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A main pathogenic factor of atherosclerosis is the local oxidative stress microenvironment. Probucol (PU) has anti-inflammatory, antioxidative and hypolipidemic effects, showing great potential to treat atherosclerosis. However, its low bioavailability limits its development. Herein, PU was encapsulated to form RP-PU with star-shaped polymers and red blood cell membranes. Star-shaped polymers show lower solution viscosity, a smaller hydrodynamic radius and a higher drug loading content than linear polymers. RP-PU had a good sustained-release effect and excellent biocompatibility. RP-PU can be efficiently internalized by cells to improve biodistribution. ApoE -/- mice were treated with RP-PU, and the contents of lipids and related metabolic enzymes were effectively reduced. The collagen fibers in the aortic root sections were reduced by RP-PU compared with control and PU. Moreover, RP-PU inhibited foam cell formation, decreased ICAM-1 and MCP-1 expression and delayed lesion formation. Consequently, RP-PU biomimetic nanoparticles can be developed as an anti-atherosclerotic nanotherapeutic., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Stimulus-responsive polymer materials have attracted much attention as drug carriers because of the ability to deliver drugs to the active site. Reactive oxygen species (ROS) play crucial roles in cellular signaling and regulation of oxygen homeostasis. However, ROS are present in abnormally high levels in many pathological environments. Based on the above points, three-arm poly(lactic- co -glycolic acid)-PO-poly(ethylene glycol) (3s-PLGA-PO-PEG or simply PP) was synthesized by using peroxalate esters (PO) as hydrogen peroxide-responsive linkages. PP was used to deliver promote hematopoietic recovery drugs erythropoietin (EPO) and EPO nanoparticles (EPO NPs) were prepared. We established a hematopoietic system injury model by ionizing radiation (IR) and unexpectedly found the good therapeutic effect of blank PP. Moreover, the administration of EPO NPs obviously decreased IR-induced ROS in bone marrow cells (BMCs) and reconstituted hematopoietic stem cells in BMCs. This study reveals a novel ROS-responsive polymer material that could be employed to remove excess ROS in the lesion and promote the efficacy of drug therapy.

Polydopamine nanoparticles (PDA NPs) were prepared via dopamine self-polymerization; then, tumor cell lysate (TCL) was covalently attached onto the PDA NPs. The TCL loading capacity was 480 μg per mg of PDA NPs, and the resulting TCL@PDA NPs (241.9 nm) had perfect storage stability and negligible cytotoxicity against APCs. Tumor-bearing mice vaccinated with TCL@PDA NPs experienced significant delay in tumor progression due to the sufficient amount of CTLs and M1-type TAM as well as the deficient number of immunosuppression-related cells in the tumor tissues. Furthermore, empty PDA NPs had the ability to modulate DC maturation and delayed the development of tumors by facilitating the production of activated T cells and decreasing the subpopulation of MDSCs within the tumor microenvironment. Overall, these PDA NPs are expected to be a promising candidate for application as antigen delivery carriers because of their facile antigen loading method as well as their simple and rapid preparation process.

Complete reendothelialization followed by inhibition of smooth muscle cell (SMC) proliferation is considered as an effective therapeutic option to prevent restenosis. We have designed poly(lactide-co-glycolide)-loaded bilayered nanoparticles (NPs) with the ability to sequentially release vascular endothelial growth factor (VEGF)-encoding plasmids from the outer layer and paclitaxel (PTX) from the core to promote endothelial regeneration as well as prevent restenosis. Comparing with conventional NPs, which release VEGF plasmid and PTX simultaneously, we expect that the bilayered NPs could release the VEGF plasmid more rapidly, followed by a delayed release of PTX, resulting in an efficient VEGF gene transfection, which ideally could promote reendothelialization and inhibit excessive SMC growth. Indeed, in the present study, we have observed efficient gene transfection using a model plasmid as well as cell growth attenuation in vitro using Chinese hamster ovary cells. Therapeutic efficacy of the bilayered NPs on restenosis was further evaluated in vivo using a rabbit model of atherosclerosis. The bilayered NPs were administered locally via balloon angioplasty to the injured aortic wall through perfusion. Twenty-eight days after the NP administration, rabbits treated with the bilayered NPs exhibited rapid reendothelialization and inhibition of restenosis, as demonstrated by histological analysis. Increased level of VEGF and decreased level of C-reactive protein, a biological marker that is closely related to atherosclerosis, were also observed from animals treated with the bilayered NPs, implicating ameliorated atherosclerosis. Our results suggest that the VEGF plasmid-/PTX-loaded bilayered NPs exert a beneficial impact on atherosclerotic restenosis by sequentially releasing VEGF and PTX in vivo.

