“Clickable” Polymer-Caged Nanobins as a Modular Drug Delivery Platform

Modularly clickable polymer-caged nanobins (PCNs) were prepared from liposome templates using a drop-in cholesterol-modified poly(acrylic acid) reagent followed by cross-linking with alkyne-functionalized diamine linker that allows for the conjugation of azide-modified targeting ligands via click ligation. These PCNs possess pH-responsive characteristics that can be used to trigger the release of encapsulated doxorubicin (DXR) payload inside the liposomal core under mild acidic conditions. After click-conjugation with azide-modified folate as an active targeting ligand, the resulting folate-conjugated, DXR-loaded PCNs (f-PCN(DXR)) demonstrated enhanced potency to folate receptor (FR)-positive tumor cells such as KB and OvCa432 over FR-negative MCF7 cells. f-PCN(DXR) can readily discriminate FR-positive tumor cells as a function of the level of cellular FR-expression, showing different degrees of potentiation in each cell. With both targeting functionalities and pH-sensitive drug-releasing triggers, f-PCN(DXR) was fifty-times more potent than the untargeted agent toward cancer cells that overexpress the folate target receptors.