Neurodegenerative disease is one of the serious diseases of the human nervous system. There is no effective way to treat neurodegenerative diseases. Flavors such as curcumin, coumarin, have attracted increasing attention due to having a beneficial therapeutic effect on Alzheimer’s disease and Parkinson’s disease. But the use of most drugs is limited in clinical treatment because of blood-brain barrier. The use of nano-drug carriers such as liposomes, polymer micelles, polymer nanoparticles and magnetic nanoparticles, which can carry drugs across the blood-brain barrier, has brought hope for the treatment of neurodegenerative diseases.Download high-res image (257KB)Download full-size imageNano-drug carriers such as liposomes, polymer micelles, and polymer nanoparticles are used for neurodegenerative diseases, which can help drug pass the blood-brain barrier easily, and improve the therapeutic effect.

AbstractDoxorubicin (DOX), one of the most widely used clinical antineoplastics, has ineffective therapeutic efficacy on glioblastoma multiforme (GBM) with extremely short survival time due to many obstacles such as blood–brain barrier (BBB), tumor angiogenesis, and glioblastoma stem cells (GSCs). To overcome, biocompatible nanoparticles named CARD-B6 loading three clinical drugs are developed. Unlike other nanomedicines, CARD-B6, with the ability of spatiotemporally controlled release, maximize the effectiveness of DOX. (1) After CARD-B6 cross the BBB via B6, combretastatin A4 that is first released via protonation of poly (β-amino ester) specifically destroys angiogenesis to facilitate the interaction between GBM and CARD-B6. (2) Internalized into glioblastoma cells later, DOX is released via the breakage of amido bond to induce apoptosis, which is facilitated by the simultaneously released all-trans retinoic acid (ATRA). (3) After endocytosis into GSCs, the rapidly released ATRA induces the GSCs differentiation and downregulates the survival pathways, which enhances the sensitivity of GSCs to the subsequently released DOX. This synergistic antitumor effect significantly extends survival time of GBM mouse model. CARD-B6 are traced by superparamagnetic iron oxide nanocubes with high r2 relaxivity for magnetic resonance imaging. Therefore, the traceable CARD-B6 with spatiotemporally controlled release ability are emerging as a powerful platform for GBM treatment.

Understanding the effects of magnetic iron nanoparticles (MINPs) on the immune response is vitally important for biomedical applications such as cancer therapy, disease diagnosis and novel cancer imaging. In this study, lipid modified MINPs were designed and prepared by introducing the neutral lipid DSPE-PEG or the zwitterionic lipid DSPE-PCB into hydrophobic MINPs through hydrophobic interaction (L-MINPs and ZL-MINPs, respectively). The effect of L-MINPs and ZL-MINPs on the intracellular accumulation and immune responses of three kinds of antigen processing cells was examined. The results indicated that the high cellular uptake efficiency of surface coated MINPs was strongly related to the nature of the coating lipid, with the zwitterionic lipid being more effective than PEGylated ones. Besides, the results from flow cytometry (FCM), confocal laser scanning microscopy (CLSM) and Prussian blue staining demonstrated a time- and concentration-dependent MINP internalization. The uptake of zwitterionic lipid modified MINPs (ZL-MINPs) induced very low cytotoxicity and a strong mixed Th1/Th2 type immune response. L-MINPs could induce a strong increase in pro-inflammatory cytokines with a slight secretion of Th2 cytokines. Besides, no IL-10 was observed in both groups, indicating that MINPs with lipid modification were absence of immunosuppression. In conclusion, this study addresses an important implication of the lipid type and Fe concentration on the immune stimulation of cells and supports the potential for further development of biomedical applications.

In order to eliminate tumors, it is necessary to kill differentiated cancer cells, cancer stem cells (CSCs) and the “vascular niche” synergistically. Although nanoparticles (NPs) have been used to deliver drugs to the action sites, inert materials with high toxicity may reduce the drug loading content and cause side-effects to kidneys and other organs in the course of degradation and excretion. Here, we report hypoxia-responsive drug–drug conjugated NPs to deliver three drugs to kill differentiated cancer cells, CSCs and the “vascular niche” synergistically, which could selectively release the drugs to treat cells in hypoxic tumors. For this purpose, an azobenzene (AZO) bond imparting hypoxia sensitivity and specificity as a crosslinker conjugated hydrophobic combretastatin A-4 (CA4) with hydrophilic irinotecan (IR) to form IR–AZO–CA4 amphiphilic molecules. These molecules self-assembled into NPs, which could encapsulate hydrophobic anti-CSCs drug cyclopamine (CP). The drug–drug conjugated NPs had high drug loading content. As expected, the AZO linker could be broken under hypoxia conditions and the NPs were disassembled to release drugs quickly. Confocal laser scanning microscopy (CLSM) results indicated that the IR–AZO–CA4/CP NPs could enhance the cellular uptake of drugs and the permeability of drugs to the inner of CSCs, beneficial for tumor therapy. Furthermore, the IR–AZO–CA4/CP NPs could inhibit the migration, invasion and mammosphere formation capacity of CSCs. More importantly, only IR–AZO–CA4/CP NPs could simultaneously inhibit differentiated cancer cells, CSCs and endothelial cells without interference on the cell under a normoxic environment. The present study suggests that the IR–AZO–CA4/CP NPs provide a promising therapeutic approach for anticancer treatment.

