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Folate-Conjugated pH-Responsive Nanocarrier Designed for Active Tumor Targeting and Controlled Release of Gemcitabine

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Abstract

Purpose

The prime end of this study was to design a novel pH-sensitive as well as a PEGylated dendritic nanocarrier for both controllable and traceable gemcitabine delivery to cancerous cells. To accomplish this goal, we took advantage of a hybrid of nanoparticles including: mesoporous silica, graphene oxide and magnetite.

Methods

The nanocarrier was prepared in a multi-step synthesis route. First, magnetite mesoporous silica was deposited on the graphene oxide matrix. Then, polyamidoamine dendrimers (up to generation 1.5) with pentaethylene hexamine end groups were grafted on the surface of the nanoparticles. In order to enhance the biostability, and as the next step, the nanocarrier was modified by polyethylene glycol. Finally, these particles were functionalized by folic acid as tumor targeting agents.

Results

According to the dynamic light scattering results, the hydrodynamic diameter of magnetic mesoporous silica graphene oxide hybrid nanoparticle was 152 ± 3 nm, while for the supramolecular hybrid nanoparticles it was about 324 ± 12 nm. Attained through the adsorption branch, the average pore diameter of these nanoparticles was 7.6 nm. Zeta potential test indicated −27.1 mV value for hybrid nanoparticles and +7.35 mV for supramolecular hybrid nanoparticles. Besides, cytotoxicity assay showed enhanced cytotoxicity of epidermoid carcinoma cell line A431 in the presence of folate conjugated carriers. The maximum release occurred at the pH 5.5, because the dendritic structure was in the open state rather than compact state.

Conclusions

The enhanced cytotoxicity of the epidermoid carcinoma cell line A431 in the presence of folate conjugated carriers, confirmed the improved cancerous cells uptake. Also, the positive surface potential would be a good property for the biological applications because the inherent negative-charged surface of cell membranes facilitates the uptake of positive particles by electrostatic interactions.

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Abbreviations

AFM:

Atomic force microscope

APTS:

Aminopropyltriethoxysilane

BET:

Brunauer–Emmett–Teller

CTAB:

Cetyltrimethyl ammonium bromide

DCC:

Dicylohexylcarbodiimide

DLS:

Dynamic light scattering

DMSO:

Dimethylsulfoxide

EDA:

Ethylenediamine

FA:

Folic acid

FBS:

Fetal bovine serum

Fe3O4@GO@mSiO2 :

Magnetic mesoporous silica coated graphene oxide

FT-IR:

Fourier transform infrared

GO:

Graphene oxide

MTT:

3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide

PAMAM:

Polyamidoamine

PBS:

Phosphate buffer saline

PEG:

Polyethylene glycol

TEM:

Transmission electron microscope

TEOS:

Tetraethyl orthosilicate

TGA:

Thermogravimetric analysis

WAXD:

Wide angle X-ray diffraction

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ACKNOWLEDGMENTS AND DISCLOSURES

We are grateful to Miss. Mohadeseh Doroudian and Mr. Behzad Pourbadiei for the help in MTT assay.

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Authors and Affiliations

  1. Polymer Research Laboratory, Department of Chemistry, Sharif University of Technology, Azadi Avenue, P.O.Box 11365-9516, Tehran, Iran

    Ali Pourjavadi, Zahra Mazaheri Tehrani & Azardokht Abedin Moghanaki

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  1. Ali Pourjavadi
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  2. Zahra Mazaheri Tehrani
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  3. Azardokht Abedin Moghanaki
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Correspondence to Ali Pourjavadi.

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Pourjavadi, A., Tehrani, Z.M. & Moghanaki, A.A. Folate-Conjugated pH-Responsive Nanocarrier Designed for Active Tumor Targeting and Controlled Release of Gemcitabine. Pharm Res 33, 417–432 (2016). https://doi.org/10.1007/s11095-015-1799-7

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  • DOI: https://doi.org/10.1007/s11095-015-1799-7

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