Therapeutic Neovascularization by Nanotechnology-Mediated Cell-Selective Delivery of Pitavastatin Into the Vascular Endothelium

Kubo, Mitsuki; Egashira, Kensuke; Inoue, Takahiro; Koga, J.; Oda, Shinichiro; Chen, Ling; Nakano, K.; Matoba, Tetsuya; Kawashima, Yasunaru; Hara, Kaori; Tsujimoto, Hiroyuki; Sueishi, Katsuo; Tominaga, Ryuji; Sunagawa, Kenji

doi:10.1161/atvbaha.108.182584

Cited by 56 publications

(65 citation statements)

References 27 publications

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“…Furthermore, the controlled intramyocardial delivery of platelet-derived growth factor was found to improve postinfarction ventricular function with increased vascularization (20). Similarly, in a recent study, the intramuscular injection of pivastatin-loaded nanoparticles that enabled sustained release of the drug resulted in enhanced angiogenesis (21). To enable a sustained release formulation of 1K1, we engineered nanoparticles from poly-lactic acid-glycolic acid (PLGA) copolymer, which is biocompatible and biodegradable and is approved by the FDA.…”

Section: Resultsmentioning

confidence: 99%

Coupling growth-factor engineering with nanotechnology for therapeutic angiogenesis

Roy

Soni

Harfouche

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Therapeutic angiogenesis is an emerging paradigm for the management of ischemic pathologies. Proangiogenic Therapy is limited, however, by the current inability to deliver angiogenic factors in a sustained manner at the site of pathology. In this study, we investigated a unique nonglycosylated active fragment of hepatocyte growth factor/scatter factor, 1K1, which acts as a potent angiogenic agent in vitro and in a zebrafish embryo and a murine matrigel implant model. Furthermore, we demonstrate that nanoformulating 1K1 for sustained release temporally alters downstream signaling through the mitogen activated protein kinase pathway, and amplifies the angiogenic outcome. Merging protein engineering and nanotechnology offers exciting possibilities for the treatment of ischemic disease, and furthermore allows the selective targeting of downstream signaling pathways, which translates into discrete phenotypes.N eovascularization in the adult holds the potential for ameliorating ischemic disease, which is the leading cause of morbidity and mortality in the United States (1). Ferrara and Kerbel recently articulated that "therapeutic angiogenesis" is an emerging and exciting frontier of cardiovascular medicine (2). However, while early preclinical studies and phase I clinical trials exhibited promising results with recombinant proteins or gene therapy, more rigorous phase II and III studies have reported conflicting outcomes (3-6). A recent review of these clinical trials highlighted vector "washout" leading to inadequate duration of exposure to the angiogenic agent as a key factor that may have impaired the effectiveness of therapy (7). Indeed, it is now established that sustained activation of downstream signal pathways promotes cellular processes critical for angiogenesis (8). We rationalized that harnessing a nanotechnology-based approach can enable a temporal control over the presentation of the angiogenic factors to the cellular target, thereby altering the activation of downstream signal transduction.While nanoformulation of angiogenic proteins is an attractive strategy, the synthesis and instability of these large complex glycosylated structures pose a significant barrier (9). Hepatocyte growth factor/scatter factor (HGF/SF) is a potent angiogenic agent (10), signaling through the Met receptor and downstream MAPK and the PI3K pathways (11-12). Interestingly, the Met receptor is upregulated during hypoxia, suggesting that the ischemic tissue will be primed for activation by HGF/SF (13). These results indicate that HGF/SF could emerge as an attractive therapy for angiogenesis. However, HGF/SF is a heparin-binding protein with a complex multidomain structure consisting of an N-terminal (N) domain, four copies of the kringle domain (K1 to K4) and a C-terminal domain homologous to that of serine proteineases (SP) (Fig. 1A) (14). Biologically active HGF/SF is produced by proteolytic cleavage of the linker connecting the fourth kringle and the SP domain yielding a two-chain (α/β)-heterodimer, in which both the α-and the...

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Section: Resultsmentioning

confidence: 99%

Coupling growth-factor engineering with nanotechnology for therapeutic angiogenesis

Roy

Soni

Harfouche

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…We and others previously showed that (1) the PLGA NP was taken up by cultured SMC mainly via endocytosis, and retained stably in the intracellular space 18,19,21,26,28) . It is likely that after cellular or tissue uptake of NP, NP slowly releases the encapsulated drug (imatinib in this case) into the cytoplasm or Table 3.…”

Section: Discussionmentioning

confidence: 99%

“…Human umbilical vein endothelial cells (HUVEC) were obtained, cultured, and used between passages 4 to 8 21) . Recombinant human VEGF165 (10 ng/mL; R&D) or PDGF at 10 ng/mL was added to the basal medium, and cells (7500 cells per well) were incubated in the presence or absence of imatinib, imatinib-NP, or vehicle for 4 days in 48-well culture plates.…”

Section: Endothelial Cell Proliferation Assaymentioning

confidence: 99%

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Imatinib Mesylate-Incorporated Nanoparticle-Eluting Stent Attenuates In-Stent Neointimal Formation in Porcine Coronary Arteries

