Zibin Gao

Nanotechnology applied to overcome tumor drug resistance

Emerging multidrug resistance (MDR) to chemotherapy is a major obstacle in successfully treating malignant diseases. Nanotechnology provides an innovative and promising alternative strategy compared to conventional small molecule chemotherapeutics to circumvent MDR. This review focuses on recent literature examples of nanotechnology applications to overcome MDR. The advantages and limitations of various nanotechnologies are discussed as well as possible approaches to overcome the limitations. Developing a practical nanotechnology-based drug delivery system requires further studies of the tumor microenvironment, the mechanisms of MDR to chemotherapy, the optimal dosage regimen of anticancer drugs and/or siRNA, the transport kinetics of nanocarriers in tumor stroma and the pharmacokinetics of drug-loaded nanocarriers within MDR tumor cells.

Mesenchymal stem cells: a potential targeted-delivery vehicle for anti-cancer drug loaded nanoparticles

UNLABELLED The targeted delivery of anticancer agents is a promising field in anticancer therapy. Mesenchymal stem cells (MSCs) have inherent tumor-tropic and migratory properties, which allow them to serve as vehicles for targeted drug delivery systems for isolated tumors and metastatic diseases. MSCs have been successfully studied and discussed as a vehicle for cancer gene therapy. However, MSCs have not yet been discussed adequately as a potential vehicle for traditional anticancer drugs. In this review, we will examine the potential of MSCs as a targeted-delivery vehicle for anticancer drug-loaded nanoparticles (NPs), summarize various challenges, and discuss possible solutions for these challenges. FROM THE CLINICAL EDITOR In this review, the feasibility of mesenchymal stem cell-based targeted delivery of anticancer agents is discussed.

Na+-K+-ATPase, a potent neuroprotective modulator against Alzheimer disease

Alzheimer disease (AD) is a neurodegenerative disorder clinically characterized by progressive cognitive and memory dysfunction, which is the most common form of dementia. Although the pathogenesis of neuronal injury in AD is not clear, recent evidences suggest that Na+‐K+‐ATPase plays an important role in AD, and may be a potent neuroprotective modulator against AD. This review aims to provide readers with an in‐depth understanding of Na+‐K+‐ATPase in AD through these modulations of some factors that are as follows, which leads to the change of learning and memory in the process of AD.

Crosstalk between dopamine receptors and the Na⁺/K⁺-ATPase (review).

Dopamine (DA) receptors, which belong to the G protein-coupled receptor family, are the target of ~50% of all modern medicinal drugs and constitute a large and diverse class of proteins whose primary function is to transduce extracellular stimuli into intracellular signals. Na+/K+-ATPase (NKA) is ubiquitous and crucial for the maintenance of intracellular ion homeostasis and excitability. Furthermore, it plays a critical role in diverse effects, including clinical cardiotonic and cardioprotective effects, ischemic preconditioning in the brain, natriuresis, lung edema clearance and other processes. NKA regulation is of physiological and pharmacological importance and has species- and tissue-specific variations. The activation of DA receptors regulates NKA expression/activity and trafficking in various tissues and cells, for example in the kidney, lung, intestine, brain, non-pigmented ciliary epithelium and the vascular bed. DA receptor-mediated regulation of NKA mediates a diverse range of cellular responses and includes endocytosis/exocytosis, phosphorylation/dephosphorylation of the α subunit of NKA and multiple signaling pathways, including phosphatidylinositol (PI)-phospholipase C/protein kinase (PK) C, cAMP/PKA, PI3K, adaptor protein 2, tyrosine phosphatase and mitogen-activated protein kinase/extracellular signal-regulated protein kinase. Furthermore, in brain and HEK293T cells, D1 and D2 receptors exist in a complex with NKA. Among D1 and D2 receptors and NKA, regulations are reciprocal, which leads to crosstalk between DA receptors and NKA. In the present study, the current understanding of signaling mechanisms responsible for the crosstalk between DA receptors and NKA, as well as with specific consequent functions, is reviewed.

Therapeutic Targets for Cerebral Ischemia Based on the Signaling Pathways of the GluN2B C Terminus

Overactivation of the N-methyl-d-aspartate receptor (NMDAR) after cerebral ischemia is a crucial reason for neuron death. Although NMDAR antagonists have exhibited neuroprotective effects in animal models, it is disappointing that several severe side effects have occurred in patients. NMDAR is a heteromer containing 2 obligate N-methyl-D-aspartate receptor 1 (GluN1) subunits and a variety of GluN2 and GluN3 subunits. The GluN2 subunit, which contributes specifically to neuron death after stroke, has been studied extensively. An opposing action of the GluN2A and GluN2B subunits in mediating cell death and cell survival was observed.1,2 The results indicate that the GluN2A subunit produces prosurvival activity, whereas the GluN2B subunit leads to a prodeath signal. However, von Engelhardt et al3 found that the GluN2A subunit can also mediate NMDA-dependent toxicity in DIV21 cultures. This paradox may have resulted because the pharmacological approach used to study subunit composition was not flawless.4 In view of this limitation and according to the methods of molecular biology, Martel et al5 demonstrated that the C-terminal domains of GluN2B promote neuronal death more efficiently than those of GluN2A in cerebral ischemia.5 In short, NMDARs containing GluN2B are more lethal than those containing GluN2A. Prodeath signaling pathways mediated by neuronal nitric oxide synthase (nNOS), death-associated protein kinase 1 (DAPK1), phosphatase and tensin homolog located on chromosome 10 (PTEN), and calcium/calmodulin-dependent protein kinase II (CaMKII) have been linked to GluN2B activation. Therapeutic targets based on these signaling pathways of the GluN2B carboxyl terminus (C terminus) will be introduced in this review. ### GluN2B–nNOS Signaling Pathway The GluN2B–nNOS signaling pathway, which plays an important role in neuron death, is the most widely studied GluN2B pathway (Figure 1). Figure 1. The GluN2B–nNOS signaling pathway. Based on the PDZ domains, postsynaptic density-95 (PSD-95) assembles GluN2B and nNOS into a macromolecular complex. After …

