Delivering Drugs to Cancer Cells and inside the Mitochondria Using a Dual-Ligand Installed Targeted Drug Delivery System

Traditional anticancer therapy faces major limitations due to the off-target toxicity of drugs. A specialized drug delivery system (DDS) has proven to be a potential approach for overcoming this barrier. Targeted delivery to cancer cells not only enhances the precision of drug localization but also minimizes adverse effects of the drug by further directing therapeutic agents selectively to their site of action inside specific intracellular organelles. Among various targets, folate receptors show a significantly higher level of expression in many cancer types, making them suitable for preclinical developments. Moreover, after this selective delivery of anticancer drugs to cancer cells, regulation of the intracellular trafficking process could also impact the efficacy of drug actions. This selective targeting of cancer cells and delivery of drugs to their sites of action could be achieved by using two different types of targeting ligands on the same DDS surface. Herein, we used a chitosan-based biopolymer, modified by cholesterol molecules using a simple chemical approach and installed dual ligands, folic acid (FA) and triphenylphosphine (TPP) for selective cancer cell targeting and further mitochondrial delivery of curcumin. Cellular uptake studies in KB cells, which overexpress folate receptors, using fluorescence microscopy and flow cytometry analysis confirmed that the targeted DDS has many-fold higher cellular uptake than the nontargeted DDS (without decoration of TPP) and the null DDS (without FA and TPP on its surface), respectively, which induced more cytotoxic effects on cancer cells. The developed chemical approach employed for polymer synthesis and ligand decoration is a simple, straightforward, and one-step process that generates a versatile and multifaceted DDS with the possibility to encapsulate a wide variety of drugs (hydrophobic, charged, small molecule, biomolecule drugs, etc.) and ligands for enhanced precision therapy.