Fabrication of Imatinib Mesylate-Loaded Lactoferrin-Modified PEGylated Liquid Crystalline Nanoparticles for Mitochondrial-Dependent Apoptosis in Hepatocellular Carcinoma
Authors: Priya Singh
Anupam Guleria
Samipta Singh
Raquibun Nisha
Shubhini A Saraf
Nidhi Mishra
Pranesh Kumar
Priyanka Maurya
Sudipta Saha
Umesh Kumar
Journal: Molecular Pharmaceutics (2021)
Discipline: PHARMACOLOGY & TOXICOLOGY
Keywords: 1H NMR-based metabolomics; HCC; IMS; LCNPs; lactoferrin.
Affiliations: Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Raibareli Road, Lucknow 226025, India, Centre of Biomedical Research, SGPGIMS Campus, Raebareli Road, Lucknow 226014, Uttar Pradesh, India

Abstract:  Hepatocellular carcinoma (HCC) is a major cause of concern as it has substantial morbidity associated with it. Previous reports have ascertained the antiproliferative activity of imatinib mesylate (IMS) against diverse types of carcinomas, but limited bioavailability has also been reported. The present study envisaged optimized IMS-loaded lactoferrin (LF)-modified PEGylated liquid crystalline nanoparticles (IMS-LF-LCNPs) for effective therapy of IMS to HCC via asialoglycoprotein receptor (ASGPR) targeting. Results displayed that IMS-LF-LCNPs presented an optimum particle size of 120.40 ± 2.75 nm, a zeta potential of +12.5 ± 0.23 mV, and 73.94 ± 2.69% release. High-resolution transmission electron microscopy and atomic force microscopy were used to confirm the surface architecture of IMS-LF-LCNPs. The results of cytotoxicity and 4,6-diamidino-2-phenylindole revealed that IMS-LF-LCNPs had the highest growth inhibition and significant apoptotic effects. Pharmacokinetics and biodistribution studies showed that IMS-LF-LCNPs have superior pharmacokinetic performance and targeted delivery compared to IMS-LCNPs and plain IMS, which was attributed to the targeting action of LF that targets the ASGPR in hepatic cells. Next, our in vivo experiment established that the HCC environment existed due to suppression of BAX, cyt c, BAD, e-NOS, and caspase (3 and 9) genes, which thus owed upstream expression of Bcl-xl, iNOS, and Bcl-2 genes. The excellent therapeutic potential of IMS-LF-LCNPs began the significant stimulation of caspase-mediated apoptotic signals accountable for its anti-HCC prospect. 1H nuclear magnetic resonance (serum) metabolomics revealed that IMS-LF-LCNPs are capable of regulating the disturbed levels of metabolites linked to HCC triggered through N-nitrosodiethylamine. Therefore, IMS-LF-LCNPs are a potentially effective formulation against HCC. 

Retracted: No

PubPeer comments:
 1. Figure 3. Magnification of Control, 10, 15 u03bcg mL is totally different. No sign of chromatin condensation and the formation of nuclear fragments and apoptotic bodies. Results are misleading. 2. The authors claim a whole pathway on the basis of only genomic data, no proteomic data is available. 3. what is the utility of 3D interactive surface plot and histogram, No explanation is there. 4. The IC50 of Imatinib Mesylate in Hepatocellular carcinoma is already reported. (50u03bcM).(Reference:- https: www.ncbi.nlm.nih.gov pmc articles PMC5346821 ). But the author reported 15u03bcg ml which is misleading and antagonist to the previous results. ,