Human immunodeficiency virus (HIV) DNA vaccine can induce cellular and humoral immunity. A safe and effective HIV DNA vaccine is urgent need to prevent the spread of acquired immune deficiency syndrome (AIDS). The major drawback of DNA vaccines is the low immunogenicity, which is caused by the poor delivery to antigen presenting cells and insufficient antigen expression. Sparked by the capability of endosomal/lysosomal escape of the zwitterionic lipid distearoyl phosphoethanol-amine-polycarboxybetaine (DSPE-PCB), we attempted to develop a zwitterionic-based cationic liposome with enhanced immunogenicity of DNA vaccines. The mannosylated zwitterionic-based cationic liposome (man-ZCL) was constructed as a DNA vaccine adjuvant for HIV vaccination. Man-ZCL could complex with DNA antigens to form a tight structure and protect them from nuclei enzyme degradation. Benefited from the capability of the specific mannose receptor mediated antigen processing cells targeting and enhanced endosomal/lysosomal escape, the man-ZCL lipoplexes were supposed to promote antigen presentation and the immunogenicity of DNA vaccines. In vitro and in vivo results revealed that man-ZCL lipoplexes showed enhanced anti-HIV immune responses and lower toxicity compared with CpG/DNA and Lipo2k/DNA, and triggered a Th1/Th2 mixed immunity. An antigen-depot effect was observed in the administration site, and this resulted in enhanced retention of DNA antigens in draining lymph nodes. Most importantly, the man-ZCL could assist to activate T cells through a non-inflammasome pathway. These findings suggested that the man-ZCL could be potentially applied as a safe and efficient DNA adjuvant for HIV vaccines.

Hypoxia has a major role in tumor development and resistance to therapy. Therefore, the effective targeting and killing of hypoxic tumor cells is a key to successful tumor control. Here, we report the hypoxia-responsive prodrug micelles to deliver hydrophobic anticancer drug, which can selectively release the drugs to treat hypoxic tumor cells in a combined way. For this purpose, an azobenzene (AZO) bond, which imparts hypoxia sensitivity and specificity as cross linker, conjugated PEG–hexanethiol (PEG–C6) with combretastatin A-4 (CA4) to form PEG–C6–AZO–CA4 amphiphilic molecule. These PEG–C6–AZO–CA4 molecules self-assemble into micelles, which can encapsulate hydrophobic anticancer drug. The drug release behavior from PEG–C6–AZO–CA4 micelles was studied under normoxic or hypoxic conditions and the combinations of CA4 with hydrophobic drugs for tumor treatment in vitro were also investigated. As the first example of using AZO linkages to develop anticancer prodrug micelles as hydrophobic anticancer drugs delivery to kill the hypoxic tumor cells in a combination way, this study establishes PEG–C6–AZO–CA4 micelles as a promising drug delivery platform for hypoxic tumor therapy.

In this study, hydrophilic polymer dextran and superhydrophilic polymer PMPC coated iron oxide immunomagnetic nanoparticles were prepared for rapid capture and detection of Salmonella. It was found that the colloidal stability of magnetic iron oxide nanoparticles in aqueous solution imposed a significant influence on the Salmonella capture efficiency. The superhydrophilic poly(2-methacryloyloxyethyl phosphorylcholine (PMPC) coating could increase the capture performance of immunomagnetic nanoparticles effectively. At the Salmonella concentration of 101–104 cfu mL−1, the dextran coated iron oxide nanoparticles obtained by a coprecipitation method showed moderate capture efficiency of about 43–48%. An iron oxide cluster obtained by a solvothermal route obviously impeded the capture behavior, causing a lower Salmonella capture efficiency of about 25% and relatively higher false-positive result. Superior capture efficiency was achieved by PHEMA/PMPC coated immunomagnetic particles. The PHEMA/PMPC coated immunomagnetic particles yielded higher capture efficiency than that of the commercial Dynal immunomagnetic particles in the experimentally contaminated milk. After 5 hours culture in peptone water, the PCR detection limit of PHEMA/PMPC coated immunomagnetic nanoparticles was 101 cfu mL−1, one order higher than that of the commercial Dynal IMB under the same conditions. The superhydrophilic PMPC coated iron oxide nanoparticles show great promise in highly sensitive detection of pathogenic bacteria.