Rapamycin nanoparticles localize in diseased lung vasculature and prevent pulmonary arterial hypertension

Segura‐Ibarra, Victor; Amione‐Guerra, Javier; Cruz-Solbes, A.S.; Cara, Francisca E.; Iruegas-Nunez, David A.; Wu, Shuxiang; Youker, Keith A.; Bhimaraj, Arvind; Torre‐Amione, Guillermo; Ferrari, Mauro; Karmouty‐Quintana, Harry; Guha, Ashrith; Blanco, Elvin

doi:10.1016/j.ijpharm.2017.03.069

Cited by 32 publications

(18 citation statements)

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“…Moreover, mutations in bone morphogenetic protein receptor 2 (BMPR2), highly prevalent in heritable PAH, have been shown to contribute to increased vascular permeability through dysregulation of the TGF-β signaling pathway ( Morrell, 2006 ). Our laboratory recently demonstrated that vascular permeability in PAH contributes to enhanced NP accumulation in diseased lungs ( Segura-Ibarra et al, 2017 ), agreeing well with previous findings by Ishihara et al (2015) . In a monocrotaline (MCT)-induced model of PAH, poly(ethylene glycol)- block -poly(ε-caprolactone) (PEG-PCL) micelles containing rapamycin (RAP) resulted in increased drug accumulation in diseased lungs compared to healthy lungs 2 h after IV administration ( Figure 3A ).…”

Section: Enhanced Np Accumulation In Lungs Undergoing Pahsupporting

confidence: 92%

“…Such permeability may be exploited by NPs to passively extravasate and accumulate in lungs undergoing PAH. Figure adapted from Segura-Ibarra et al (2017) , reproduced with permission courtesy of Elsevier.…”

Section: Enhanced Np Accumulation In Lungs Undergoing Pahmentioning

confidence: 99%

“…(C) Surface intensity plot of the image from panel B representing NP signal. Figure adapted from Segura-Ibarra et al (2017) , reproduced with permission courtesy of Elsevier.…”

Section: Enhanced Np Accumulation In Lungs Undergoing Pahmentioning

confidence: 99%

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Nanotherapeutics for Treatment of Pulmonary Arterial Hypertension

Segura‐Ibarra

Hassan

et al. 2018

Front. Physiol.

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Pulmonary arterial hypertension (PAH) is a devastating and fatal chronic lung disease. While current pharmacotherapies have improved patient quality of life, PAH drugs suffer from limitations in the form of short-term pharmacokinetics, instability, and poor organ specificity. Traditionally, nanotechnology-based delivery strategies have proven advantageous at increasing both circulation lifetimes of chemotherapeutics and accumulation in tumors due to enhanced permeability through fenestrated vasculature. Importantly, increased nanoparticle (NP) accumulation in diseased tissues has been observed pre-clinically in pathologies characterized by endothelial dysfunction and remodeled vasculature, including myocardial infarction and heart failure. Recently, this phenomenon has also been observed in preclinical models of PAH, leading to the exploration of NP-based drug delivery as a therapeutic modality in PAH. Herein, we discussed the advantages of NPs for efficacious treatment of PAH, including heightened therapeutic delivery to diseased lungs for increased drug bioavailability, as well as highlighted innovative nanotherapeutic approaches for PAH.

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Section: Enhanced Np Accumulation In Lungs Undergoing Pahsupporting

confidence: 92%

Section: Enhanced Np Accumulation In Lungs Undergoing Pahmentioning

confidence: 99%

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Nanotherapeutics for Treatment of Pulmonary Arterial Hypertension

Segura‐Ibarra

Hassan

et al. 2018

Front. Physiol.

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“…Гистологический анализ выявил минимальные изменения в толщине легочной артерии и отсутствие ремоделирования желудочков сердца. Важно отметить, что крысы, получавшие рапамицин в наночастицах, имели менее выраженные побочные эффекты препарата по сравнению с животными, получавшими свободный рапамицин (Segura-Ibarra et al, 2017). Ингибиторы фосфодиэстеразы 5-го типа (PDE-5), в том числе силденафилцитрат (СЦ), также являются эффективными фармакологическими агентами в лечении легочной гипертензии (Barnett, Machado, 2006).…”

Section: варианты методик применения антисмысловых нуклеотидов в тераunclassified

