Phototherapy including photodynamic therapy (PDT) and photothermal therapy (PTT) has attracted great attention. However, applications of some photosensitizers remain an obstacle by their poor photostability. To enhance the treatment efficiency of photosensitizers and tumor theranostic effect, herein, we reported a novel carrier-free, theranostic nanodrug by self-assembly of small molecule dual anticancer drugs and photosensitizer for tumor targeting. The developed carrier-free small molecule nanodrug delivery system was formed by hydrophobic ursolic acid, paclitaxel, and amphipathic indocyanine green (ICG) associated with electrostatic, π-π stacking, and hydrophobic interactions exhibiting water stability. The self-assembling of ICG on the dual anticancer nanodrug significantly enhanced water solubility of hydrophobic anticancer drugs and ICG photostability contributing to long-term near-infrared (NIR) fluorescence imaging and effective chemophototherapy of tumor. The in vivo NIR fluorescence imaging showed that the theranostic nanodrug could be targeted to the tumor site via a potential enhanced permeability and retention effect proving the efficient accumulation of nanoparticles in the tumor site. Dramatically, chemophototherapy of tumor-bearing mice in vivo almost completely suppressed tumor growth and no tumor recurrence was observed. Encouraged by its carrier-free, prominent imaging and effective therapy, the small molecule nanodrug via self-assembly will provide a promising strategy for synergistic cancer theranostics.

Ursolic acid (UA) is a food-plant-derived natural product which has good anticancer activities and low toxicity. However, the poor water solubility of UA limits its application in clinic. To address this issue, we developed a carrier-free nanodrug by self-assembly of UA. Here, we showed that UA nanoparticles (NPs) have a near-spherical shape with a diameter of ∼150 nm. UA NPs exhibited higher antiproliferative activity; significantly caused apoptosis; decreased the expression of COX-2/VEGFR2/VEGFA; and increased the immunostimulatory activity of TNF-α, IL-6, and IFN-β and decreased the activity of STAT-3 in A549 cells in vitro. Furthermore, UA NPs could inhibit tumor growth and have the ability of liver protection in vivo. More importantly, UA NPs could significantly improve the activation of CD4+ T-cells, which indicated that UA NPs have the potential for immunotherapy. Overall, a carrier-free UA nanodrug may be a promising drug to further enhance their anticancer efficacy and immune function.

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Ursolic acid and doxorubicin co-assembled into nanoparticles were modified with an aptamer for enhanced anti-tumor effects.