An Ultra-Thin Polymer Coating for the Tethering of Adenoviral Vector to the Surface of Coronary Stents

Our group has previously demonstrated stent-based gene delivery with either viral or plasmid vectors. However, these previous studies utilized bulky PLGA or collagen stent coatings, known to cause inflammatory reactions in stented arteries. In the present experiments we successfully attached adenoviruses either directly, or via anti-adenovirus antibodies to the steel surface of stents using chemical coordination with biphosphonates

Biphosphonate-Mediated Gene Vector Delivery from the Metal Surfaces of Stents

The clinical use of metallic expandable intravascular stents has resulted in imporved therapeutic outcomes for coronary artery disease. However, arterial reobstruction after stenting, in-stent restenosis, remains an important problem. Gene therapy to treat in-stent restenosis by using gene vector delivery from the metallic stent surfaces has never been demonstrated. The present studies investigated the hypothesis that metal-biphosphonate binding can enable site-specific gene vector delivery from metal surfaces. Polyallylamine biphosphonate (PAA-BP) was synthesized by using Michael addition methodology. Exposure to aqueous solutions of PAA-BP resulted in the formation of a monomolecular biphosphonate later on metal alloy surfaces (steel, nitinol, and cobalt-chromium), as demonstrated by x-ray photoelectron spectroscopy. Surface-bound PAA-BP enabled adenoviral (Ad) tethering due to covalent thiol-binding of either anti-Ad antibody or a recombinant Ad-receptor protein, D1. In arterial smooth muscle cell cultures, alloy samples configured with surface-tethered Ad were demonstrated to achieve site-specific transduction with a reporter gene, (GFP). Rat carotid stent angioplasties using metal stents exposed to aqueous PAA-BP and derivatized with anti-knob antibody or D1 resulted in extensive localized Ad-GFP expression in the arterial wall. In a separate study with a model therapeutic vector, Ad-inducible nitric oxide synthase (iNOS) attached to the biphosphonate-treated metal stent surface via D1, significant inhibition of restenosis was demonstrated (neointimal/media ration 1.68 ± 0.27 and 3.4 ± 0.35; Ad-iNOS vs. control, P \u3c 0.01). Is is concluded that effective gene vector delivery from metallic stent surfaces can be achieved using this approach

Nanocarrier-Based Delivery of SN22 as a Tocopheryl Oxamate Prodrug Achieves Rapid Tumor Regression and Extends Survival in High-Risk Neuroblastoma Models

Despite the use of intensive multimodality therapy, the majority of high-risk neuroblastoma (NB) patients do not survive. Without significant improvements in delivery strategies, anticancer agents used as a first-line treatment for high-risk tumors often fail to provide clinically meaningful results in the settings of disseminated, recurrent, or refractory disease. By enhancing pharmacological selectivity, favorably shifting biodistribution, strengthening tumor cell killing potency, and overcoming drug resistance, nanocarrier-mediated delivery of topoisomerase I inhibitors of the camptothecin family has the potential to dramatically improve treatment efficacy and minimize side effects. In this study, a structurally enhanced camptothecin analog, SN22, reversibly coupled with a redox-silent tocol derivative (tocopheryl oxamate) to allow its optimally stable encapsulation and controlled release from PEGylated sub-100 nm nanoparticles (NP), exhibited strong NB cell growth inhibitory activity, translating into rapid regression and durably suppressed regrowth of orthotopic, MYCN-amplified NB tumors. The robust antitumor effects and markedly extended survival achieved in preclinical models recapitulating different phases of high-risk disease (at diagnosis vs. at relapse with an acquired loss of p53 function after intensive multiagent chemotherapy) demonstrate remarkable potential of SN22 delivered in the form of a hydrolytically cleavable superhydrophobic prodrug encapsulated in biodegradable nanocarriers as an experimental strategy for treating refractory solid tumors in high-risk cancer patients

Magnetically Responsive Biodegradable Nanoparticles Enhance Adenoviral Gene Transfer in Cultured Smooth Muscle and Endothelial Cells

