Development and application of hyaluronic acid in tumor targeting drug delivery

Hyaluronic acid (HA) is a natural polysaccharide that has gained much attention due to its biocompatibility, enzyme degradation capacity and active tumor targeting capacity. Its receptor, CD44, is overexpressed in many kinds of cancers and is associated with tumor progress, infiltration and metastasis. Therefore, many researchers have developed various HA-based drug delivery systems for CD44-mediated tumor targeting. In this review, we systemically overview the basic theory of HA, its receptor and hyaluronidase, then we categorize the studies in HA-based drug delivery systems according to the functions of HA, including tumor-targeting materials, enzyme-sensitive biodegradable modality, pH-sensitive component, reduction-sensitive component, and the gel backbone. Finally, the perspective is discussed.

The preparation and pharmacokinetic evaluation of the self-assembled nanoparticles of the dihydroartemisinin prodrug of the reduction-sensitive / 中国药学杂志

OBJECTIVE: To prepare the self-assembled nanoparticles of the reduction-response dihydroartemisinin prodrug and study its pharmacokinetics. METHODS: Dihydroartemisinin as raw material, lauryl as the carrier, a dihydroartemisinin prodrug was designed and synthesized with disulfide bond as a connected arm. Molecular self-assembled technique was adopted to prepare the self-assembled nanoparticles of the dihydroartemisinin prodrug (DSCNs). Transmission electron microscopy (TEM) observed the nanoparticles morphology. Melvin granularity instrument measured the particle size, size distribution and Zeta potential. The properties of the optimized prescription were investigated, and their pharmacokinetics were evaluated. RESULTS: DSCNs were spherical with uniform size, the coating rate, drug loadings, average particle size, PDI and Zeta potential were (96.75±0.03)%, (80.60±2.6)%, (128.5±3.0) nm, (0.151±0.044) and (-16.6±0.9)mV, respectively. Vitamin E-TPGS (TPGS) was selected as the stabilizer of DSCNs to prevent the accumulation of nanoparticles, and DSCNs remained stable after 12 weeks. In vitrostudy showed that the release of DHA in prodrug was increased with the increase of the concentration of glutathione (GSH). Pharmacokinetic studies showed that DSCNs could significantly increase the blood concentration of DHA. CONCLUSION: The optimized preparation has long-term stability, which could be the basis for the further application of self-assembled nanoparticles to the drug sustained release system.

In vitro targeting efficiency evaluation of reduction-responsive co-loaded doxorubicin/siRNA nanoparticles / 药学学报

In this study a reduction-responsive nanoparticles (NPs) modified with hyaluronic acid (HA) was prepared for the co-delivery of doxorubicin (DOX) and siRNA and then evaluated as a lung cancer targeting delivery system in vitro. The amphiphilic polymer of poly-L-lysine-lipoic acid (PLA) based on poly-L-lysine (PLL) with lipoic acid (LA) was synthesized via amidation reaction and characterized by 1H NMR. The DOX loaded PLA NPs were prepared via dialysis method, and siRNA was loaded via electrostatic attraction to prepare the co-delivery NPs system (PLA/DOX-siRNA-NPs). Then PLA/DOX-siRNA-NPs were coated with HA to obtain HA-PLA/DOX-siRNA-NPs. The tumor microenvironment-responsive properties under different pH or reduction condition of HA-PLA/DOX-siRNA-NPs were evaluated by investigating the particle size and zeta potential. Cellular uptake of HA-PLA/DOX-siRNAFAM-NPs by A549 cells and endosomal escape of siRNA were studied using confocal laser scanning microscope (CLSM). 1H NMR spectrum demonstrated that PLA was successfully synthesized with LA grafting rate of 25.1%. The encapsulation efficiency (EE) and drug loading (DL) of HA-PLA/DOX-NPs was (86.93±8.91)% and (4.17±0.68)%, respectively, and siRNA was loaded at an N/P of 6:1 in carrier. HA-PLA/DOX-siRNA-NPs exhibited a suitable size of (167.3±9.9) nm and negative charge of (-15.5±1.4) mV with the optimal ratio of PLA and HA of 1:3. Additionally, the zeta potential of HA-PLA/DOX-siRNA-NPs significantly increased with charge reversal from negative to positive after the treatment with HAase, and the particle size of HA-PLA/DOX-siRNA-NPs changed significantly under the condition of 10 mmol·L-1 glutathione (GSH). The release profiles in vitro demonstrated that HA-PLA/DOX-NPs exhibited a maintained release behavior at pH 7.4 and the adding of GSH (10 mmol·L-1) led to rapid release of DOX from NPs. In vitro cellular uptake and subcellular distribution study demonstrated that themodification of HA enhanced the affinity of NPs to A549 cells and targeting ability, and the cellular uptake of HA-PLA/DOX-siRNAFAM-NPs significantly increased after the treatment with HAase. It was observed that HA-PLA/DOX-siRNAFAM-NPs could escape from endo-lysosomes followed by sharp payloads release to their relative targets. All these results demonstrated that the co-loaded NPs have a high entrapment efficiency of DOX and siRNA. And they also exhibited an active tumor targeting efficiency and tumor microenvironment-responsive properties, which were beneficial to cellular uptake and intracellular release of DOX and siRNA. In conclusion, these reduction-responsive NPs modified with HA have great potential as co-delivery systems for antitumor agents and siRNA.

A detachable coating of cholesterol-anchored PEG improves tumor targeting of cell-penetrating peptide-modified liposomes

Cell-penetrating peptides (CPPs) have been widely used to enhance the membrane translocation of various carriers for many years, but the non-specificity of CPPs seriously limits their utility in vivo. In this study, cholesterol-anchored, reduction-sensitive PEG (first synthesized by our laboratory) was applied to develop a co-modified liposome with improved tumor targeting. Following optimization of the formulation, the in vitro and in vivo properties of the co-modified liposome were evaluated. The co-modified liposome had a much lower cellular uptake and tumor spheroid uptake, but a much higher tumor accumulation compared to CPP-modified liposome, indicating the non-specific penetration of CPPs could be attenuated by the outer PEG coating. With the addition of exogenous reducing agent, both the in vitro and in vivo cellular uptake was markedly increased, demonstrating that the reduction-sensitive PEG coating achieved a controllable detachment from the surface of liposomes and did not affect the penetrating abilities of CPPs. The present results demonstrate that the combination of cholestervsitive PEG and CPPs is an ideal alternative for the application of CPP-modified carriers in vivo.

The application of reduction-sensitive polymeric micelles in tumor targeting drug delivery / 中国药学杂志

OBJECTIVE: To introduce the application of reduction-sensitive polymeric micelles in the field of tumor targeting drug delivery. METHODS: In the past decades, tumor targeted drug delivery systems have become important research area because they promise to resolve several key therapeutical issues including low treatment efficacy and significant side effects. On the basis of published literatures, the recent developments in reduction-sensitive polymeric micelles used for tumor targeting drug delivery were reviewed, with an emphasis on their structure characteristics as well as their biomedical applications from the cellular level and animal level, respectively. RESULTS AND CONCLUSION: As a novel intelligent drug delivery system, reduction-sensitive polymeric micelles can effectively control drug release with low side effects and high therapeutic effects both in vitro and in vivo. It has great potential in tumor targeting drug delivery.