Magnetic nanoparticle transport within flowing blood and into surrounding tissue

Magnetic drug delivery refers to the physical confinement of therapeutic magnetic nanoparticles to regions of disease, tumors, infections and blood clots. Predicting the effectiveness of magnetic focusing in vivo is critical for the design and use of magnetic drug delivery systems. However, current simple back-of-the-envelope estimates have proven insufficient for this task. In this article, we present an analysis of nanoparticle distribution, in and around a single blood vessel (a Krogh tissue cylinder), located at any depth in the body, with any physiologically relevant blood flow velocity, diffusion and extravasation properties, and with any applied magnetic force on the particles. For any such blood vessel our analysis predicts one of three distinct types of particle behavior (velocity dominated, magnetic dominated or boundary-layer formation), which can be uniquely determined by looking up the values of three nondimensional numbers we define. We compare our predictions to previously published magnetic-focusing in vitro and in vivo studies. Not only do we find agreement between our predictions and prior observations, but we are also able to quantitatively explain behavior that was not understood previously

A dynamic magnetic shift method to increase nanoparticle concentration in cancer metastases: a feasibility study using simulations on autopsy specimens

A nanoparticle delivery system termed dynamic magnetic shift (DMS) has the potential to more effectively treat metastatic cancer by equilibrating therapeutic magnetic nanoparticles throughout tumors. To evaluate the feasibility of DMS, histological liver sections from autopsy cases of women who died from breast neoplasms were studied to measure vessel number, size, and spatial distribution in both metastatic tumors and normal tissue. Consistent with prior studies, normal tissue had a higher vascular density with a vessel-to-nuclei ratio of 0.48 ± 0.14 (n = 1000), whereas tumor tissue had a ratio of 0.13 ± 0.07 (n = 1000). For tumors, distances from cells to their nearest blood vessel were larger (average 43.8 μm, maximum 287 μm, n ≈ 5500) than normal cells (average 5.3 μm, maximum 67.8 μm, n ≈ 5500), implying that systemically delivered nanoparticles diffusing from vessels into surrounding tissue would preferentially dose healthy instead of cancerous cells. Numerical simulations of magnetically driven particle transport based on the autopsy data indicate that DMS would correct the problem by increasing nanoparticle levels in hypovascular regions of metastases to that of normal tissue, elevating the time-averaged concentration delivered to the tumor for magnetic actuation versus diffusion alone by 1.86-fold, and increasing the maximum concentration over time by 1.89-fold. Thus, DMS may prove useful in facilitating therapeutic nanoparticles to reach poorly vascularized regions of metastatic tumors that are not accessed by diffusion alone

Abordul laparoscopic în achalazia cardiei – experienţa personală

Spitalul Clinic de Urgenţă “Bagdasar-Arseni” Bucureşti, România, Spitalul Clinic “Carol Davila” Bucureşti, România, Spitalul Judeţean de Urgenţă Piteşti, România, Al XI-lea Congres al Asociației Chirurgilor „Nicolae Anestiadi” din Republica Moldova și cea de-a XXXIII-a Reuniune a Chirurgilor din Moldova „Iacomi-Răzeșu” 27-30 septembrie 2011Obiective. Ne propunem prin prezenta lucrare să analizăm metoda laparoscopică în tratamentul chirurgical al herniei gastrice transhiatale, criteriile de includere pentru chirurgia laparoscopică, limitele metodei şi nu în ultimul rând curba de invăţare într-un serviciu de chirurgie generală. Material şi metodă. Intervalul luat în calcul a fost iunie 2008 – iunie 2011 pe un lot de 9 pacienţii, marea lor majoritate femei, la care s-a intervenit chirurgical laparoscopic pentru achalazia cardiei. Am analizat atât metoda laparoscopică din punct de vedere a abordului în comparatie cu chirurgia clasicaă, cât şi pacienţii din punct de vedere al sexului, vârstei, tarelor asociate. Am practicat miotomie Heller în marea majoritate a cazurilor asociată cu o valvă anterioară Dor. Rezultate. Din punct de vedere al rezultatului postoperator rezultatele sunt cel puţin comparabile cu cele din chirurgia clasică, dar laparoscopia are avantajul invazivităţii minime, duratei scurte de spitalizare, reintegrării socio- profesionale rapide şi, nu în ultimul rând, reducerea costurilor per ansamblu. După o dotare corespunzatoare şi după parcurgerea curbei de învaţare, rezultatele postoperatorii sunt benefice, iar superioritatea metodei, mai ales în cazurile cu patologie asociată marcată, este evidentă. Concluzii. Caracterele expuse ale chirurgiei laparoscopice în patologia incriminată o fac net superioară metodei clasice ma ales prin caracterul minim invaziv şi scurtarea timpului operator şi implicit al celui anestezic. Rezultatele, cel putin comparabile cu cele din chirurgia deschisă, fac din metoda laparoscopică tratamentul de elecţie mai ales din punct de vedere socio- profesional, dar şi din punct de vedere economic

