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Impact of Reverse Micelle Loaded Lipid Nanocapsules on the Delivery of Gallic Acid into Activated Hepatic Stellate Cells: A Promising Therapeutic Approach for Hepatic Fibrosis

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A Correction to this article was published on 06 October 2020

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Abstract

Purpose

Gallic acid (GA) is a polyphenolic compound with proven efficacy against hepatic fibrosis in experimental animals. However, it suffers from poor bioavailability and rapid clearance that hinders its clinical investigation. Accordingly, we designed and optimized reverse micelle-loaded lipid nanocapsules (RMLNC) using Box-Behnken design that can deliver GA directly into activated-hepatic stellate cells (aHSCs) aiming to suppress hepatic fibrosis progression.

Methods

GA-RMLNC was prepared using soft energy, solvent free phase inversion temperature method. Effects of formulation variables on particle size, zeta potential, entrapment efficiency (EE%) and GA release were studied. In-vivo biodistribution of GA-RMLNC in rats and in-vitro activities on aHSCs were also explored.

Results

Nano-sized GA-RMLNCs (30.35 ± 2.34 nm) were formulated with high GA-EE% (63.95 ± 2.98% w/w) and physical stability (9 months). The formulated system showed burst GA release in the first 2 h followed by sustained release profile. In-vivo biodistribution imaging revealed that RMLNC-loaded with rhodamine-B accumulated mainly in rats’ livers. Relative to GA; GA-RMLNC displayed higher anti-proliferative activities, effective internalization into aHSCs, marked down-regulation in pro-fibrogenic biomarkers’ expressions and elevated HSCs’ apoptosis.

Conclusions

These findings emphasize the promising application of RMLNC as a delivery system in hepatic fibrosis treatment, where successful delivery of GA into aHSCs was ensured via increased cellular uptake and antifibrotic activities.

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Abbreviations

ANOVA :

Analysis of variance

aHSCs :

activated Hepatic stellate cells

cDNA :

Complementary DNA

COL1A1 :

Collagen type I

DAPI :

4′,6-diamidino-2-phenylindole

DMEM :

Dulbecco’s Modified Eagle’s Medium

ECM :

Extracellular matrix

EE%:

Entrapment efficiency percentage

FBS:

Fetal bovine serum

GA:

Gallic acid

HBSS:

Hanks Balanced Salt Solution

HPLC:

High performance liquid chromatography

KH2PO4 :

Potassium dihydrogen phosphate

LNC:

Lipid nanocapsules

Na2HPO4 :

Disodium hydrogen phosphate

NP:

Nanoparticles

PBS:

Phosphate buffer saline

PDI:

Polydispersity index

PIT:

Phase inversion temperature

PS:

Particle size

Q2h:

Percentage drug released after 2 h

qRT-PCR:

Quantitative Real-Time Polymerase Chain Reaction System

RMLNC:

Reverse micelle loaded lipid nanocapsules

RM:

reverse micelle

SA:

Stearylamine

SEM:

standard error means

SRB:

Sulphorhodamine B assay

TEM:

Transmission electron microscopy

TGF-β1:

Transforming growth factor-β1

ZP:

Zeta potential

α-SMA:

α-smooth muscle actin

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Acknowledgments

The authors would like to appreciate the great help and efforts offered by Assistant lecturer, Mohamed Ahmed Naseef Soliman (Pharmaceutics and Industrial Pharmacy Department, Faculty of Pharmacy, Cairo University) in the formulation procedure and the in vivo evaluation.

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Authors and Affiliations

  1. Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Kasr Al Aini street, PO Box 11562, Cairo, Egypt

    Shaimaa Ali Ali Radwan, Aliaa Nabil ElMeshad, Raguia Aly Shoukri & Carol Yousry

  2. Department of Pharmacology, Theodor Bilharz Research Institute, Kornaish El Nile, Warrak El-Hadar, Imbaba (P.O. 30), Giza, 12411, Egypt

    Walaa H. El-Maadawy

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  1. Shaimaa Ali Ali Radwan
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Radwan, S.A.A., El-Maadawy, W.H., ElMeshad, A.N. et al. Impact of Reverse Micelle Loaded Lipid Nanocapsules on the Delivery of Gallic Acid into Activated Hepatic Stellate Cells: A Promising Therapeutic Approach for Hepatic Fibrosis. Pharm Res 37, 180 (2020). https://doi.org/10.1007/s11095-020-02891-z

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