(692b) Synthesis, Characterization, Cellular Internalization and Mitochondrial Targeting of Triphenylphosphonium-Conjugated PAMAM Dendrimer Nanocarriers
Lung cancer is the leading cause of cancer related death worldwide with over 1.3 million deaths annually. Less than 15% of those diagnosed with lung cancer have an overall prognosis greater than 5 years. Therefore, new strategies to fight lung cancer have tremendous potential in improving the health and survival rate of a large number of patients. Mitochondria play vital roles in energy production within cells, are key to eukaryotic cell survival, in the generation of reactive oxygen species, in the regulation of calcium homeostasis, and importantly, in the regulation of programmed cell death. Mitochondrial dysfunction is related to a range of diseases including cancer. A change in the cellular bioenergetics is a crucial marker of cancer, as well as resistance to apoptosis, invasiveness, malignancy, and decreased autophagy. Many of these factors have been linked to mitochondrial dysfunction, making mitochondria vital intracellular targets for anticancer therapies.
Delocalized lipophilic cations (DLCs), such as triphenylphosphonim cations (TPP), are the most widely used mitochondrial targeting agents due to their delocalized positive charge, which allows them to pass through plasma and mitochondrial membranes in a potential driven process, showing 100-1000 fold selective accumulation into the cell cytosol and mitochondrial compartments. DLCs also accumulate more readily into tumor cells as they possess more negative plasma and mitochondrial membrane potentials. Therefore, the use of DLCs such as TPP may offer unique strategies to deliver numerous anticancer agents preferentially to cancerous cells, and can thus be very effective in maximizing drug effects while reducing side effects. The combination of DLCs with drug nanocarriers, such as poly(amido amine) (PAMAM) dendrimers, may afford further opportunities for the cellular and intracellular targeting and controlled release of therapeutics to treat lung cancer.
In this work, we report i) the synthesis and characterization of triphenylphosphonim cations (TPP) to PAMAM dendrimers, which are potential nanocarriers of anticancer agents, ii) the cellular internalization and colocalization of such nanocarriers in A549 alveolar epithelial adenocarcinomal cell line using flow cytometry and confocal microscopy, respectively, and iii) the effect of PEG-TPP conjugation to PAMAM dendrimers on cellular internalization and colocalization in A549 cells.
This study is also relevant in the delivery of other agents to the mitochondria for the treatment of mitochondrial disorders related to other diseases such as diabetes, neurodegenerative, neuromuscular disorders, and inherited mitochondrial diseases not necessarily associated with cancer.