Synergistic Inhibition of Endothelial Cell Proliferation, Tube Formation, and Sprouting by Cyclosporin A and Itraconazole

Pathological angiogenesis contributes to a number of diseases including cancer and macular degeneration. Although angiogenesis inhibitors are available in the clinic, their efficacy against most cancers is modest due in part to the existence of alternative and compensatory signaling pathways. Given that angiogenesis is dependent on multiple growth factors and a broad signaling network in vivo, we sought to explore the potential of multidrug cocktails for angiogenesis inhibition. We have screened 741 clinical drug combinations for the synergistic inhibition of endothelial cell proliferation. We focused specifically on existing clinical drugs since the re-purposing of clinical drugs allows for a more rapid and cost effective transition to clinical studies when compared to new drug entities. Our screen identified cyclosporin A (CsA), an immunosuppressant, and itraconazole, an antifungal drug, as a synergistic pair of inhibitors of endothelial cell proliferation. In combination, the IC50 dose of each drug is reduced by 3 to 9 fold. We also tested the ability of the combination to inhibit endothelial cell tube formation and sprouting, which are dependent on two essential processes in angiogenesis, endothelial cell migration and differentiation. We found that CsA and itraconazole synergistically inhibit tube network size and sprout formation. Lastly, we tested the combination on human foreskin fibroblast viability as well as Jurkat T cell and HeLa cell proliferation, and found that endothelial cells are selectively targeted. Thus, it is possible to combine existing clinical drugs to synergistically inhibit in vitro models of angiogenesis. This strategy may be useful in pursuing the next generation of antiangiogenesis therapy

The behaviors of ferromagnetic nano-particles in and around blood vessels under applied magnetic fields

In magnetic drug delivery, therapeutic magnetizable particles are typically injected into the blood stream and magnets are then used to concentrate them to disease locations. The behavior of such particles in-vivo is complex and is governed by blood convection, diffusion (in blood and in tissue), extravasation, and the applied magnetic fields. Using physical first-principles and a sophisticated vessel-membrane-tissue (VMT) numerical solver, we comprehensively analyze in detail the behavior of magnetic particles in blood vessels and surrounding tissue. For any blood vessel (of any size, depth, and blood velocity) and tissue properties, particle size and applied magnetic fields, we consider a Krogh tissue cylinder geometry and solve for the resulting spatial distribution of particles. We find that there are three prototypical behaviors (blood velocity dominated, magnetic force dominated, and boundary-layer formation) and that the type of behavior observed is uniquely determined by three non-dimensional numbers (the magnetic-Richardson number, mass Péclet number, and Renkin reduced diffusion coefficient). Plots and equations are provided to easily read out which behavior is found under which circumstances ([Fig. 5], [Fig. 6], [Fig. 7] and [Fig. 8]). We compare our results to previously published in-vitro and in-vivo magnetic drug delivery experiments. Not only do we find excellent agreement between our predictions and prior experimental observations, but we are also able to qualitatively and quantitatively explain behavior that was previously not understood

Cyclosporin a disrupts notch signaling and vascular lumen maintenance.

Cyclosporin A (CSA) suppresses immune function by blocking the cyclophilin A and calcineurin/NFAT signaling pathways. In addition to immunosuppression, CSA has also been shown to have a wide range of effects in the cardiovascular system including disruption of heart valve development, smooth muscle cell proliferation, and angiogenesis inhibition. Circumstantial evidence has suggested that CSA might control Notch signaling which is also a potent regulator of cardiovascular function. Therefore, the goal of this project was to determine if CSA controls Notch and to dissect the molecular mechanism(s) by which CSA impacts cardiovascular homeostasis. We found that CSA blocked JAG1, but not Dll4 mediated Notch1 NICD cleavage in transfected 293T cells and decreased Notch signaling in zebrafish embryos. CSA suppression of Notch was linked to cyclophilin A but not calcineurin/NFAT inhibition since N-MeVal-4-CsA but not FK506 decreased Notch1 NICD cleavage. To examine the effect of CSA on vascular development and function, double transgenic Fli1-GFP/Gata1-RFP zebrafish embryos were treated with CSA and monitored for vasculogenesis, angiogenesis, and overall cardiovascular function. Vascular patterning was not obviously impacted by CSA treatment and contrary to the anti-angiogenic activity ascribed to CSA, angiogenic sprouting of ISV vessels was normal in CSA treated embryos. Most strikingly, CSA treated embryos exhibited a progressive decline in blood flow that was associated with eventual collapse of vascular luminal structures. Vascular collapse in zebrafish embryos was partially rescued by global Notch inhibition with DAPT suggesting that disruption of normal Notch signaling by CSA may be linked to vascular collapse. However, multiple signaling pathways likely cause the vascular collapse phenotype since both cyclophilin A and calcineurin/NFAT were required for normal vascular function. Collectively, these results show that CSA is a novel inhibitor of Notch signaling and vascular function in zebrafish embryos