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Phytantriol Based “Stealth” Lyotropic Liquid Crystalline Nanoparticles for Improved Antitumor Efficacy and Reduced Toxicity of Docetaxel

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ABSTRACT

Purpose

The present work focuses on design and development of surface functionalized LCNPs for improving tumor delivery of DTX.

Methods

Phytantriol based “stealth” LCNPs were prepared using hydrotrope method and optimized. The potential of developed formulation was further assessed using cell culture experiments, in vivo pharmacokinetics, in vivo pharmacodynamics and toxicity studies.

Results

A biphasic drug release pattern was observed with sustained release of drug till 72 h. In vitro cell culture experiments revealed efficient internalization within MCF-7 cells with 25.80-fold decrease in IC50 value for PEG-LCNPs as compared to free DTX. Mechanistic insights demonstrated preferential co-localization of LCNPs in the vicinity of the nucleus. Furthermore, in vivo pharmacokinetic studies revealed 14.45-fold enhancement in circulation half-life of PEG-LCNPs as compared to marketed formulation Taxotere®. In vivo efficacy studies PEG-LCNPs in DMBA induced breast cancer model revealed ~81% reduction in the tumor burden compared to Taxotere® which caused/achieve only 47% reduction or showed only 47% decrease. Furthermore, safety profile was noted for PEG-LCNPs as compared to Taxotere®, measured as a function of hepato- and nephro-toxicity.

Conclusions

Surface functionalization of LCNPsis a viable approach for improving the therapeutic potential of DTX.

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Abbreviations

ALT:

Alanine aminotransferase

AST:

Aspartate aminotransferase

AUC:

Area under curve

BUN:

Blood urea nitrogen

CLSM:

Confocal laser scanning microscope

CoQ10:

Coenzyme Q 10

DAPI:

4′,6-diamidino-2-phenylindole

DMBA:

7,12-dimethylbenz[a]anthracene

DSPE:

1, 2-Distearoyl-sn-glycero-3-phospho-ethanolamine

DTX:

Docetaxel

EPR:

Enhanced permeation and retention

FBS:

Fetal bovine serum

FDA:

Food and Drugs Administration

GMO:

Glyceryl monooleate

HBSS:

Hanks’s balanced salt solution

IAEC:

Institutional animal ethics committee

ICH:

International conference on harmonization

LCNPs:

Liquid crystalline nanoparticles

MCF-7:

Human adenocarcinoma breast cancer cell line

MRT:

Mean residence time

MTT:

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

PDI:

Polydispersity index

PEG:

Polyethylene glycol

SAXS:

Small angle X ray spectroscopy

TEM:

Transmission electron microscopy

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ACKNOWLEDGMENTS AND DISCLOSURES

The authors are thankful to Director, NIPER for financial support, necessary infrastructure and facilities. N.K.S and K.T. are grateful to Council of Scientific and Industrial Research (CSIR), GOI, New Delhi, for providing research fellowships. The technical support rendered by Mr. Rahul Mahajan is also duly acknowledged.

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Authors and Affiliations

  1. Centre for Pharmaceutical Nanotechnology, Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S., Nagar (Mohali), Punjab, 160062, India

    Sanyog Jain, Neha Bhankur, Nitin K. Swarnakar & Kaushik Thanki

Authors
  1. Sanyog Jain
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  2. Neha Bhankur
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  3. Nitin K. Swarnakar
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  4. Kaushik Thanki
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Corresponding author

Correspondence to Sanyog Jain.

Additional information

This work is a part of Indian Patent Application No. 680/DEL/2013 filed on March 08 2013

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Jain, S., Bhankur, N., Swarnakar, N.K. et al. Phytantriol Based “Stealth” Lyotropic Liquid Crystalline Nanoparticles for Improved Antitumor Efficacy and Reduced Toxicity of Docetaxel. Pharm Res 32, 3282–3292 (2015). https://doi.org/10.1007/s11095-015-1706-2

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  • DOI: https://doi.org/10.1007/s11095-015-1706-2

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