Effective cellular internalization, cell cycle arrest and improved pharmacokinetics of Tamoxifen by cholesterol based lipopolymeric nanoparticles
Authors: Saurabh Sharma
Kishan S Italiya
Samrat Mazumdar
Deepak Chitkara
Anupama Mittal
Journal: International Journal of Pharmaceutics (2018)
Discipline: PHARMACOLOGY & TOXICOLOGY
Keywords: Cholesterol; Lipopolymer; Nanoparticles; Pharmacokinetics; Tamoxifen.
Affiliations: Department of Pharmacy, Birla Institute of Technology and Science (BITS-PILANI), Pilani, Rajasthan 333031, India., Department of Pharmacy, Birla Institute of Technology and Science (BITS-PILANI), Pilani, Rajasthan 333031, India. Electronic address: .

Abstract:  The present study aims at the development of cholesterol based lipopolymeric nanoparticles for improved entrapment, better cell penetration and improved pharmacokinetics of Tamoxifen (TMX). Self-assembling cholesterol grafted lipopolymer, mPEG-b-(CB-{g-chol}-co-LA) was synthesized from poly(ethyleneglycol)-block-2-methyl-2-carboxyl-propylenecarboxylic acid-co-poly (l-lactide) [mPEG-b-(CB-{g-COOH}-co-LA)] copolymer followed by carbodiimide coupling for attaching cholesterol. Lipopolymeric nanoparticles were prepared using o/w solvent evaporation technique, which were subsequently characterized to determine its particle size, entrapment efficiency, release pattern and compared with mPEG-PLA nanoparticles. Further, in order to assess the in vitro efficacy, cytotoxicity studies, uptake, apoptosis assay and cell cycle analysis were performed in breast cancer cell lines (MCF-7 and 4T1). Finally, the pharmacokinetic profile of TMX loaded mPEG-b-(CB-{g-chol}-co-LA) lipopolymeric nanoparticles was also performed. TMX loaded lipopolymeric nanoparticles of particle size 151.25 ± 3.74 (PDI 0.123) and entrapment efficiency of 73.62 ± 3.08% were formulated. The haemolytic index, protein binding and in vitro drug release of the optimized nanoparticles were found to be comparable to that of the TMX loaded mPEG-PLA nanoparticles. Lipopolymeric nanoparticles demonstrated improved IC50 values in breast cancer cells (22.2 μM in 4T1; 18.8 μM in MCF-7) than free TMX (27.6 μM and 23.5 μM respectively) and higher uptake efficiency. At IC50 values, TMX loaded lipopolymeric nanoparticles induced apoptosis and cell cycle arrest (G0/G1 phase) to similar extent as that of free drug. Pharmacokinetic studies indicated ∼2.5-fold increase in the half-life (t1/2) (p &lt; 0.001) and ∼2.7-fold (p &lt; 0.001) increase in the mean residence time (MRT) of TMX following incorporation into lipopolymeric nanoparticles. Thus, mPEG-b-(CB-{g-chol}-co-LA) lipopolymeric nanoparticles offer a more promising approach for delivery of Tamoxifen in breast cancer by improving drug internalization and prolonging the mean residence time of the drug indicating possibility of dose reduction and hence bypassing the adverse effects of TMX therapy. 

Retracted: No

PubPeer comments:
 ![file] Different experiment group has identical image. , 
 #1 Dear Dr. Elaphomyces Citrinusuff0c Thank you for carefully reading our manuscript. We also found the same typographical error in Figure 1 C (right panel of line1) when we reviewed this article during experiment. After discussing with the journal and providing the original data, they agree to publish a correction article, which links from the PDF and HTML versions of the paperuff0cin order to address this error. These changes do not affect the interpretation or conclusions of this work. We apologize for not finding this error in proof version and thank you again. , 
 Some regions in Figure 6C seem to have been  cloned although none are identical. Do the authors have access to the original image? *** ![file] , 
 u201cRE: Scientific Reports (2015) - doi: 10.1038 srep40088 Iu2019m writing to follow up on our previous correspondence regarding the Scientific Reports paper, https: www.nature.com articles srep40088. We have looked into the recent issues raised at https: pubpeer.com publications F7F0932ABD14AD994B78F0D05B9442#3 but given the information received from the authors (including original images), we are not convinced that formal editorial action is warranted at this time. Thank you for your willingness to bring these concerns to our attention. Best wishes,u201d , 
 Two more duplicates. ![file] ,