An intracellular enzyme-responsive polymeric prodrug with synergistic effect of chemotherapy and two-photon photodynamic therapy

Abstract The combination of chemotherapy/photodynamic therapy (PDT) has shown synergistically enhanced anticancer efficacies. However, precise delivery of therapeutic agents to the site-of-action and activation of PDT in deep tissues are still challenging. Herein, a poly [oligo (ethylene glycol) methyl ether methacrylate] (polyOEGMA)-functionalized dendritic polymer-paclitaxel prodrug with a hydrophobic core was designed and prepared to encapsulate pyropheophorbide a (PPa) and an imidazole derivative, two-photon (TP) absorption compound T1. As a short peptide GFLG that was sensitive to intracellular cathepsin B was inserted into the branches of the dendritic polymer and also used as a linker to conjugate paclitaxel (PTX) to the polymer, the nanosystem released PTX in a tumor microenvironment-responsive manner and was partially degraded. The TP compound T1 had a high energy-transfer efficiency and displayed an enhanced two-photon photodynamic therapy (TP-PDT) effect, thus resulting in an increased anticancer efficacy, which was confirmed with the results of in situ TP-PDT anti-tumor efficiencies and apoptosis assays. The synergistic effect on inhibition of tumor growth in the 4T1 xenograft mice was achieved due to the combination of chemotherapy (PTX) and PDT (PPa or TP-PDT compound T1). Importantly, the chemo/TP-PDT combined system achieved a much higher tumor growth inhibition (TGI, 67.23%) in the tissue surrounded with thick swine muscle as compared to the group treated with PTX and PPa (48.92%). The prodrug-based nanosystem loaded with PTX and TP-PDT agents could overcome the challenge of conventional one-photon PDT with a short penetration depth into tissues to achieve a notably enhanced synergistic anticancer efficacy.