Optimization and testing of functionalized antitumor nanoparticles combined with membrane lipid therapy | Department of Biophysics and Cell Biology

Malignant tumors represent the second leading cause of death in developed countries. Although emerging treatment modalities, such as targeted and personalized pharmacotherapy and immunotherapy, can significantly prolong patient survival, the further development of anticancer strategies remains essential. Chemotherapeutics still remain the frontline choice for advanced-stage malignancies, particularly when surgery or radiotherapy is not feasible. However, their clinical utility is limited by their lack of specificity, which leads to adverse effects caused by collateral damage to healthy cells and their inability to enter target cells because of low membrane permeability. The latter results from unfavorable alterations in membrane lipid composition, including cholesterol elevation, which are closely associated with neoplastic transformation and impaired immune responses. For example, we recently demonstrated that such changes may decrease the cellular entry of cell-penetrating peptides holding promising antitumor potential.
In our work, we aim at enhancing the delivery and therapeutic efficiency of conventional chemotherapeutics by combining them with membrane lipid therapy approaches to modify membrane lipid composition and biophysical properties of target tumor cells mainly through reducing cholesterol levels, and with cell-penetrating peptides or cyclodextrin-based nanoparticles as carriers bearing specific tumor cell-targeting signals. Currently, we are designing nanoparticles containing cell-penetrating peptides or cyclodextrins and tumor-targeting signals, and evaluating the efficacy of this combined therapeutic approach in conventional two-dimensional cell models, more pathophysiologically relevant three-dimensional cell models, and murine mammary adenocarcinoma xenografts. We also aim to characterize the potential immune-related benefits of membrane lipid therapy in tumors.