Study of amphotericin B magnetic liposomes for brain targeting

This study aims to prepare amphotericin B magnetic liposomes (AmB-MLPs), which may improve drug concentration in brain, enhance magnetic targeting for brain and reduce drug toxicity in the presence of magnetic field. AmB-MLPs were prepared by means of film dispersion-ultrasonication, and their physical properties were characterized. In vivo, the magnetic targeting for brain by carotid artery administration was investigated. The particle size of AmB-MLPs was 240±11 nm, the encapsulation efficiency was 79.32±2.03%, and the saturation magnetization was 32.54 memu g⁻¹ at room temperature, which had good magnetic responsiveness. The group of AmB injection was delivered by carotid artery, nevertheless they all died after 20 min. AmB-MLPs were injected by carotid artery, and the drug concentration in brain tissue was obviously increased in presence of magnetic field than that of in absence of magnetic field (P<0.05). The Prussian blue staining in brain of SD rats showed that the density of blue staining-positive particles in brain tissue of applying magnetic field group was higher than that of non magnetic field group. These results suggested that AmB-MLPs could reinforce brain targeting and reduce drug toxicity when they were injected by carotid artery under the effect of magnetic field.

Preparation and drug release mechanism of CTS-TAX-NP-MSCs drug delivery system

Targeting delivery of anticancer agents is a promising field in anticancer therapy. Inherent tumor-tropic and migratory properties of mesenchymal stem cells (MSCs) make them potential vehicles for targeting drug delivery systems for tumors. Although, MSCs have been successfully studied and discussed as a vehicle for cancer gene therapy, they have not yet been studied adequately as a potential vehicle for traditional chemical anticancer drugs. In this study, we have engineered MSCs as a potential targeting delivery vehicle for paclitaxel (TAX)-loaded nanoparticles (NPs). The size, surface charge, starving time of MSCs, incubating time and concentration of NPs could influence the efficiency of NPs uptake. In vitro release of TAX from CTS (chitosan)-TAX-NP-MSCs and the expression of P-glycoprotein demonstrated that release of TAX from MSCs might involve both passive diffusion and active transport. In vitro migration assays indicated that MSCs at passage number 3 have the highest migrating ability. Although, the migration ability of CTS-TAX-NP-MSCs could be inhibited by uptake of CTS-TAX-NPs, this ability could recover 6 days after the internalization.

The Functional and Molecular Properties, Physiological Functions, and Pathophysiological Roles of GluN2A in the Central Nervous System

The NMDA receptor, which is heavily involved in several human brain diseases, is a heteromeric ligand-gated ion channel that interacts with multiple intracellular proteins through the C-termini of different subunits. GluN2A and GluN2B are the two primary types of GluN2 subunits in the forebrain. During the developmental period, there is a switch from GluN2B- to GluN2A-containing NMDA receptors in synapses. In the adult brain, GluN2A exists at synaptic sites more abundantly than GluN2B. GluN2A plays important roles not only in synaptic plasticity but also in mediating physiological functions, such as learning and memory. GluN2A has also been involved in many common human diseases, such as cerebral ischemia, seizure disorder, Alzheimer’s disease, and systemic lupus erythematosus. The following review investigates the functional and molecular properties, physiological functions, and pathophysiological roles of the GluN2A subunit.

Glutamate Transporters/Na+, K+-ATPase Involving in the Neuroprotective Effect as a Potential Regulatory Target of Glutamate Uptake

The glutamate (Glu) transporters GLAST and GLT-1, as the two most important transporters in brain tissue, transport Glu from the extracellular space into the cell protecting against Glu toxicity. Furthermore, GLAST and GLT-1 are sodium-dependent Glu transporters (GluTs) that rely on sodium and potassium gradients generated principally by Na+, K+-ATPase to generate ion gradients that drive Glu uptake. There is an interaction between Na+, K+-ATPase and GluTs to modulate Glu uptake, and Na+, K+-ATPase α, β or γ subunit can be directly coupled to GluTs, co-localizing with GLAST or GLT-1 in vivo to form a macromolecular complex and operate as a functional unit to regulate glutamatergic neurotransmission. Therefore, GluTs/Na+, K+-ATPase may be involved in the neuroprotective effect as a potential regulatory target of Glu uptake in neurodegenerative diseases induced by Glu-mediated neurotoxicity as the final common pathway.

The Role of GluN2A in Cerebral Ischemia: Promoting Neuron Death and Survival in the Early Stage and Thereafter

Over-activation of NMDA receptors is a crucial step required for brain damage following a stroke. Although clinical trials for NMDA receptor blockers have failed, the role of GluN2A subunit in cerebral ischemia has been extensively evaluated in recent years. However, the effect of GluN2A on neuron damage induced by cerebral ischemia remains a matter of controversy. The underlying reason may be that GluN2A mediates both pro-death and pro-survival effects. These two effects result from two mutually excluding pathways, Ca2+ overload-dependent pro-death signaling and C-terminal-dependent pro-survival signaling, respectively. During the early stage of cerebral ischemia, over-activation of GluN2A plays an important role in Ca2+ overload. Under this condition, pro-death signaling might overcome pro-survival signaling. When GluN2A activity is restored almost to the normal level over time, pro-survival signaling of GluN2A will be dominant. The hypothesis that GluN2A promotes neuron death and survival in the early stage of cerebral ischemia and thereafter will be introduced in detail in this review.