Fasudil and DETA NONOate, Loaded in a Peptide-Modified Liposomal Carrier, Slow PAH Progression upon Pulmonary Delivery

Abstract

We investigated the feasibility of a combination therapy comprising fasudil, a Rho-kinase inhibitor, and DETA NONOate (diethylenetriamine NONOate, DN), a long-acting nitric oxide donor, both loaded in liposomes modified with a homing peptide, CAR (CARSKNKDC), in the treatment of pulmonary arterial hypertension (PAH). We first prepared and characterized unmodified and CAR-modified liposomes of fasudil and DN. Using individual drugs alone or a mixture of fasudil and DN as controls, we studied the efficacy of the two liposomal preparations in reducing mean pulmonary arterial pressure (mPAP) in monocrotaline (MCT) and SUGEN-hypoxia-induced PAH rats. We also conducted morphometric studies (degree of muscularization, arterial medial wall thickness, and collagen deposition) after treating the PAH rats with test and control formulations. When the rats were treated acutely and chronically, the reduction in mPAP was more pronounced in the liposomal formulation-treated rats than in plain drug-treated rats. CAR-modified liposomes were more selective in reducing mPAP than unmodified liposomes of the drugs. Both drugs, formulated in CAR-modified liposomes, reduced the degree of muscularization, medial arterial wall thickness, and collagen deposition more than the combination of plain drugs did. As seen with the in vivo data, CAR-modified liposomes of fasudil or DN increased the levels of the vasodilatory signaling molecule, cGMP, in the smooth muscle cells of PAH-afflicted human pulmonary arteries. Overall, fasudil and DN, formulated in liposomes, could be used as a combination therapy for a better management of PAH.

Metal-organic framework (MOF) nanomedicine preparations of sildenafil designed for the future treatment of pulmonary arterial hypertension

“…Whilst this idea is relatively novel, a limited number of studies are emerging describing nanomedicine formulations suitable for application in PAH. These include (i) a liposome-conjugate that combines the Rho-kinase inhibitor and vasodilator drug fasudil with the nitric oxide (NO) donor DETA NONOate [7], (ii) a liposome-encapsulated Iloprost nano-formulation [8] and from our own group, a polymeric NO-releasing nanoparticle [3]. Unfortunately liposomes and polymers as nano-formulation platforms have limitations including: (i) difficulty of in vivo imaging without further chemical modification, (ii) low solubility window, (iii) difficulty of drug fusion and encapsulation, (iv) high production cost and (v) difficulty in maintaining stability and bioactivity of drugs during the conjugation process [9,10].…”

Systemically Administered, Target-Specific, Multi-Functional Therapeutic Recombinant Proteins in Regenerative Medicine

“…Nanoparticles offer an option to modify them on their surface, by applying targeting elements to the surface of the particles. The modified particles can be targeted to the diseased vasculature [13,16,19,102,104,105,[107][108][109]. This could be especially important because many nanoparticles (especially the ones made from inorganic materials) are rapidly removed from the circulation by the reticuloendothelial system [19].…”

“…The nanoparticle approach eliminates a major limitation of the CAR peptide co-administration [28], short half-life of the peptide and the drug and provides extended selective vasodilation in PAH. CAR peptide delivered nanoparticles that contained anti-hypertensive drugs induced selective vasodilation in pulmonary vasculature (no concomitant drop of blood pressure in the systemic circulation) and extended the duration of selective vasodilation up to 15 times from the one obtained by conventional drug administration [102,104,105,107,108,110,111]. Other, recent examples of targeted nanoparticles are the demonstration of targeting nanoparticles loaded with antibiotics to infection foci for an enhanced anti-bacterial activity [44] and macrophage-specific nanoparticles that introduce an oligonucleotide directly to the cytosol for gene knockdown to enhance the macrophages´capacity to combat staphylococcus aureus infection [112].…”

Systemically Administered, Target-specific, Multi-functional Therapeutic Recombinant Proteins in Regenerative Medicine

“…Nanoparticles offer an option to modify them on their surface, by applying targeting elements to the surface of the particles. The modified particles can be targeted to the diseased vasculature [13,16,19,95,97,98,[100][101][102] . This could be especially important because many nanoparticles (especially the ones made from inorganic materials) are rapidly removed from the circulation by the reticuloendothelial system [19] .…”

“…The nanoparticle approach eliminates a major limitation of the CAR peptide co-administration [26] , short half-life of the peptide and the drug. CAR peptide delivered nanoparticles containing anti-hypertensive drugs induce selective vasodilation in pulmonary vasculature (no concomitant drop of blood pressure in the systemic circulation) and extend the duration of selective vasodilation up to 15 x from one obtained by conventional drug administration [95,97,98,100,101,103,104] . Recent examples of targeted nanoparticles are the demonstration of targeting nanoparticles loaded with antibiotics to infection foci for an enhanced anti-bacterial activity [42] and macrophage-specific nanoparticles that introduce an oligonucleotide directly to the cytosol for gene knockdown to enhance the macrophage capacity to combat staphylococcus aureus infection [105] .…”