Precise dapagliflozin delivery by cardiac homing peptide functionalized mesoporous silica nanocarries for heart failure repair after myocardial infarction

Abstract

Myocardial infarction (MI) may cause irreversible damage or destroy to part of the heart muscle, affecting the heart's ability and power to pump blood as efficiently as before, often resulting in heart failure (HF). Cardiomyocyte death and scar formation after MI may then trigger chronic neurohormonal activation and ventricular remodeling. We developed a biocompatible and mono-dispersed mesoporous silica nanoparticles (MSN) divergent porous channel for dapagliflozin (DAPA) loading. After surface modification of the cardiac-targeting peptides, the novel drug delivery system was successfully homed, and precisely released drugs for the hypoxic and weak acid damaged cardiomyocytes. Our biocompatible MSN- based nanocarriers for dapagliflozin delivery system could effective cardiac repair and regeneration in vivo, opening new opportunities for healing patients with ischemic heart disease in clinical.

Keywords: dapagliflozin; heart failure repair; hypoxia-inducible factor 1-α (HIF-1α); myocardial infarction; nano-targeted drugs delivery system.

FIGURE 1

Dapagliflozin-loaded biocompatible mesoporous silica nanoparticles with surface functionalization of cardiac homing peptide fabrication for precise heart failure repair after myocardial infarction.

FIGURE 2

TEM image (A), magnification TEM image (B) and SEM image of the bi-phase prepared MSN (C). DLS result of size distribution of MSN (D). Zeta-potential data of MSN, DAPA@MSN, MSN-CHP and DAPA@MSN-CHP (E). DAPA release curve of DAPA@MSN-CHP under different pH values (F). The corresponding physical and chemical parameters of the DDS (G).

FIGURE 3

CLSM images of DAPA@MSN-CHP and DAPA@MSN with 12 h incubation (A). Western blot result of HIF-1α expression in HF tissues and normal tissue (B). Cell viabilities of cardiomyocytes toward MSN-CHP under hypoxia and normoxia conditions (C). Cell viabilities of cardiomyocytes after different treatments in hypoxic conditions. Pure normoxia condition was set as the control group (D). Bax, cleaved Caspase-3, Caspase-3 and BCL-2 expressions of cardiomyocytes after different treatments under hypoxia conditions (E). All error bars represent mean ± SD (n = 4). Data analysis was performed using one-way ANOVA, ^** p < 0 01, ^*** p < 0 001.

FIGURE 4

M-mode echocardiogram representative images of MI, MI + DAPA, MI + DAPA@MSN and MI + DAPA@MSN-CHP treatments. The healthy mice were set as controls (A). Estimation of the function of MI hearts by ejection fraction (B) and fractional shortening (C) after MI, MI + DAPA, MI + DAPA@MSN and MI + DAPA@MSN-CHP treatments. The healthy mice were set as controls. All error bars represent mean ± SD (n = 4). Data analysis was performed via one-way ANOVA, ^** p < 01, ^*** p < 001.

FIGURE 5

Representative H & E images (A) Masson’s trichrome stain images (B) of cardiac sections after MI, MI + DAPA, MI + DAPA@MSN and MI + DAPA@MSN-CHP treatments. The healthy mice were set as controls.

FIGURE 6

H&E-stained photographs of major organs after 3 days treatment of PBS and MSN-CHP (A). Blood biochemistry results from PBS and MSN-CHP treated mice, respectively (B).