Antisense oligonucleotides for the arterial hypertension mechanisms study and therapy

et al. 2018

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Arterial hypertension is one of the most common chronic diseases in adults all over the world. This pathology can not only reduce patients’ life quality, but can also be accompanied by a number of complications. Despite the fact that there is a large group of antihypertensive drugs on the market, mainly representing different combinations of inhibitors of the renin-angiotensin system, adrenoreceptor blockers in combination with diuretics, there is no generally accepted “gold standard” for drugs that would not have side effects. The review discusses the main aspects of antisense oligonucleotides use in the context of arterial hypertension. It is well known that the medical implementation of antisense oligonucleotides aims to block the expression of particular genes involved in the pathology development, and a key advantage of this technique is a high selectivity of the effect. However, with the undoubted advantages of the method, there are difficulties in its application, related both to the properties of the oligonucleotides themselves (insufficient stability and poor penetration into cells), and to the variety of mechanisms of the origin of a particular pathology, arterial hypertension, in our case. The review provides a brief description of the main molecular targets for antisense treatment of hypertensive disease. The newest targets for therapy with oligonucleotides – microRNAs – are discussed. The main modifications of antisense nucleotides, designed to increase the duration of their effects and simplify the delivery of this type of drugs to the targets are discussed, in particular, combining antisense oligonucleotides with adenovirus-based expression vectors. Particular attention is given to antisense oligonucleotides in the complex with nanoparticles. The review discusses the results of the use of titanium dioxide (TiO2) containing antisense nanocomposites for the angiotensin converting enzyme in rats with stress induced arterial hypertension (ISIAH). It was shown that the use of antisense oligonucleotides continues to be a promising technique for studying the mechanisms of various forms of hypertensive disease and has a high potential for therapeutic use.

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“…In addition, it appears also important to better understand the dynamic and unadapted remodeling of the extracellular matrix (ECM) remodeling that also forms a permissive milieu that favors the structural remodeling of the pulmonary vascular wall. In this context, considerable progress has been made and different promising molecular targets have been identified including the MIF-CD74 axis, 69 the rate-limiting enzyme in serotonin biosynthesis expressed in peripheral tissues tryptophan hydroxylase (TPH)-1, 76,135-137 the apelin-APJ signaling, 138,139 the RhoA/ROCK signaling, [140][141][142][143][144][145][146][147] the bone morphogenetic protein receptor type II (BMPRII) and BMP9, [148][149][150][151] the renin-angiotensin-aldosterone system (RAAS), 106 the transcriptional factor hypoxia-inducible factor (HIF), [152][153][154][155][156] the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway, [157][158][159] the HIPPO signaling pathway, 68,126 the two-pore-domain potassium channel TASK-1, 160,161 the Notch3 signaling, 63,162 the forkhead box protein O1 (FoxO1), 83 granulocyte macrophage colony-stimulating factor (GM-CSF), 163 leukotriene B4 (LTB4), 164 and leptin [107][108][109] signaling pathways.…”

Section: Accumulation Of Pulmonary Vascular Cells In Remodeled Pulmonmentioning

confidence: 99%

Pathology and Pathobiology of Pulmonary Hypertension

Dorfmüller

Guignabert

2017

Semin Respir Crit Care Med

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Pulmonary hypertension (PH) is a hemodynamic state defined by a mean pulmonary artery pressure ≥ 25 mm Hg during resting right heart catheterization. PH can result from precapillary (arterial) or postcapillary (venous) pathophysiological mechanisms. Interestingly, recent PH pathology has shown that pulmonary arterial or pulmonary venous remodelling are rarely independent phenomena, but frequently occur in combined fashion in lungs from patients suffering from different forms of PH, including pulmonary arterial hypertension (PAH). In PAH, it is now becoming clear that aberrant signals present in vessel wall microenvironment, which is largely orchestrated by dysfunctional pulmonary endothelial cells, are key contributors of the pulmonary vascular remodeling process, fostering proliferation, and survival and migration of resident pulmonary vascular cells such as smooth muscle cells, myofibroblasts, and pericytes. In addition, both genetic and environmental factors are also critical in the development of pulmonary vascular inflammation and chronic impairment of the pulmonary endothelium. This article outlines the current understanding of this disease from the point of view of pathology and pathobiology.

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Rapamycin nanoparticles localize in diseased lung vasculature and prevent pulmonary arterial hypertension

Cited by 32 publications

References 45 publications

Nanotherapeutics for Treatment of Pulmonary Arterial Hypertension

Nanotherapeutics for Treatment of Pulmonary Arterial Hypertension

Antisense oligonucleotides for the arterial hypertension mechanisms study and therapy

Pathology and Pathobiology of Pulmonary Hypertension

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