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Controlled delivery of Gemcitabine Hydrochloride using mannosylated poly(propyleneimine) dendrimers

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Abstract

The aim of the present investigation was to deliver Gemcitabine Hydrochloride (GmcH), an anticancer bioactive, specifically to lung tumor cells using mannosylated 4.0G poly(propyleneimine) dendrimers (M-PPI). 4.0G poly(propyleneimine) (PPI) dendrimers was synthesized using ethylenediamine as core and conjugated with mannose by ring opening reactions, followed by Schiff’s reaction in the presence of sodium acetate buffer (pH 4.0). Synthesized PPI dendrimers and mannose-conjugated dendrimers were characterized using IR, NMR spectroscopy, and scanning electron microscopy. GmcH was loaded into PPI and M-PPI dendrimers using equilibrium dialysis method to develop the formulations, GmcH-PPI and GmcH-M-PPI, respectively. The developed formulations were evaluated for drug loading, in vitro release kinetics, in vitro stability, hemolytic toxicity, cytotoxicity, pharmacokinetic, and biodistribution studies. The dendrimeric formulation of GmcH showed pH-sensitive release with faster release at acidic pH, i.e., pH 4.0 in comparison with physiological pH 7.4. M-PPI conjugate showed significant reduction in hemolytic toxicity as compared to plain 4.0G PPI dendrimers towards human erythrocytes. In the cytotoxicity studies with A-549 lung adenocarcinoma cell line, the GmcH-M-PPI formulation showed the lowest IC50 value. Further, the pharmacokinetic and tissue distribution studies of free drug GmcH, GmcH-PPI, and GmcH-M-PPI in albino rats of Sprague–Dawley strain suggested the mean residence time of GmcH-M-PPI conjugate to be significantly higher (24.85 h) than free GmcH and GmcH-PPI. Deposition of drug (396.1 ± 4.7 after 2 h) in lung was found to be significantly higher with GmcH-M-PPI formulation in comparison with Gmch and GmcH-PPI.

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Abbreviations

GmcH:

Gemcitabine Hydrochloride

M-PPI:

Mannosylated poly(propyleneimine) dendrimer

GmcH-PPI:

Gemcitabine-loaded plain poly(propyleneimine) dendrimer

GmcH-M-PPI:

Gemcitabine-loaded mannosylated poly(propyleneimine) dendrimer

4.0G PPI:

4th generation poly(propyleneimine) dendrimers

TEM:

Transmission electron microscopy

1H NMR:

Proton nuclear magnetic resonances

FTIR:

Fourier transform infrared spectroscopy

UV:

Ultra violet spectroscopy

A-549:

Lung adenocarcinoma epithelial cell lines

MTT:

Methyl thiazole tetrazolium assay

IC50 :

Concentration of drug for 50 % inhibition of cell growth

MRT:

Mean residence time

PTA:

Phosphotungustic acid

PBS:

Phosphate-buffered saline

RBCs:

Red blood cells

ACN:

Acrylonitrile

MWCO 12–14 kDa:

Molecular weight cut off 12–14 kDa

EDA:

Ethylenediamine

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Acknowledgments

The author Namrata Soni is grateful to AICTE for providing financial support in form of JRF. All the authors are thankful to SAIF, Punjab University, Chandigarh, for 1H NMR and FTIR spectroscopy; AIIMS, New Delhi for TEM and TATA Memorial Institute, Mumbai for cell line studies.

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Authors and Affiliations

  1. Pharmaceutics Research Laboratory, Department of Pharmaceutical Sciences, Dr. H. S. Gour Central University, Sagar, 470 003, India

    Namrata Soni, Keerti Jain, Umesh Gupta & N. K. Jain

  2. National Institute of Pharmaceutical Education and Research (NIPER Raebareli), Raebareli, U.P., 229 010, India

    Keerti Jain

  3. Department of Pharmacy, School of Chemical Sciences and Pharmacy, Central University of Rajasthan, Bandarsindri, Ajmer, 305817, India

    Umesh Gupta

  4. School of Pharmaceutical Sciences, Rajiv Gandhi Technical University, Bhopal, M.P., 462 036, India

    N. K. Jain

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  1. Namrata Soni
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Soni, N., Jain, K., Gupta, U. et al. Controlled delivery of Gemcitabine Hydrochloride using mannosylated poly(propyleneimine) dendrimers. J Nanopart Res 17, 458 (2015). https://doi.org/10.1007/s11051-015-3265-1

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