Previous reports showed that arginine-rich peptides and oligoarginines facilitated the cellular internalization of DNA and proteins. A number of studies demonstrated that arginine-conjugated chitosan (CS)/DNA nanoparticles (ACGN) mediated significantly higher expression of the transgenes when compared with CS/DNA nanoparticles (CGN). However, the underlying mechanisms remain poorly understood. In the current study, the endocytic pathways through which cells internalize ACGN and CGN were explored by incubating the fluorescent CGN or ACGN with A10 cells in the presence of a variety of inhibitors of different endocytic pathways. The data accumulated in the current study revealed that conjugation of arginine moieties onto CS molecules enhanced the cellular uptake of the polymer/DNA nanoparticles and their transgenic efficacy, probably due to changes in the endocytic pathways, which led to the preference of internalization of ACGN by the caveolin-mediated endocytosis in comparison with that of CGN. These findings provide further support to the previous observations that ACGN mediated much higher expression of the transgenes when compared with CGN., (Copyright © 2011 Wiley Periodicals, Inc.)

Previous studies showed that arginine-conjugated chitosan (ACS)/DNA nanoparticles (ACGN) mediated significantly higher expression of the transgenes when compared with chitosan (CS)/DNA nanoparticles (CGN). However, the interactions between ACGN and immune cells still remain poorly understood. The present study investigated whether ACGN affected the initial differentiation direction of human naive CD4(+) T cells, either directly or indirectly. It was demonstrated that both ACGN and CGN induced slightly higher production of IL-12 by THP-1 cells in the order of ACGN > CGN. However, this macrophage stimulating activity was much less significant when compared with lipopolysaccharide and did not impact on the differentiation of the naive CD4(+) T cells separated from the nanoparticles and THP-1 cells by a 0.1-μm diameter polycarbonate semipermeable membrane, which allows the pass through of macromolecules including IL-12. It also demonstrated that, when directly exposed to naive CD4(+) T cells, none of the nanoparticles induced either the activation of the naive CD4(+) T cells in the absence of recombinant human IL-4 (rhIL-4) or IFN-γ (rhIFN-γ) that induce naive CD4(+) T cell polarization or any changes in the differentiation direction of the naive CD4(+) T cells in the presence of the corresponding cytokines., (Copyright © 2010 Wiley Periodicals, Inc.)

Arginine-chitosan conjugate (Arg-CS) was demonstrated to mediate significantly elevated expression of the transgenes in comparison to chitosan (CS). However, little is known about the hemocompatibility of Arg-CS/DNA nanoparticles (ACGN). This study evaluated the coagulation properties of the ACGN and CS/gene nanoparticles (CGN) by looking at the impact of the nanoparticles on the activated partial thrombin time (APTT), prothrombin time (PT), thrombin time (TT), and hemolysis ratio (HR). It demonstrated that both ACGN and CGN, at the concentration containing 50 μg/mL of DNA, led to moderate increases of APTT but no obvious change in PT and TT in vitro. Intravenous injection of CGN or ACGN (125 μg of DNA content/100 g of body weight) into rat did not result in any significant changes in PT but moderately increased APTT and TT. ACGN was demonstrated to be a slightly stronger inhibitor of blood coagulation as compared to CGN. No obvious hemolysis was induced by the nanoparticles. Taken together, the results in the present study indicated that introduction of arginine moieties into chitosan enhanced its anticoagulant property, which would be beneficial for applications in direct contact with blood., (© 2010 Wiley Periodicals, Inc.)

