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Core-shell nanoparticulate formulation of gemcitabine: lyophilization, stability studies, and in vivo evaluation

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Abstract

Core-shell nanoparticulate formulation of gemcitabine was prepared by incorporating gemcitabine in a hydrophilic bovine serum albumin (BSA) core surrounded by hydrophobic poly(dl-lactic acid-co-glycolic acid) (PLGA) shell with a particle size of 243 nm and encapsulation efficiency of 40.5 %. Prepared formulations were lyophilized, wherein several cryoprotectants were screened for product attributes such as cake appearance, reconstitution with water, and size constancy. Trehalose was screened as a lyoprotectant, which showed stability for 6 months at 5 °C and 25 °C/60 % relative humidity (RH) conditions. However, an increase in particle size was observed at accelerated conditions (40 °C/75 % RH). In vitro evaluation of these nano-formulations in MCF-7 breast cancer cells showed enhanced cellular uptake (90 %) as compared to GEMCITE® uptake (51 %) in 6 h along with reduced IC50 value at 72 h (16 μM versus 30 μM). In vivo studies in Sprague Dawley rats showed C max, t 1/2, and area under the curve (AUC) at 2.55 μg/ml, 13.6 h, and 28,322.5 μg/l/h, respectively, whereas GEMCITE® at the same dose showed significantly lower corresponding values at 1.94 μg/ml, 6.89 h, and 13,967 μg/l/h. In the same study, AUC and C max of inactive metabolite of gemcitabine (dFdU) were reduced by 33 and 42 %, respectively, for these nanoparticles compared to GEMCITE®. In 7,12-dimethylbenz[a]anthracene (DMBA)-induced breast cancer model, significantly reduced tumor growth was observed in gemcitabine-loaded-nanoparticle-treated animals compared with GEMCITE®-treated animal at equivalent dose (121 versus 243 % in 30 days). The results indicated that our core-shell nanoparticles are more effective for tumor reduction compared to marketed formulation of gemcitabine, GEMCITE®.

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Acknowledgments

The Department of Biotechnology, India, is gratefully acknowledged for providing financial support. Authors are thankful to the Department of Science and Technology, India, for CLSM and TEM facilities at NIPER, SAS Nagar. The Ranbaxy Science Foundation (RSF), India, is duly acknowledged for recognizing this work for Ranbaxy Science Scholar Award 2011.

Conflict of interest

Authors DC, AM, RIM, and NK declare that they have no conflict of interest.

Animal studies disclosure

All procedures performed in studies involving animals were approved by the Institutional Animal Ethics Committee (IAEC), NIPER, SAS Nagar, India, and were in accordance with the CPCSEA guidelines, India, for the care and use of laboratory animals.

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Authors and Affiliations

  1. Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar, Punjab, 160 062, India

    Deepak Chitkara & Neeraj Kumar

  2. Department of Pharmaceutical Sciences, University of Nebraska Medical Center, 986025 Nebraska Medical Center, Omaha, NE, 68198, USA

    Deepak Chitkara, Anupama Mittal & Ram I. Mahato

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  1. Deepak Chitkara
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  2. Anupama Mittal
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Correspondence to Ram I. Mahato or Neeraj Kumar.

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Chitkara, D., Mittal, A., Mahato, R.I. et al. Core-shell nanoparticulate formulation of gemcitabine: lyophilization, stability studies, and in vivo evaluation. Drug Deliv. and Transl. Res. 4, 439–451 (2014). https://doi.org/10.1007/s13346-014-0206-y

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