cornea permeability. Central composite design-response surface methodology was applied for the optimization of curcumin-loaded P123/TPGS mixed micelles (CUR-MMs). Characterization tests showed that CUR-MMs were in spherical shape with small size and low critical micelle concentration. After dispersing the micelles in gellan gum solution (0.2%, w/w) at the ratio of 3:1 and 1:1 (v/v), respectively, CUR-MM-ISGs were formed and presented transparent appearance. Sustained release profile was obtained in vitro for both CUR-MM-ISGs (3:1 or 1:1, v/v). The irritation test proved that CUR-MM-ISGs as ophthalmic formulations were gentle and biocompatible towards ocular tissues. In addition, the ex vivo corneal penetration study indicated that the cumulative drug permeation amount of CUR-MM-ISGs (3:1, v/v) was respectively 1.16-fold and 1.32-fold higher than CUR-MM-ISGs (1:1, v/v) and curcumin solution. It can be concluded from these results that the developed ion-sensitive mixed micelle in situ gel system is a potential ophthalmic delivery carrier for curcumin as a poorly soluble drug.

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.

Internal stimuli-responsive nanocarriers for drug delivery: Design strategies and applications

The design of internal stimuli-responsive nanocarriers has been extensively used for delivery of various active compounds including drugs, peptides and genes. These nanosystems are not only designed for improved solubility, enhanced bioavailability, and prolonged blood circulation time, furthermore, they can be tailored chemically to achieve selective drug release at the desired sites of action, which can enable them to bypass physiological or pathological obstacles and achieve enhanced therapeutic efficacy. This review presents current functional moieties responsive to a variety of internal stimuli, including pH, redox, enzyme, temperature. Their design strategies and biomedical applications are also highlighted in detail. It is expected that this review can provide inspiration and impetus for exploiting more promising internal stimuli-responsive nano-systems for drug delivery.

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.

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.

Self-assembled nanoparticles based on chondroitin sulfate-deoxycholic acid conjugates for docetaxel delivery: Effect of degree of substitution of deoxycholic acid

Hydrophobically-modified polymers based on chondroitin sulfate with different degree of substitution (DS) of deoxycholic acid (DOCA) were developed for docetaxel delivery. Chondroitin sulfate-deoxycholic acid (CSAD) bioconjugates were synthesized via the linker of adipic dihydrazide by amide bond. They were characterized with spherical shape, mean diameter of around 165.2nm and negative zeta potential (-14.87 to -20.53mV). An increase of DOCA DS reduced size of nanoparticles, while increasing drug loading efficiency. Drug release in vitro showed a triphasic sustained pattern and higher accumulative drug release percentage was observed with increased DS of DOCA on polymer. Self-assemblies with higher DS also had enhanced internalization of nanoparticles and stronger cytotoxicity at the cellular level. The self-assemble nanoparticles demonstrate to be excellent targeting drug delivery systems and the desired therapeutics can be achieved via the alteration of DS.