Novel Milrinone Nanoformulation for Use in Cardiovascular Diseases: Preparation and in Vitro Characterization

Abstract

Cardiovascular diseases are the leading causes of mortality across the globe. Over the years, various drug formulations and delivery methods have been tested for cardiac repair. Milrinone (MRN) is a widely known cardiac inotrope drug used for the treatment of congestive heart failure in patients, however, its efficacy is limited. This study is the first to report the design of a novel MRN-nanoformulation using human serum albumin nanoparticles (HSA-NPs). The HSA-NPs exhibit promising drug delivery characteristics, such as target specificity, nonimmunogenicity, biocompatibility, and enhanced bioavailability. This article describes a MRN-nanoformulation design for in vitro drug release, cellular uptake, biocompatibility, and other features. The MRN-nanoformulation was prepared by the ethanol desolvation technique and key parameters were optimized to obtain a desired particle size of 154.2 ± 5.8 nm, zeta potential of -29.5 ± 2.9 mV, and a drug encapsulation efficiency of 41.1 ± 1.7%. Molecular docking studies have revealed that MRN binds in the hydrophobic cavity of HSA, which has also been indicated by circular dichroism and enzyme-mediated drug release studies in the presence of trypsin, pepsin, proteinase K, protease, and cathepsin D. The intracellular uptake of fluorescently tagged MRN-HSA-NPs using HUVEC and H9c2 cells was evaluated by flow cytometry. The nanoparticle toxicity results indicated that MRN-HSA-NPs show significantly lower cytotoxicity and higher cell viability ( P < 0.0001) as compared to the MRN-lactate drug in HUVEC (61.6 ± 3.7% vs 36.2 ± 2.9%) and H9c2 (58.8 ± 5.7% vs 18.8 ± 4.9%) cells. These studies indicate that the novel MRN-nanoformulation offers better drug delivery procedures than currently used methods and has potential in treatment of congestive heart failure and other cardiovascular diseases.

Synthesis and characterization of peptide conjugated human serum albumin nanoparticles for targeted cardiac uptake and drug delivery

“…The MTT assay was performed for cell viability where H9c2 cells were treated with AT1-HSA-MRN-NPs, AT1-HSA-NPs, MRN-HSA-NPs and MRN Lactate containing 1mM MRN concentrations for 4, 24 and 48 hours. The 1mM MRN concentration was optimized in our previous study and is being used here for consistency of results 33 . The safety analysis of MRN-HSA-NPs was conducted using HUVEC and H9c2 cells in our previous study and therefore was not repeated here 33 .…”

“…This will be the first study demonstrating a new synthesis scheme for development of a novel nanoparticle formulation, AT1-HSA-MRN-NPs, for targeted drug delivery to the heart. Previously, we presented the preparation and binding of HSA-NPs with milrinone (MRN), a cardiac inotrope and vasodilator drug, widely used for the treatment of CHF 12 .…”

“…[20][21][22] . Computational modeling and enzyme release studies have shown that MRN binds hydrophobically to the HSA molecule 23 . HSA-NPs are known to improve the blood circulation time of otherwise insoluble or free drugs and are anticipated to improve the bioavailability of MRN as well 24,25 .…”

The Rapeutic Effect of Milrinone Combined With Labetalol in Treatment of Severe Cardiopulmonary Failure Caused by Hand, Foot and Mouth Disese

“…By inhibting phospho-diesterase, it increases camp concentration in heart muscle cell as well as smooth muscle cell, opens calcium chanel, leading to inotropic, pre/after load reduction and vaso-dialation effect. But it has no inhibitory effect on autonomic hyperfuction and catecholamine release [13]. So labetalol as a selective beta blocker will block beta receptor to prevent Norepinephrine and Epinephrine activation, therefore block ion Chanel abnormality during catecholamine storm, inhibits sodium and calcium influx and potassium efleux.…”

Triphenylphosphonium and D-&alpha;-tocopheryl polyethylene glycol 1000 succinate-modified, tanshinone IIA-loaded lipid-polymeric nanocarriers for the targeted therapy of myocardial infarction

“…cellular uptake of TPP-TPgs/TN/lPNs PC cells were grown in DMEM supplemented with 10% FBS. 30 The cells were maintained in a humidified incubator at 37°C and 5% CO 2 at an initial density of 1×10 4 cells/well in black clear-bottom 96-well plates. The cells were incubated in fresh medium after 24 h of incubation and treated with fluorescently tagged FITC-containing LPNs and NPs.…”