Jian-Qing Gao

Glioma targeting and blood-brain barrier penetration by dual-targeting doxorubincin liposomes.

Effective chemotherapy for glioblastoma requires a carrier that can penetrate the blood-brain barrier (BBB) and subsequently target the glioma cells. Dual-targeting doxorubincin (Dox) liposomes were produced by conjugating liposomes with both folate (F) and transferrin (Tf), which were proven effective in penetrating the BBB and targeting tumors, respectively. The liposome was characterized by particle size, Dox entrapment efficiency, and in vitro release profile. Drug accumulation in cells, P-glycoprotein (P-gp) expression, and drug transport across the BBB in the dual-targeting liposome group were examined by using bEnd3 BBB models. In vivo studies demonstrated that the dual-targeting Dox liposomes could transport across the BBB and mainly distribute in the brain glioma. The anti-tumor effect of the dual-targeting liposome was also demonstrated by the increased survival time, decreased tumor volume, and results of both hematoxylin-eosin staining and terminal deoxynucleotidyl transferase dUTP nick end labeling analysis. The dual-targeting Dox liposome could improve the therapeutic efficacy of brain glioma and were less toxic than the Dox solution, showing a dual-targeting effect. These results indicate that this dual-targeting liposome can be used as a potential carrier for glioma chemotherapy.

Potential neurotoxicity of nanoparticles

With the rapid development of nanotechnology, there is a growing interest on the application of nanoparticles in various fields such as photonics, catalysis, magnetics, and biotechnology including cosmetics, pharmaceutics, and medicines. However, little is known about their potential toxicity to human health. Owing to their special properties, nanoparticles have the capacity to bypass the blood-brain barrier (BBB). However, the toxic effects of nanoparticles on central nervous system (CNS) function are still lacking. And the interactions of nanoparticles with the cells and tissues in CNS are poorly understood. Thus, neurotoxicity induced by nanoparticles is still a new topic that requires more attention. In this review, we summarized the pathways by which the nanoparticles could enter into the CNS and the recent investigations on the neurotoxicity of nanoparticles both in vitro and in vivo, as well as the potential mechanisms. Furthermore, the future direction in the neurotoxicity studies of nanoparticles is also discussed.

Overcoming drug resistance of MCF-7/ADR cells by altering intracellular distribution of doxorubicin via MVP knockdown with a novel siRNA polyamidoamine-hyaluronic acid complex.

Drug resistance is one of the critical reasons leading to failure in chemotherapy. Enormous studies have been focused on increasing intracellular drug accumulation through inhibiting P-glycoprotein (Pgp). Meanwhile, we found that major vault protein (MVP) may be also involved in drug resistance of human breast cancer MCF-7/ADR cells by transporting doxorubicin (DOX) from the action target (i.e. nucleus) to cytoplasma. Herein polyamidoamine (PAMAM) dendrimers was functionalized by a polysaccharide hyaluronic acid (HA) to effectively deliver DOX as well as MVP targeted small-interfering RNA (MVP-siRNA) to down regulate MVP expression and improve DOX chemotherapy in MCF-7/ADR cells. In comparison with DOX solution (IC50=48.5 μM), an enhanced cytotoxicity could be observed for DOX PAMAM-HA (IC50=11.3 μM) as well as enhanced tumor target, higher intracellular accumulation, increased blood circulating time and less in vivo toxicity. Furthermore, codelivery of siRNA and DOX by PAMAM-HA exhibited satisfactory gene silencing effect as well as enhanced stability and efficient intracellular delivery of siRNA, which allowed DOX access to nucleus and induced subsequent much more cytotoxicity than siRNA absent case as a result of MVP knockdown. This observation highlights a promising application of novel nanocarrier PAMAM-HA, which could co-deliver anticancer drug and siRNA, in reversing drug resistance by altering intracellular drug distribution.

