IR783-enabled thioketal-bridged paclitaxel nanoprodrugs with ROS-responsive release for tumor imaging and chemotherapy.

Paclitaxel (PTX), a potent chemotherapeutic agent, faces significant clinical limitations due to poor aqueous solubility, systemic toxicity, and non-specific biodistribution, particularly in advanced peritoneal metastases. To overcome these challenges, we developed a carrier-free, self-assembled theranostic nanoprodrug system, IPSP NPs, integrating a thioketal-bridged paclitaxel dimer (PSP) with the near-infrared (NIR) fluorophore IR783. This innovative design enables reactive oxygen species (ROS)-responsive drug release and simultaneous NIR imaging. Comprehensive characterization confirmed the formation of stable, monodisperse IPSP NPs (∼161 nm) with high encapsulation efficiencies for both PSP (∼72.4%) and IR783 (∼89.4%). In vitro studies demonstrated robust ROS-triggered PTX release from IPSP NPs and a "prodrug latency effect" in colon cancer cells, showcasing stability at low concentrations and high cytotoxicity at therapeutic levels. In vivo evaluations in a CT26-Luc1 murine peritoneal metastasis model revealed favorable biodistribution with sustained tumor accumulation and significant tumor suppression comparable to free PTX. Histopathological analysis (H&E, Ki-67, TUNEL) demonstrated profound tumor cell damage, induced apoptosis, and inhibited proliferation by IPSP NPs. Crucially, IPSP NPs exhibited superior biosafety profiles, evidenced by normal organ histologies and improved renal function (reduced uric acid levels) compared to free PTX, highlighting reduced off-target toxicity. This work establishes a promising strategy for polymer-free theranostic nanoparticles, offering enhanced tumor targeting, controlled drug release, imaging capabilities, and improved safety for cancer therapy.