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Targeted and Controlled Drug Delivery to a Rat Model of Heart Failure Through a Magnetic Nanocomposite

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Abstract

As a novel cardiac myosin activator, Omecamtive Mecarbil (OM) has shown promising results in the management of systolic heart failure in clinical examinations. However, the need for repeated administration along with dose-dependent side effects made its use elusive as a standard treatment for heart failure (HF). We hypothesized that improved cardiac function in systolic HF models would be achieved in lower doses by targeted delivery of OM to the heart. To test this hypothesis, a nanocomposite system was developed by composing chitosan and a magnetic core (Fe3O4), loaded with OM, and directed toward the rats’ heart via a 0.3 T magnet. HF-induced rats were injected with saline, OM, and OM-loaded nanocomposite (n = 8 in each group) and compared with a group of healthy animals (saline injected, n = 8). Knowing the ejection fraction (EF) of healthy (93.68 ± 1.37%) and HF (71.7 ± 1.41%) rats, injection of nanocomposites was associated with improved EF (EF = 89.6 ± 1.40%). Due to increased heart targeting of nanocomposite (2.5 folds), improved cardiac function was seen with only 4% of the OM dose required for infusion, while injecting the same dose of OM without targeting was unable to stop HF progression (EF = 55.33 ± 3.16%) during 7 days. In conclusion, heart nanocomposites targeting improves the EF by up to 18% by only using 4% of the doses traditionally used in treating the HF.

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Abbreviations

OM:

Omecamtive Mecarbil

HF:

Heart failure

MI:

Myocardial infarction

PECAM-1:

Platelet endothelial cell adhesion molecule

cTnI:

Cardiac troponin I

Ang II:

Angiotensin II

SPION:

Superparamagnetic iron oxide nanoparticle

FDA:

Food and drug administration

Nd:

Neodymium

Fe:

Iron

B:

Boron

ICP:

Inductively coupled plasma

HR-TEM:

High resolution transmission electron microscopy

VSM:

Vibrating sample magnetometer

DI:

Deionized

HPLC:

High performance liquid chromatography

TEM:

Transmission electron microscopy

Fe-SEM:

Field emission scanning electron microscopy

MTT:

3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromidefor

OD:

Optical density

PBS:

Phosphate buffer saline

LVID:

Left ventricular internal dimension

LVPW:

Posterior wall thickness

IVS:

Interventricular septal thickness

ESV:

End systolic volume

SV:

Stroke volume

HR:

Heart rate

FS:

Fractional shortening

EF:

Ejection fraction

CO:

Cardiac output

DMEM:

Dulbecco’s modified eagle’s medium

FBS:

Fetal bovine serum

DMSO:

Dimethyl sulfoxide

NBF:

Neutral buffered formalin

H&E:

Hematoxylin and eosin

MT:

Masson’s trichrome

EE:

Encapsulation efficiency

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Acknowledgments

The authors would like to thank Dr. Alireza Imani at Physiology Department, Faculty of Medicine, Tehran University of Medical Sciences, for saving our time and expenses by suggesting ISO for HF induction.

Conflict of interest

None declared.

Author information

Authors and Affiliations

  1. Department of Tissue Engineering, Amirkabir University of Technology, Tehran, Iran

    Nasim Kiaie & Shahriar Hojjati Emami

  2. Research Center for Advanced Technologies in Cardiovascular Medicine, Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran

    Shahram Rabbani & Hossein Ahmadi Tafti

  3. Schools of Metallurgy & Materials Engineering, College of Engineering, University of Tehran, Tehran, Iran

    Rouhollah Mehdinavaz Aghdam

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  1. Nasim Kiaie
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  2. Shahriar Hojjati Emami
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  3. Shahram Rabbani
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Correspondence to Shahriar Hojjati Emami or Hossein Ahmadi Tafti.

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Kiaie, N., Emami, S.H., Rabbani, S. et al. Targeted and Controlled Drug Delivery to a Rat Model of Heart Failure Through a Magnetic Nanocomposite. Ann Biomed Eng 48, 709–721 (2020). https://doi.org/10.1007/s10439-019-02394-y

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