Mesenchymal stem cells: A promising targeted-delivery vehicle in cancer gene therapy

The targeting drug delivery systems (TDDS) have attracted extensive attention of researchers in recent years. More and more drug/gene targeted delivery carriers, such as liposome, magnetic nanoparticles, ligand-conjugated nanoparticles, microbubbles, etc., have been developed and under investigation for their application. However, the currently investigated drug/gene carriers have several disadvantages, which limit their future use in clinical practice. Therefore, design and development of novel drug/gene delivery vehicles has been a hot area of research. Recent studies have shown the ability of mesenchymal stem cells (MSCs) to migrate towards and engraft into the tumor sites, which make them a great hope for efficient targeted-delivery vehicles in cancer gene therapy. In this review article, we examine the promising of using mesenchymal stem cells as a targeted-delivery vehicle for cancer gene therapy, and summarize various challenges and concerns regarding these therapies.

PEGylated adenovirus vectors containing RGD peptides on the tip of PEG show high transduction efficiency and antibody evasion ability

PEGylation of adenovirus vectors (Ads) is an attractive strategy in gene therapy. Although many types of PEGylated Ad (PEG‐Ads), which exhibit antibody evasion activity and long plasma half‐life, have been developed, their entry into cells has been prevented by steric hindrance by polyethylene glycol (PEG) chains. Likewise, sufficient gene expression for medical treatment could not be achieved.

Non-viral gene delivery carrier and its three-dimensional transfection system

An increasing number of non-viral vectors are being developed for the use of gene delivery nowadays, among which cationic polymers and lipoplexes receive most attention. Most of these researches are focused on how to increase the transfection efficiency of non-viral vectors as well as the reduction of toxicity. In this review, we go over new strategies to reduce the toxicity of cationic polyplexes such as poly(ethylene-imine) and the construction of highly effective gene transfer vector lipoplexes. In addition, since transformation of gene expression system from two-dimensional (2D) substrate to 3D scaffold triggers far better transfection efficiency, the non-viral vectors applied in 3D transfection system have also been reviewed.

Doxorubicin-loaded PEG-PCL copolymer micelles enhance cytotoxicity and intracellular accumulation of doxorubicin in adriamycin-resistant tumor cells

Background Multidrug resistance remains a major obstacle to successful cancer chemotherapy. Some chemical multidrug resistance inhibitors, such as ciclosporin and verapamil, have been reported to reverse resistance in tumor cells. However, the accompanying side effects have limited their clinical application. In this study, we have developed a novel drug delivery system, ie, a polyethyleneglycol-polycaprolactone (PEG-PCL) copolymer micelle encapsulating doxorubicin, in order to circumvent drug resistance in adriamycin-resistant K562 tumor cells. Methods Doxorubicin-loaded diblock copolymer PEG-PCL micelles were developed, and the physicochemical properties of these micelles, and accumulation and cytotoxicity of doxorubicin in adriamycin-resistant K562 tumor cells were studied. Results Doxorubicin-loaded micelles were prepared using a solvent evaporation method with a diameter of 36 nm and a zeta potential of +13.8 mV. The entrapment efficiency of doxorubicin was 48.6% ± 2.3%. The micelles showed sustained release, increased uptake, and cellular cytotoxicity, as well as decreased efflux of doxorubicin in adriamycin-resistant K562 tumor cells. Conclusion This study suggests that PEG-PCL micelles have the potential to reverse multidrug resistance in tumor cells.

Mesenchymal Stem Cells as a Novel Carrier for Targeted Delivery of Gene in Cancer Therapy Based on Nonviral Transfection

