TY - JOUR
T1 - Core-shell nanoparticulate formulation of gemcitabine
T2 - lyophilization, stability studies, and in vivo evaluation
AU - Chitkara, Deepak
AU - Mittal, Anupama
AU - Mahato, Ram I.
AU - Kumar, Neeraj
N1 - Funding Information:
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.
Publisher Copyright:
© 2014, Controlled Release Society.
PY - 2014/11/18
Y1 - 2014/11/18
N2 - 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 Cmax, t1/2, 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 Cmax 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®.
AB - 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 Cmax, t1/2, 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 Cmax 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®.
KW - Breast cancer
KW - Core-shell nanoparticles
KW - Gemcitabine
KW - Pharmacokinetics
KW - Stability
UR - http://www.scopus.com/inward/record.url?scp=84911469316&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84911469316&partnerID=8YFLogxK
U2 - 10.1007/s13346-014-0206-y
DO - 10.1007/s13346-014-0206-y
M3 - Article
C2 - 25787206
AN - SCOPUS:84911469316
SN - 2190-393X
VL - 4
SP - 439
EP - 451
JO - Drug Delivery and Translational Research
JF - Drug Delivery and Translational Research
IS - 5-6
ER -