Nema sumnje da je terorizam jedan od trenutno najozbiljnijih problema savremenog društva. Veoma je važno da nacionalni pravni sistemi budu efikasni i dobro pripremljeni za izazove globalnog terorizma. Efikasnost, ali na pogrešan način, može dovesti do inkriminacija u krivičnom zakonodavstvu demokratskog društva koje ukazuju na autoritativne težnje. Zakonski okviri variraju od države do države što otežava opsežnu uporednu studiju, ali, ipak uočavamo razlike između zemalja koje prate međunarodne tendencije i onih koje smatraju da je njihovo postojeće represivno zakonodavstvo prilagođeno suzbijanju terorizma. Cilj ovog rada je da ukaže na to da su nacionalne jurisdikcije, na čelu s krivičnopravnim odredbama, ključna karika u suzbijanju terorizma. Ovom analizom ispitaćemo, takođe, trenutne zakonske strategije i trendove u borbi protiv terorizma i proveriti da li su tačne tvrdnje da nove zakonske odredbe u oblasti borbe protiv terorizma predstavljaju deo same logike terorizma i da negiraju pravnu državu.There is no doubt that terrorism is one of the most serious problems of contemporary society. It is very important for national legal systems to be efficient and well prepared to meet the global terrorism challenges. Legal frameworks vary widely from state to state, making a comprehensive comparative study difficult. However, there are some differences between those countries which follow international tendencies and those which believe that their existing repressive legislation is appropriate for fight against terrorism. The aim of this paper is to show that national jurisdictions, with their criminal law provisions, remain critical bodies on the first line of defence against terrorism. The paper deals with legal strategies and trends in fighting terrorism, and we will try to answer whether new legal provisions really follow the logic of terrorism and deny the rule of law

Stent-mediated gene delivery for site-specific transgene administration to the airway epithelium and management of tracheobronchial tumors.

BACKGROUND: Gene therapy is currently under investigation as a means of managing a variety of pulmonary diseases. Unfortunately, gene transfer to bronchial epithelium has been hampered by the lack of stable and efficient transduction. Recent studies have shown that gene vectors could be tethered to the metallic surfaces of intra-arterial stents. This approach enables efficacious and site-specific adenoviral gene delivery to the vascular endothelium. OBJECTIVES: We hypothesized that airway mesh stents impregnated with viral gene vectors could be used for local gene delivery to benign and malignant bronchial epithelium. METHODS: Serotype 5 adenoviral vectors (Ad5, E1-/E3-) containing the reporter genes green fluorescent protein (Ad.GFP) or β-galactoside/LacZ (Ad.LacZ), or a therapeutic gene, Ad.INF-β, were coupled to either metallic mesh disks or stents via anti-Ad knob antibodies. These platforms were assessed for their ability to transfect bronchial epithelial cells from both rats and humans, as well as murine (L1C2) and human (A549) lung cancer cell lines. Gene transfer was quantified by fluorescent microscopy, scanning fluorimetry for Ad.GFP, and light microscopy studies assessing β-galactosidase staining for Ad.LacZ. Metallic mesh and stent-mediated gene transfer was also performed in a murine flank tumor model and in a rat endotracheal tumor model in order to evaluate the therapeutic potential. RESULTS: In these studies, murine and human non-small cell lung cancer (NSCLC) cells were successfully transfected with reporter genes in vitro. Ad.LacZ-complexed mesh successfully transfected reporter genes into established murine flank NSCLC tumors. In addition, Ad.LacZ-tethered stents could effectively transfect both tracheobronchial epithelium and submucosal glands in rats. Similar epithelial transfection was achieved in ex vivo human bronchial epithelium. Pilot in vivo experimentation provided data supporting the concept that therapeutic genes could also be delivered with this technology. In additional pilot in vivo experiments, the growth of murine flank tumors was inhibited by placement of mesh disks coupled with Ad.muINF-β, and rats bearing endotracheal tumors demonstrated a trend towards prolonged survival with insertion of Ad.ratINF-β-tethered stents. CONCLUSIONS: Stent-mediated gene delivery successfully enabled site-specific vector administration to target rat and human airway cells in cell culture, organ culture and in vivo. Local tracheobronchial gene delivery via stents could provide a viable clinical solution for overcoming the difficulties encountered with vector delivery within the lungs, in particular by lowering requisite vector titers and by directing desired vectors to areas of interest. This strategy may prove valuable for treating tumors involving the tracheobronchial tree, as well as other nonmalignant tracheobronchial disorders