Fabrication of Imatinib Mesylate-Loaded Lactoferrin-Modified PEGylated Liquid Crystalline Nanoparticles for Mitochondrial-Dependent Apoptosis in Hepatocellular Carcinoma

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. 1 H 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.

Synthesis and appraisal of dalbergin-loaded PLGA nanoparticles modified with galactose against hepatocellular carcinoma: In-vitro, pharmacokinetic, and in-silico studies

“…As a result, the stability test revealed that the DLMF formulation is stable for the DL system. The combination of PLGA and the capacity of PVA to shield medicines from chemical instability can be credited for the NPs’ remarkable physical stability ( Nisha et al, 2020b ; Abdelmoneem, M.A., et al, 2019 ). Later, this method was repeated on a bigger measurer, and a greater quantity of DLMF was synthesized for evaluation and in vitro and in vivo experiments, as performed as previously with other components ( Kumar et al, 2018 ).…”

“…The optimized formulation was chosen based on the preset criterion of highest %EE and least particle size. We assessed the changes in response parameters and chose the optimized formulation with the highest desirability (near 1), subsequently creating the formulation in three copies to guarantee the accuracy of the optimization ( Nisha et al, 2020b ).…”

“…Following this step, the HepG2 cells were fixed in ethanol at a concentration of 70%, and until evaluation, the samples were mounted in fluorescent mounting media (Dako Denmark A/S, Glostrup, Denmark). Finally, images were captured with the use of a confocal laser scanning microscope (Model: LSM900, Make: Zeiss, Germany) ( Nisha et al, 2020b ).…”

“…A test tube containing 100 μL of test plasma and 100 μL of ACN was vortexed for 30 min to create the test samples. To assess the final outcomes, WinNonlin version 1.5.3 was used ( Nisha et al, 2020a ; Kumar, P., et al, 2018 ; Nisha et al, 2020b ).…”

Oxidative stress in obesity-associated hepatocellular carcinoma: sources, signaling and therapeutic challenges

“…In comparison, active targeting can significantly improve the local drug concentration delivered through modifications of nanoparticles with affinity ligands to bind with receptors expressed on tumor cells. Studies have demonstrated target HCC therapies through different cell surface receptors (i.e., asialoglycoprotein receptor (ASGPR) [100], folate receptor [101], or CD44 [102]). Nevertheless, the majority of these receptors are common tumor biomarkers that are not HCC specific and cannot be used as predictive markers to monitor the therapeutic efficacy of nanomedicines.…”