AR13 peptide-conjugated liposomes improve the antitumor efficacy of doxorubicin in mice bearing C26 colon carcinoma; in silico, in vitro, and in vivo study.

Currently, liposomes have emerged as efficient and safer nano-carriers for targeted therapy in different cancers. This work aimed to employ PEGylated liposomal doxorubicin (Doxil®/PLD), modified with AR13 peptide, to target Muc1 on the surface of colon cancerous cells. We performed molecular docking and simulation studies (using Gromacs package) of AR13 peptide against Muc1 to analyze and visualize the peptide-Muc1 binding combination. For in vitro analysis, the AR13 peptide was post-inserted into Doxil® and verified by TLC, 1H NMR, and HPLC techniques. The zeta potential, TEM, release, cell uptake, competition assay, and cytotoxicity studies were performed. In vivo antitumor activities and survival analysis on mice bearing C26 colon carcinoma were studied. Results showed that after 100 ns simulation, a stable complex between AR13 and Muc1 formed, and molecular dynamics analysis confirmed this interaction. In vitro analysis demonstrated significant enhancement of cellular binding and cell uptake. The results of in vivo study on BALB/c mice bearing C26 colon carcinoma, revealed an extended survival time to 44 days and higher tumor growth inhibition compared to Doxil®. Thus, the AR13 peptide could be explored as a potent ligand for Muc1, improving therapeutic antitumor efficiency in colon cancer cells.

Molecular dynamics simulation of drug delivery across the cell membrane by applying gold nanoparticle carrier: Flutamide as hydrophobic and glutathione as hydrophilic drugs as the case studies.

In this study, molecular dynamics simulation is applied to investigate drug transport in both pure state and conjugated with neutral gold nanoparticle (AuNP) as a drug carrier inside dipalmitoylphosphatidylcholine (DPPC) membrane. Flutamide (Flu) as a hydrophobic and Glutathione (GSH) as a hydrophilic anticancer drug are selected as the case studies. Dynamics of each drug including adhesion on and penetration into the cell membrane are investigated. Pure and conjugated form of drugs inside the water and near the membrane are studied. Simulation results show that the interaction between drug molecules and DPPC changes after drug conjugating with AuNP. GSH, as a hydrophilic drug, intends to remain above the membrane bilayer and after conjugating with AuNP diffuses inside DPPC. However, hydrophobic Flu molecule likes to diffuse inside DPPC, but after conjugating with AuNP, its diffusion inside the lipid bilayer decreases, and its retention time at the surface of DPPC increases. Presence of Flu-NP at the surface of DPPC could enhance its impact on blocking dihydrotestosterone binding at androgen receptors resulting in tumor cell growth arrest. In addition, the tendency of GSH-NP for diffusion to the DPPC is a positive factor for the successful transport of heavy metals such as AuNP without rapid clearance through either the hepatobiliary pathway or the renal system. In conclusion, such MD simulation results may solve problems in nanomedicine translation and turn into a bridge toward maximizing targeting and minimizing nanotoxicity of metal NPs.