Masuda

Nakano

Funakoshi

et al. 2011

JAT

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Aim:The use of currently marketed drug-eluting stents (DES) presents safety concerns, including an increased risk for late thrombosis in the range of 0.6% per year in patients, including acute coronary syndrome, which is thought to result from delayed endothelial healing effects. A new DES system targeting vascular smooth muscle cells without adverse effects on endothelial cells is therefore needed. Platelet-derived growth factor (PDGF) plays a central role in the pathogenesis of restenosis; therefore, we hypothesized that imatinib mesylate (PDGF receptor tyrosine kinase inhibitor) encapsulated bioabsorbable polymeric nanoparticle (NP)-eluting stent attenuates in-stent neointima formation. Methods: Effects of imatinib-incorporated NP-eluting stent on neointima formation and endothelial healing were examined in a pig coronary artery stent model. Effects of imatinib-NP were also examined in cultured cells. Results: In a cultured cell study, imatinib-NP attenuated the proliferation of vascular smooth muscle cells associated with inhibition of the target molecule (phosphorylation of PDGF receptor-), but showed no effect on endothelial proliferation. In a pig coronary artery stent model, imatinib-NPeluting stent markedly attenuated in-stent neointima formation and stenosis by approximately 50% as assessed by angiographic, histopathological, and intravascular ultrasound imaging analyses. Imatinib-NP-eluting stent also attenuated MAP kinase activity, but did not affect inflammation and re-endothelialization. Conclusion: These data suggest that suppression of neointima formation by a imatinib-NP-eluting stent holds promise as a molecular-targeting NP delivery system for preventing in-stent restenosis.

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“…In these patients, intimal hyperplasia and subsequent obstruction of the graft causes life-threatening situations and a loss in the quality of life. Macrophage activation and smooth muscle emia 39,49,50) . This therapeutic angiogenesis may be a potential novel therapy for patients with peripheral arterial diseases because there are no available medical therapies other than surgical revascularization.…”

Section: Plga Nanoparticles For the Treatment Of Cardiovascular Diseasesmentioning

confidence: 99%

Anti-inflammatory Nanoparticle for Prevention of Atherosclerotic Vascular Diseases

Koga

Matoba

Egashira

2016

JAT

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Recent technical innovation has enabled chemical modifications of small materials and various kinds of nanoparticles have been created. In clinical settings, nanoparticle-mediated drug delivery systems have been used in the field of cancer care to deliver therapeutic agents specifically to cancer tissues and to enhance the efficacy of drugs by gradually releasing their contents. In addition, nanotechnology has enabled the visualization of various molecular processes by targeting proteinases or inflammation. Nanoparticles that consist of poly (lactic-co-glycolic) acid (PLGA) deliver therapeutic agents to monocytes/macrophages and function as anti-inflammatory nanoparticles in combination with statins, angiotensin receptor antagonists, or agonists of peroxisome proliferator-activated receptor-(PPAR ). PLGA nanoparticle-mediated delivery of pitavastatin has been shown to prevent inflammation and ameliorated features associated with plaque ruptures in hyperlipidemic mice. PLGA nanoparticles were also delivered to tissues with increased vascular permeability and nanoparticles incorporating pitavastatin, injected intramuscularly, were retained in ischemic tissues and induced therapeutic arteriogenesis. This resulted in attenuation of hind limb ischemia. Ex vivo treatment of vein grafts with imatinib nanoparticles before graft implantation has been demonstrated to inhibit lesion development. These results suggest that nanoparticle-mediated drug delivery system can be a promising strategy as a next generation therapy for atherosclerotic vascular diseases. nm. In tumor tissues or at the site of inflammation, the integrity of these endothelial layers is impaired and the nanoparticles can extravasate to the extravascular space through the enlarged interspace between endothelial cells. In tumor tissues, immature lymphatic vessels retard elimination of nanoparticles. These effects are known as enhanced permeability and retention effects 22,23) . Surface modification with polyethylene glycol (PEG) prevents entrapment of nano particles by the reticuloendothelial system due to its hydrophilic property. Therefore, these nanoparticles are called stealth nanoparticles 24,25) . J Atheroscler Nanoparticles as a Research Tool for AtherosclerosisClinical applications of nanoparticles are advanced in the field of diagnostic medicine. For example, magnetic nanoparticles with iron cores are available in MRI for macrophage imaging 26) . These so-called superparamagnetic iron oxide (SPIO) nanoparticles are used as a negative contrast agent in MRI. The iron core is modified with hydrophilic polymers including dextran, carboxymethylated dextran, polyvinyl alcohol, starches, chitosan, polymethyl methacrylate, PEG, poly (lactic-co-glycolic) acid (PLGA), polyvinylpyrrolidone, and polyacrylic acid 27) . These particles have been tested in patients to evaluate inflammation, plaque vulnerability, and therapeutic effects of lipid lowering drugs, especially in the carotid arteries of patients 26,28,29) . Adhesion molecules are also targets of molecu...

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Therapeutic Neovascularization by Nanotechnology-Mediated Cell-Selective Delivery of Pitavastatin Into the Vascular Endothelium

Abstract: NP-mediated cell-selective statin delivery may be a more effective and integrative strategy for therapeutic neovascularization in patients with severe organ ischemia.

Cited by 56 publications

References 27 publications

Coupling growth-factor engineering with nanotechnology for therapeutic angiogenesis

Coupling growth-factor engineering with nanotechnology for therapeutic angiogenesis

Imatinib Mesylate-Incorporated Nanoparticle-Eluting Stent Attenuates In-Stent Neointimal Formation in Porcine Coronary Arteries

Anti-inflammatory Nanoparticle for Prevention of Atherosclerotic Vascular Diseases

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