Suppression of cancer proliferation and metastasis by a versatile nanomedicine integrating photodynamic therapy, photothermal therapy, and enzyme inhibition

Cancer therapeutics are varied and target diverse processes in cancer progression. Photodynamic therapy (PDT), photothermal therapy (PTT), and the inhibition of pro-cancer proteases are non-invasive anticancer therapeutics that attract increasing attentions for their enhanced specificities and milder systemic toxicities compared to traditional therapeutics. These modalities offer advantages to compensate for the shortcomings of their counterparts. For instance, PDT or PTT efficiently eliminates locally confined tumor cells while exhibiting no effect on metastatic tumor cells. In contrast, the inhibition of pro-cancer proteases systemically suppresses the proliferation and metastasis of cancer cells but does not eradicate existing cancer cells. To synergize these therapeutics, we hereby report a versatile nanoparticle that integrates the effects of PDT, PTT, and enzyme-inhibition. This nanoparticle (CIKP-NP) was synthesized by covalently or non-covalently modifying a photothermal nanoparticle with a photosensitizer, a pro-cancer protease inhibitor, and an albumin-binding molecule. After confirming the PDT, PTT, albumin-binding, and enzyme-inhibition properties at the molecular level, we demonstrated that CIKP-NP killed tumor cells through PDT or PTT and suppressed tumor cell invasion through enzyme-inhibition. In addition, through a breast cancer xenograft mouse model, we demonstrated that CIKP-NP suppressed tumor growth by PDT or PTT effect. Notably, the synergism of PDT and PTT significantly enhanced its anticancer efficiency. Furthermore, CIKP-NP significantly suppressed cancer metastasis in a lung metastatic mouse model. Last, biodistribution and the in vivo retention of CIKP-NP confirmed the tumor-targeting property. Beyond demonstrating the anti-tumor and anti-metastatic efficacy of CIKP-NP, our study also suggests a new strategy to synergize multiple anticancer therapeutics.