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Gemcitabine Co-Encapsulated with Curcumin in Folate Decorated PLGA Nanoparticles; a Novel Approach to Treat Breast Adenocarcinoma

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Abstract

Purpose

Curcumin (CUR), an antioxidant with p-glycoprotein inhibiting activity may be encapsulated with gemcitabine (GEM) as nanosuspension to enhance its anticancer potentiality synergistically.

Methods

Folate conjugated single (CUR/GEM) and dual (CUR + GEM) drug-loaded nanoformulations were prepared and evaluated for P-glycoprotein-1 (pgy-1) gene resistance, followed by in vitro cellular uptake and cytotoxicity assay in cells. The in vivo biodistribution and scintigraphic imaging was done after radiolabeling the nanoparticles with 99mTechnetium (99mTc). The tumor inhibition study was conducted in nude mice bearing MDA-MB-231 xenografts.

Results

The folate conjugated dual drug formulations (FCGNPs) gave better results in suppressing the pgy-1 gene and also showed higher cellular uptake, cytotoxicity, apoptosis, and cell cycle arrest. The radiolabeled nanoformulations were highly stable and FCGNPs showed higher accumulation in the MDA-MB-231 tumor region than folate unconjugated dual drug NPs (CGNPs) as evidenced by scintigraphic imaging and biodistribution studies. The in vivo therapeutic efficacy of FCGNPs was higher compared to unconjugated and respective single-drug formulations.

Conclusion

Two drugs in one platform lower breast adenocarcinoma by lowering drug resistance and improving cytotoxic effects.

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Abbreviations

AFM:

Atomic Force Microscopy

cm:

Centimeter

CUR:

Curcumin

CNPs:

Curcumin loaded nanoparticles

CGNPs:

Curcumin and gemcitabine loaded nanoparticles

DAPI:

4,6-diamino-2-phenylindole

DCC:

N,N′-Dicyclohexylcarbodiimide

DCM:

Dichloromethane

DMSO:

Dimethyl sulfoxide

DSC:

Differential Scanning Calorimetry

EDC-HCl:

1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide-hydrochloride

EPR:

Enhanced Permeability and Retention

FCNPs:

Folate conjugated curcumin loaded nanoparticles

FCGNPs:

Folate conjugated curcumin and gemcitabine loaded nanoparticles

FGNPs:

Folate conjugated gemcitabine loaded nanoparticles

FE-SEM:

Field Emission Scanning electron microscope

FTIR:

Fourier Transform Infrared

g:

Gram

GEM:

Gemcitabine

GNPs:

Gemcitabine loaded nanoparticles

h:

Hour

HRP:

Horseradish-peroxidase

M:

Molar

ml:

Millilitre

MTT:

3-(4,5-Dimethylthiazol-2-yl) -2,5-Diphenyltetrazolium Bromide

NHS:

N-Hydroxysuccinimide

NP:

Nanoparticle

PDI:

Polydispersity index

PI:

Propidium iodide

PLGA:

Poly-D,L-lactic-co-glycolic acid

PVA:

Polyvinyl alcohol

PVDF:

Polyvinylidene fluoride

RME:

Receptor-mediated Endocytosis

rpm:

Rotation per minute

RT-PCR:

Reverse transcription polymerase chain reaction

Tc:

Technetium

TEM:

Transmission electron microscope

TGI:

Tumor Growth Inhibition

TLC:

Thin-layer chromatography

UV-vis:

UltraViolet-visible

XPS:

X-ray photoelectron spectroscopy

XRD:

X-Ray Diffraction

μg:

Microgram

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Acknowledgements AND DISCLOSURES

The authors would like to acknowledge the Director of CSIR-Indian Institute of Chemical Biology, Kolkata for providing necessary facilities to carry out the experiments. R.M. gratefully acknowledges DST-INSPIRE for providing the fellowship. The authors would like to acknowledge Dr. Manabendra Mukherjee and Mr. Goutam Sarkar of Saha Institute of Nuclear Physics for helping with the XPS experiment and TEM facility of the same institute for carrying out transmission electron microscopy. The authors acknowledge SEM facility of Jadavpur University for their help in SEM experiments. The authors would like to thank Mr. T. Muruganandan and Mrs. Debalina Chakraborty for their help in AFM and flow cytometry experiments respectively.

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Authors and Affiliations

  1. Infectious Diseases and Immunology Division, CSIR-Indian Institute of Chemical Biology, 4 Raja S.C. Mullick Road, Kolkata, 700032, India

    Ria Mukhopadhyay, Ramkrishna Sen, Brahamacharry Paul, Julekha Kazi & Mita Chatterjee Debnath

  2. Regional Radiation Medicine Center, Thakurpukur Cancer Center and Welfare Home Campus, Kolkata, India

    Shantanu Ganguly

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  1. Ria Mukhopadhyay
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Mukhopadhyay, R., Sen, R., Paul, B. et al. Gemcitabine Co-Encapsulated with Curcumin in Folate Decorated PLGA Nanoparticles; a Novel Approach to Treat Breast Adenocarcinoma. Pharm Res 37, 56 (2020). https://doi.org/10.1007/s11095-020-2758-5

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