Focused ultrasound-mediated cerium-based nanoreactor against Parkinson's disease via ROS regulation and microglia polarization.

Neuronal damage caused by oxidative stress and inflammatory microenvironment dominated by microglia are the main obstacles in the treatment of Parkinson's disease (PD). In this study, we developed an integrated nanoreactor Q@CeBG by encapsulating CeO2 nanozyme and quercetin (Que) into glutathione-modified bovine serum albumin, and then selected focused ultrasound (FUS) to temporarily open the blood-brain barrier (BBB) to enhance the accumulation level of Q@CeBG in the brain. Q@CeBG exhibited superior multi-ROS scavenging activity. Under the assistance of FUS, Q@CeBG nanoreactor can penetrate the BBB and act on neurons as well as microglia, reducing the neuron's oxidative stress level and polarizing microglia's phenotype from proinflammatory M1 to anti-inflammatory M2. In vitro and In vivo experiments demonstrated that Q@CeBG nanoreactor with good biocompatibility exhibit outstanding neuroprotection and immunomodulatory effects. In short, this dual synergetic nanoreactor will become a reliable platform against PD.

NIR-Assisted MgO-Based Polydopamine Nanoparticles for Targeted Treatment of Parkinson's Disease through the Blood-Brain Barrier.

The blood-brain barrier (BBB) is a major limiting factor that prevents the treatment of Parkinson's disease (PD). In the present study, MgOp@PPLP nanoparticles are explored by using MgO nanoparticles as a substrate, polydopamine as a shell, wrapping anti-SNCA plasmid inside, and modifying polyethylene glycol, lactoferrin, and puerarin on the surface to improve the hydrophilicity, brain targeting and antioxidant properties of the particles, respectively. MgOp@PPLP exhibits superior near-infrared radiation (NIR) response. Under the guidance of photothermal effect, these MgOp@PPLP particles are capable of penetrating the BBB and be taken up by neuronal cells to exert gene therapy and antioxidant therapy. In both in vivo and in vitro models of PD, MgOp@PPLP exhibits good neuroprotective effects. Therefore, combined with noninvasive NIR radiation, MgOp@PPLP nanoplatform with good biocompatibility becomes an ideal material to combat neurodegenerative diseases.

Rational design of small-molecules to recognize G-quadruplexes of c-MYC promoter and telomere and the evaluation of their in vivo antitumor activity against breast cancer.

DNA G4-structures from human c-MYC promoter and telomere are considered as important drug targets; however, the developing of small-molecule-based fluorescent binding ligands that are highly selective in targeting these G4-structures over other types of nucleic acids is challenging. We herein report a new approach of designing small molecules based on a non-selective thiazole orange scaffold to provide two-directional and multi-site interactions with flanking residues and loops of the G4-motif for better selectivity. The ligands are designed to establish multi-site interactions in the G4-binding pocket. This structural feature may render the molecules higher selectivity toward c-MYC G4s than other structures. The ligand-G4 interaction studied with 1H NMR may suggest a stacking interaction with the terminal G-tetrad. Moreover, the intracellular co-localization study with BG4 and cellular competition experiments with BRACO-19 may suggest that the binding targets of the ligands in cells are most probably G4-structures. Furthermore, the ligands that either preferentially bind to c-MYC promoter or telomeric G4s are able to downregulate markedly the c-MYC and hTERT gene expression in MCF-7 cells, and induce senescence and DNA damage to cancer cells. The in vivo antitumor activity of the ligands in MCF-7 tumor-bearing mice is also demonstrated.

Co-delivery of PSMA antigen epitope and mGM-CSF with a cholera toxin-like chimeric protein suppressed prostate tumor growth via activating dendritic cells and promoting CTL responses.

Subunit vaccines derived from tumor antigens play a role in tumor therapy because of their unique advantages. However, because of the weak immunogenicity of peptides in subunit vaccines, it is difficult to trigger an effective cytotoxic T lymphocyte (CTL) response, which is critical for cancer therapy. A requirement for the activation of CTL cells by exogenous antigens is the stimulation of antigen presenting cells (APC) with the help of adjuvants and cross-presentation to T lymphocytes. Standard nonconjugated adjuvant-peptide mixtures do not ensure co-targeting of the antigen and the adjuvant to the same APC, which limits the effects of adjuvants. In this study, a fusion protein consisting of murine granulocyte-macrophage colony stimulating factor (mGM-CSF) fused with CTA2 (A2 subunit of cholera toxin) was generated and assembled with CTB-PSMA624-632 (prostate specific membrane antigen (PSMA) peptide 624-632 fused to CTB) to obtain a cholera toxin-like protein. The chimeric protein retained the biological activity of mGM-CSF and had stronger GM1 binding activity than (CTB-PSMA624-632)5. C57BL/6J mice immunized with the CT-like chimeric protein exhibited delayed tumor growth following challenge with human PSMA-EGFP-expressing RM-1 cells. Experiment results showed that the CT-like chimeric protein could induce the maturation of DC cells and improve CTL responses. Overall, these results indicate that the nasal administration of a CT-like chimeric protein vaccine results in the development of effective immunity against prostate tumor cells and might be useful for future clinical anti-tumoral applications.

Synthesis of Double Interfering Biodegradable Nano-MgO Micelle Composites and Their Effect on Parkinson's Disease.

Although gene therapy targeting the α-synuclein gene (SNCA) has achieved outstanding results in the treatment of Parkinson's disease (PD), the lack of a suitable gene delivery system and inadequate therapeutic effects remains a tremendous obstacle for RNAi therapy. Here, a degradable nano-MgO micelle composite (MgO(pDNA)-INS-Plu-mRNA-NGF) with double interference (mediated by RNAi and α-synuclein (α-syn)-targeted mRNA) was constructed. Binding mRNA treatment significantly increased the inhibitory effect compared to the reduction of α-syn expression by RNAi alone. Moreover, the cell experiments demonstrated that the viability of the PD cell model can be significantly improved by nano-MgO micelle composite treatment. More importantly, the composite has the ability to penetrate the blood brain barrier and deliver genes and mRNA to neurons through endocytosis mediated by the nerve growth factor and its receptors, thus significantly downregulating the expression of α-syn in the PD mice model without causing damage to other major organs. Overall, this work provides a novel insight into the design of biomaterials for gene therapy for PD.

An in vitro and in vivo study of the brain-targeting effects of an epidermal growth factor-functionalized cholera toxin-like chimeric protein.

The development of neuroprotective drugs has proven to be extremely difficult because of the blood-brain barrier. Intranasal administration is thought to transport the drug from the nasal cavity along the olfactory and trigeminal nerves to the brain, thus bypassing the blood-brain barrier. However, macromolecular protein drugs have low delivery efficiency via this route in general. We hypothesized that an innocuous cholera toxin-like chimeric protein could better enhance the efficiency of protein delivery through the intranasal route. To test this hypothesis, we designed an enhanced green fluorescent protein (EGFP) chimera to evaluate the effect of the cholera toxin (CT) as a carrier for drug delivery into the brain. Then, the EGFP was replaced with epidermal growth factor (EGF) in the chimeric protein, and the therapeutic effect of the new chimeric protein was studied in an LPS-induced neuritis mouse model. The results suggest that the CT-like chimeric protein can bypass the blood-brain barrier and enter the brain in approximately 30 min. This EGF chimeric protein can effectively protect the spatial cognitive ability of and confer anti-anxiety protection to mice. The results indicate that cholera toxin-like chimeric proteins are potential tools for effectively delivering macromodecular drugs into the brain through intranasal administration.