| Liposomes comprise one of the most biocompatible platforms for encapsulating chemotherapeutic agents and deliver them to diseased cells. Although they have the potential to decrease the toxic side effects often associated with conventional small-molecule drugs, bare liposomes are often unstable in biological environments, leading to low shelf-life and short circulation time. Additionally they lack the ability to target a particular diseased sites and specific triggers that can release the encapsulated drug under predefined condition. To overcome these limitations, clickable polymer-caged nanobins (PCNs) were prepared from liposome templates using a cholesterol-terminated poly(acrylic acid) that can be cross-linked with diamine linker to create a protective shell around the liposome core and make it more stable. These PCNs possess pH-responsive characteristics that can be used to trigger the release of encapsulated doxorubicin (DXR) inside the liposomal core under mild acidic conditions. Given these design advantages, PCNDXR can effectively inhibit in vivo tumor growth in a murine model of breast cancer. Importantly, PCNDXR was well-tolerated by mice and drug-encapsulation attenuated the adverse toxicity of DXR.;The PCN strategy allows for the additional incorporation of targeting groups and other drugs into the protective shell. With an alkyne-functionalized diamine cross-linker, azide-modified targeting ligands can be orthogonally linked to the shell via click ligation. In one example, click-conjugation with azide-modified folate afforded folate-conjugated, DXR-loaded PCNs (f-PCN DXR) with enhanced potency to folate receptor (FR)-positive tumor cells over FR-negative cells. f-PCNDXR 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.;Given the PCNs can offer a chemical tunability as a multi-component platform, cisplatin-prodrug can be conjugated to the unmodified acrylate groups on the protective shells of the PCNs to provide a new strategy for combination chemotherapy regimens. The co-delivery of DXR and cisplatin-prodrug to cancer cells via this PCN platform dramatically enhanced the overall cytotoxicity at reduced dose levels of each drug, enhancing the synergy in the combination of two agents. With readily modifiable surface chemistry and pH-sensitive drug-releasing triggers, PCNs constitutes a highly versatile delivery platform that can be used with conventional liposomal technology. |
