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Zinc Protoporphyrin Polymeric Nanoparticles: Potent Heme Oxygenase Inhibitor for Cancer Therapy

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ABSTRACT

Purpose

Oxidation therapy is an antitumor strategy in which, apoptosis or necrosis is caused by either excess delivery of reactive oxygen species (ROS) as an oxidant or anti-oxidant inhibition. Heme oxygenase (HO) is an anti-oxidant enzyme that plays an important role in cell growth and proliferation. The purpose of this study was to prepare poly lactic-co-glycolic acid (PLGA) nanoparticles (NPs) loaded with zinc protoporphyrin (ZnPP) to deliver the HO inhibitor into tumor.

Methods

PLGA NPs were prepared using nanoprecipitation technique and their characteristics were optimized by Box-Behnken experimental design. Scanning electron microscopy and in vitro studies consisting of drug release, HO inhibitory effect, cytotoxicity and cellular uptake followed by in vivo biodistribution and blood cytotoxicity were carried out. Internalization of coumerin-6 loaded NPs by PC3 cells was visualized by confocal laser scanning microscopy beside quantitatively analysis.

Results

NPs average size, entrapment efficiency and drug loading were 100.12 ± 5.345 nm, 55.6% ± 2.49 and 7.98% ± 0.341 respectively. Equal HO inhibitory effect of NPs compared to free ZnPP was observed. The IC50 value of ZnPP-NPs for PC3 human prostate cancer cells was found to be 2.14 ± 0.083 μM.

Conclusion

In conclusion, ZnPP loaded PLGA NPs could exhibit enough HO inhibitory effect against cancer cells to be considered as a promising candidate for cancer treatment investigation.

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Abbreviations

ALT:

Alanine aminotransferase

AST:

Aspartate aminotransferase

BUN:

Blood Urea Nitrogen

CLSM:

Confocal laser scanning microscopy

Cr:

Creatinine

DL:

Drug loading

DMSO:

Dimethyl sulfoxide

EE:

Entrapment efficiency

FBS:

Fetal Bovine Serum

Hb:

Hemoglobin

HO:

Heme oxygenase

LDH:

Lactate dehydrogenase

MTT:

3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide

NADPH:

Nicotinamide adenine dinucleotide phosphate

NPs:

Nanoparticles

PBS:

Phosphate buffer saline

PDI:

Poly Dispersity Index

PLGA:

Poly lactic-co-glycolic acid

RBC:

Red Blood cells

ROS:

Reactive Oxygen Species

RPMI:

1640 Roswell Park Memorial Institute medium

SEM:

Scanning electron microscopy

WBC:

White Blood Cells

ZnPP:

Zinc protoporphyrin IX (ZnPP)

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ACKNOWLEDGMENTS AND DISCLOSURES

Authors would like to express their profound thanks to Mr. A.R. Kazemi for his technical assistance in animal experiments. This work is a part PhD thesis of first author and was financially supported by a grant from Tehran University of Medical Sciences.

Author information

Authors and Affiliations

  1. Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran

    Hasti Rouhani, Nima Sepehri, Fatemeh Atyabi & Rassoul Dinarvand

  2. Nanotechnology Research Centre, Faculty of Pharmacy, Tehran University of Medical sciences, Tehran, Iran

    Hasti Rouhani, Nima Sepehri, Fatemeh Atyabi & Rassoul Dinarvand

  3. Nano Alvand Co., Avicenna Tech. Park, Tehran University of Medical Sciences, Tehran, Iran

    Hasti Rouhani & Nima Sepehri

  4. Department of Molecular Biology, Pasteur Institute of Iran, Tehran, Iran

    Hamed Montazeri

  5. Department of Drug and Food Control, Faculty of Pharmacy and Pharmaceutical quality assurance Research Center, Tehran University of Medical Sciences, Tehran, Iran

    Mohammad Reza Khoshayand

  6. Department of Toxicology-Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran

    Mohammad Hossein Ghahremani & Seyed Nasser Ostad

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  1. Hasti Rouhani
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  2. Nima Sepehri
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Correspondence to Rassoul Dinarvand.

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Rouhani, H., Sepehri, N., Montazeri, H. et al. Zinc Protoporphyrin Polymeric Nanoparticles: Potent Heme Oxygenase Inhibitor for Cancer Therapy. Pharm Res 31, 2124–2139 (2014). https://doi.org/10.1007/s11095-014-1313-7

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  • DOI: https://doi.org/10.1007/s11095-014-1313-7

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