The success of gene therapy relies largely on an effective targeted gene delivery system. Till recently, more and more targeted delivery carriers, such as liposome, nanoparticles, microbubbles, etc., have been developed. However, the clinical applications of these systems were limited for their several disadvantages. Therefore, design and development of novel drug/gene delivery vehicles became a hot topic. Cell-based delivery systems are emerging as an alternative for the targeted delivery system as we described previously. Mesenchymal stem cells (MSCs) are an attractive cell therapy carrier for the delivery of therapeutic agents into tumor sites mainly for their tumor-targeting capacities. In the present study, a nonviral vector, PEI(600)-Cyd, prepared by linking low molecular weight polyethylenimine (PEI) and β-cyclodextrin (β-CD), was used to introduce the therapeutical gene, tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), to MSCs. Meanwhile, the characterization, transfection efficiency, cytotoxicity, cellular internalization, and its mechanism of this nonviral vector were evaluated. The in vitro expression of TRAIL from MSCs-TRAIL was demonstrated by both enzyme-linked immunosorbent assay and Western blot analysis. The lung tumor homing ability of MSCs was further confirmed by the in vitro and in vivo model. Moreover, the therapeutic effects as well as the safety of MSCs-TRAIL on lung metastases bearing C57BL/6 mice and normal C57BL/6 mice were also demonstrated. Our results supported both the effectiveness of nonviral vectors in transferring the therapeutic gene to MSCs and the feasibility of using MSCs as a targeted gene delivery carrier, indicating that MSCs could be a promising tumor target delivery vehicle in cancer gene therapy based on nonviral gene recombination.

The healing and anti-scar effects of astragaloside IV on the wound repair in vitro and in vivo

ETHNOPHARMACOLOGICAL RELEVANCE Astragaloside IV is the chief ingredient of Radix Astragali, which has been used in the Traditional Chinese Medicine as a major component of many polyherbal formulations for the repair and regeneration of injured organ and tissues. This study is to investigate the influence of astragaloside IV on both of the wound healing and scar formation. MATERIALS AND METHODS For the in vitro evaluation, the influence of the astragaloside IV in the wound scratch test of keratinocytes and the secretion of transforming growth factor-β1, a key factor contributing to scar formation were determined. With the rat skin excision model, the in vivo regulation of astragaloside IV on wound closure, angiogenesis and collagen disposition were also evaluated. RESULTS Astragaloside IV was shown to significantly promote the migration of keratinocytes in wound scratching assay. The superior effect of Astragaloside IV was observed at 100 μmol/L, in which the recover rates was increased with 2 and 3 folds after 48 h and 96 h respectively than that of blank control (P<0.01). Animal skin closure measurement showed that astragaloside IV could stimulate the wound healing, e.g. with 21% recover in contrast to the 8% of blank control at the 6th day. Biomechanic and Massons trichrome stain analysis indicated that astragaloside IV may improve the strength of the repaired skin and promoted the angiogenesis and collagen synthesis. Meanwhile, the picrosirius-sirus red stain and Elisa test definitely showed the anti-scar effects of astragaloside IV by decreasing the levels of collagen I/III and TGF-β1 secretion by firbroblasts with a dose-dependent manner (25-100 μmol/L). CONCLUSIONS Astragaloside IV was shown a promising natural product with both healing and anti-scar effects for wound treatment. These results give the evidence for the application of astragaloside IV in the treatment of injury.

Silk fibroin/gelatin electrospun nanofibrous dressing functionalized with astragaloside IV induces healing and anti-scar effects on burn wound

Functional wound dressing has provided new challenges for researchers who focus on burn to improve skin graft quality, reduce scarring, and develop a pluristratified dermal or epidermal construct of a burn wound. This study aimed to investigate the effect of a silk fibroin/gelatin (SF/GT) electrospun nanofibrous dressing loaded with astragaloside IV (AS) on deep partial-thickness burn wound. AS-loaded SF/GT-blended nanofibrous dressing was prepared by electrospinning nanotechnology. The optimal ratio (25:75) of silk fibroin to gelatin was further optimized by evaluating ATR-FTIR characteristics, mechanical properties, porosity, swelling rate, degradation, and release profile of the AS-loaded SF/GT nanofibrous dressing. In contrast to the blank control, the AS-loaded SF/GT nanofibrous dressing promoted cell adhesion and proliferation with good biocompatibility in vitro (p<0.01). This dressing also accelerated wound healing and inhibited scar formation in vivo by stimulating wound closure (p<0.05), increasing angiogenesis, regulating newly formed types of collagen, and improving collagen organization. These results showed that SF/GT nanofibrous dressing is a promising topical drug delivery system. Furthermore, AS-functionalized SF/GT nanofibrous dressing is an excellent topical therapeutic that could be applied to promote healing and elicit anti-scar effects on partial-thickness burn wound.