Evaluation of PLA-PEG Micellar Nanocarriers with Trastuzumab for Targeted Delivery of Doxorubicin to HER2+ Breast Cancer Cells: A Molecular Dynamics Simulation

Context Breast cancer that is HER2-positive is still recognized as one of the more aggressive forms of breast cancer, which strongly suggests the need for more effective targeted forms of therapy. To develop better therapeutic approaches, understanding how drug delivery systems and monoclonal antibodies interact will be important. This work explores a new targeted delivery system for doxorubicin that employs PLA-PEG micellar copolymers with trastuzumab for better therapeutic effect against HER2-positive breast cancer. Molecular docking analysis suggests that there is a hydrogen bonding interaction between the COOH terminal group of the PLA-PEG micelle and the amine groups of trastuzumab, indicating favorable interactions with a COOH linker that was established on the PEG terminus. Among four different PLA-PEG molecular weight combinations evaluated using molecular dynamics simulation, PLA5K-PEG5K demonstrated optimal stability and absorption properties, as determined by structural and energetic analyses. The PLA5K-PEG5K-doxorubicin system with trastuzumab preserved structural integrity in aqueous solution and also indicates a favorable absorption and stability over time. Also, the behavior of this system near a POPE membrane was investigated, which obtained high interaction energy values, indicating great potential to deliver drugs into cells. These computational findings allow for the theoretical groundwork of a better-targeted delivery system, which could lead to improved outcomes for patients suffering from HER2-positive breast cancer. Methods Molecular docking studies were performed to assess protein-polymer binding between trastuzumab and PLA-PEG copolymers. Molecular dynamics (MD) simulations were completed to assess the stability and adsorption of the different PLA-PEG molecular weight combinations in an aqueous environment. System stability was examined through solvent-accessible surface area analysis, energy analysis, and radius of gyration measurements. Evaluation of membrane interactions was performed with a POPE model to assess their potential as a delivery vehicle, cellular delivery potential, and the energetics of the interactions. All MD simulations were run under periodic boundary conditions, and each system was simulated for 50 ns using Gromacs.