Acidic pH-Triggered Release of Doxorubicin from Ligand-Decorated Polymeric Micelles Potentiates Efficacy against Cancer Cells

Current chemotherapeutic strategies against various intractable cancers are futile due to inefficient delivery, poor bioavailability, and inadequate accumulation of anticancer drugs in the diseased site with toxicity caused to the healthy neighboring cells. Drug delivery systems aiming to deliver effective therapeutic concentrations to the site of action have emerged as a promising approach to address the above-mentioned issues. Thus, as several receptors have been identified as being overexpressed on cancer cells including folate receptor (FR), where up to 100-300 times higher overexpression is shown in cancer cells compared to healthy cells, approximately 1-10 million receptor copies per cancer cell can be targeted by a folic acid (FA) ligand. Herein, we developed FA-decorated and doxorubicin-conjugated polymeric micelles of 30 nm size. The hydrophilic block comprises poly(ethylene glycol) units, and the hydrophobic block contains doxorubicin conjugated aspartic acid units. Decoration of FA on the micelle surface induces ligand-receptor interaction, resulting in enhanced internalization into the cancer cell and inside the endolysosomal compartment. Under acidic pH, the micelle structure is disrupted and the hydrazone bond is cleaved, which covalently binds the doxorubicin with the hydrophobic backbone of the polymer and release the drug. We observed that the cellular uptake and nuclear colocalization of the targeted micelle are 2-4 fold higher than the control micelle at various incubation times in FR-overexpressed various cancer cell lines (KB, HeLa, and C6). These results indicate significant prospects for anticancer therapy as an effective and translational treatment strategy.