Role of Flow-Sensitive Endothelial Genes in Atherosclerosis and Antiatherogenic Therapeutics Development.

Atherosclerosis is a chronic inflammatory disease that is the underlying cause of cardiovascular disease which initiates from endothelial dysfunction from genetic and environmental risk factors, including biomechanical forces: blood flow. Endothelial cells (ECs) lining the inner arterial wall regions exposed to disturbed flow are prone to atherosclerosis development, whereas the straight regions exposed to stable flow are spared from the disease. These flow patterns induce genome- and epigenome-wide changes in gene expression in ECs.

Current Nanomedicine for Targeted Vascular Disease Treatment: Trends and Perspectives.

Nanotechnology has been developed to deliver cargos effectively to the vascular system. Nanomedicine is a novel and effective approach for targeted vascular disease treatment including atherosclerosis, coronary artery disease, strokes, peripheral arterial disease, and cancer. It has been well known for some time that vascular disease patients have a higher cancer risk than the general population.

Hypoxia inducible factor 1α inhibitor PX-478 reduces atherosclerosis in mice.

Background And Aims: Hypoxia inducible factor 1α (HIF1α) plays a critical role in atherosclerosis as demonstrated in endothelial-targeted HIF1α -deficient mice. However, it has not been shown if specific pharmacological inhibitors of HIF1α can be used as potential drugs for atherosclerosis. PX-478 is a selective inhibitor of HIF1α, which was used to reduce cancer and obesity in animal models.

Conditional Antisense Oligonucleotides Triggered by miRNA.

Antisense oligonucleotides (ASOs) are single-stranded short nucleic acids that silence the expression of target mRNAs and show increasing therapeutic potential. Since ASOs are internalized by many cell types, both normal and diseased cells, gene silencing in unwanted cells is a significant challenge for their therapeutic use. To address this challenge, we created conditional ASOs that become active only upon detecting transcripts unique to the target cell.

Effects of Decomplexation Rates on Ternary Gene Complex Transfection with α-Poly(l-Lysine) or ε-Poly(l-Lysine) as a Decomplexation Controller in An Easy-To-Transfect Cell or A Hard-To-Transfect Cell.

The tight binding of pDNA with a cationic polymer is the crucial requirement that prevents DNA degradation from undesired DNase attack to safely deliver the pDNA to its target site. However, cationic polymer-mediated strong gene holding limits pDNA dissociation from the gene complex, resulting in a reduction in transfection efficiency. In this study, to control the decomplexation rate of pDNA from the gene complex in a hard-to-transfect cell or an easy-to-transfect cell, either -poly(l-lysine) (APL) or -poly(l-lysine) (EPL) was incorporated into branched polyethylenimine (bPEI)-based nanocomplexes (NCs).

Effect of pH-Responsive Charge-Conversional Polymer Coating to Cationic Reduced Graphene Oxide Nanostructures for Tumor Microenvironment-Targeted Drug Delivery Systems.

Tumor tissue represents a slightly acidic pH condition compared to normal tissue due to the accumulation of lactic acids via anaerobic metabolism. In this work, pH-responsive charge-conversional polymer (poly(ethylene imine)-poly(l-lysine)-poly(l-glutamic acid), PKE polymer) was employed for endowing charge-conversional property and serum stability to poly(ethylene imine) conjugated reduced graphene oxide-based drug delivery system (PEI-rGO). Zeta-potential value of PEI-rGO coated with PKE polymer (PKE(PEI-rGO)) was -10.

pH-Responsive Charge-Conversional Poly(ethylene imine)-Poly(l-lysine)-Poly(l-glutamic acid) with Self-Assembly and Endosome Buffering Ability for Gene Delivery Systems.

Poly(ethylene imine)-poly(l-lysine)-poly(l-glutamic acid) (PKE) polymers with various glutamic acid portions were synthesized by ring opening polymerization of l-lysine -carboxyanhydride (NCA) and l-glutamic acid NCA from poly(ethylene imine) 1.8 kDa (PEI) as a macroinitiator. It was found that their glutamic acid residues could buffer endosomal pH.

Effects of the Physicochemical, Colloidal, and Biological Characteristics of Different Polymer Structures between α-Poly(l-lysine) and ε-Poly(l-lysine) on Polymeric Gene Delivery.

Though α-poly(l-lysine) (APL) has been well-studied in gene delivery, ε-poly(l-lysine) (EPL) with same repeating unit of l-lysine but different structure has been rarely investigated. This study compared various effects of their different structures in gene delivery processes. EPL showed less cytotoxicity and more proton buffering capacity for endosomal release than APL.

Agmatine-Containing Bioreducible Polymer for Gene Delivery Systems and Its Dual Degradation Behavior.

Agmatine-containing bioreducible polymer, poly(cystaminebis(acrylamide)-agmatine) (poly(CBA-AG)) was synthesized for gene delivery systems. It could form 200-300 nm sized and positively charged polyplexes with pDNA, which could release pDNA in reducing the environment due to the internal disulfide bonds cleavage. Poly(CBA-AG) also showed a spontaneous degradation behavior in aqueous condition in contrast to the backbone polymer, poly(cystaminebis(acrylamide)-diaminobutane) (poly(CBA-DAB)) lacking guanidine moieties, probably due to the self-catalyzed hydrolysis of internal amide bonds by guanidine moieties.

Crosslinked Polypropylenimine Dendrimers With Bioreducible Linkages for Gene Delivery Systems and Their Reductive Degradation Behaviors.

Crosslinked bioreducible polypropylenimine-cystaminebisacrylamides (PPI-CBAs) were synthesized for gene delivery systems. They formed nano-sized polyplexes with high stability even in reducing condition probably due to the re-crosslinking. PPI-CBAs displayed high transfection efficiency comparable to PEI25k in serum condition.

Cationic methylcellulose derivative with serum-compatibility and endosome buffering ability for gene delivery systems.

In this work, methylcellulose was employed as a template polymer with graft of polyethylenimine 0.8 kDa (PEI0.8k) for gene delivery systems.

Anticancer activity of ferulic acid-inorganic nanohybrids synthesized via two different hybridization routes, reconstruction and exfoliation-reassembly.

We have successfully prepared nanohybrids of biofunctional ferulic acid and layered double hydroxide nanomaterials through reconstruction and exfoliation-reassembly routes. From X-ray diffraction and infrared spectroscopy, both nanohybrids were determined to incorporate ferulic acid molecules in anionic form. Microscopic results showed that the nanohybrids had average particle size of 150 nm with plate-like morphology.

Therapeutic gene delivery using bioreducible polymers.

Bioreducible polymers, which can be degraded in reducing environment due to the cleavage of internal disulfide bonds, have been developed for gene delivery systems. They show high stability in extracellular physiological condition and cytoplasm-specific release of genetic materials, as well as decreased cytotoxicity because cytoplasm is a reducing environment containing high level of reducing molecules such as glutathione. Based on these advantages, recently, many bioreducible polymers have been further investigated with therapeutic genes for the treatment of diseases and demonstrated promising results.