The biosafety of gene delivery vectors has received much more attention in recent years. In this article, the biosafety of non-viral gene delivery vectors was mainly discussed. Recent developments in researches on toxicity, nano-effect, blood compatibility and immune response of non-viral gene delivery vectors were reviewed.

Two kinds of chitosan of different molecular weight (50 kDa and 400 kDa) were employed to form nanoparticles with 32P-labeled plasmid DNA at different N/P ratios by complex coacervation method. The characteristics of chitosan gene nanoparticles (CGN) were measured. The cellular uptake of DNA nanoparticles was evaluated by A10 and K562 cells. The in vitro cytotoxicity of DNA nanoparticles was determined by the MTT assays. Cellular uptake of the DNA nanoparticles increased with increasing chitosan molecular weight and N/P ratio. It also correlated with the zeta potential of the DNA nanoparticles. Chitosan-DNA nanoparticles were much less cytotoxic when compared with Lipofectamine 2000-DNA nanoparticles.

The preparation and cell transfection of chitosan-DNA nanoparticles were studied. The TFPI (tissue factor pathway inhibitor) or EGFP (enhanced green fluorescent protein) plasmid DNA was encapsulated with chitosan to form gene nanoparticles. The results with TEM showed that the nanoparticles were of sphere shape. The mean diameter of the nanoparticles was 149 nm and the diameter ranged from 80-250 nm, which were measured by the photo related spectrometry (PCS). The encapsulation efficiency of DNA was 96% +/- 1.38% and the DNA content in the nanoparticles was 37% +/- 3.0%. The encapsulated DNA could be protected from the degradation by DNase I. The transfection efficiency of chitosan nanoparticles were about equivalent to that of the LipofectAMINETM reagent. Our results also showed that chitosan nanoparticles were nontoxic to cultured cells.

Chitosan (CS) is one of the most widely studied polymers in non-viral gene delivery since it is a cationic polysaccharide that forms nanoparticles with DNA and hence protects the DNA against digestion by DNase. However, the impact of CS/DNA nanoparticle on the immune system still remains poorly understood. Previous investigations did not found CS/DNA nanoparticles had any significant impact on the function of human and murine macrophages. To date, little is known about the interaction between CS/DNA nanoparticles and naive CD4 T cells. This study was designed to investigate whether CS/DNA nanoparticles affect the initial differentiation direction of human naive CD4 T cells. The indirect impact of CS/DNA nanoparticles on naive CD4 T cell differentiation was investigated by incubating the nanoparticles with human macrophage THP-1 cells in one chamber of a transwell co-incubation system, with the enriched human naive CD4 T cells being placed in the other chamber of the transwell. The nanoparticles were also co-incubated with the naive CD4 T cells to explore their direct impact on naive CD4 T cell differentiation by measuring the release of IL-4 and IFN-γ from the cells. It was demonstrated that CS/DNA nanoparticles induced slightly elevated production of IL-12 by THP-1 cells, possibly owing to the presence of CpG motifs in the plasmid. However, this macrophage stimulating activity was much less significant as compared with lipopolysaccharide and did not impact on the differentiation of the naive CD4 T cells. It was also demonstrated that, when directly exposed to the naive CD4 T cells, the nanoparticles induced neither the activation of the naive CD4 T cells in the absence of recombinant cytokines (recombinant human IL-4 or IFN-γ) that induce naive CD4 T cell polarization, nor any changes in the differentiation direction of naive CD4 T cells in the presence of the corresponding cytokines. [ABSTRACT FROM AUTHOR]