Ultrasmall-Superbright Neodymium-Upconversion Nanoparticles via Energy Migration Manipulation and Lattice Modification: 808 nm-Activated Drug Release

Nd³⁺-sensitized upconversion nanoparticles are among the most promising emerging fluorescent nanotransducers. They are activated by 808 nm irradiation, which features merits such as limited tissue overheating and deeper penetration depth, and hence are attractive for diagnostic and therapeutic applications. Recent studies indicate that ultrasmall nanoparticles (<10 nm) are potentially more suitable for clinical application due to their favorable biodistribution and safety profiles. However, upconversion nanoparticles in the sub-10 nm range suffer from poor luminescence due to their ultrasmall size and greater proportion of lattice defects. To reconcile these opposing traits, we adopt a combinatorial strategy of energy migration manipulation and crystal lattice modification, creating ultrasmall-superbright Nd³⁺-sensitized nanoparticles with 2 orders of magnitude enhancement in upconversion luminescence. Specifically, we configure a sandwich-type nanostructure with a Yb³⁺-enriched intermediate layer [Nd³⁺]–[Yb³⁺–Yb³⁺]–[Yb³⁺–Tm³⁺] to form a positively reinforced energy migration system, while introducing Ca²⁺ into the crystal lattice to reduce lattice defects. Furthermore, we apply the nanoparticles to 808 nm light-mediated drug release. The results indicate time-dependent cancer cells killing and better antitumor activities. These ultrasmall-superbright dots have unraveled more opportunities in upconversion photomedicine with the promise of potentially safer and more effective therapy

Redox-Sensitive Hydroxyethyl Starch–Doxorubicin Conjugate for Tumor Targeted Drug Delivery

Doxorubicin (DOX) is one of the most potent anticancer agents in cancer chemotherapy, but the clinical use of DOX is restricted by its severe side effects caused by nonspecific delivery. To alleviate the side effects and improve the antitumor efficacy of DOX, a novel redox-sensitive hydroxyethyl starch–doxorubicin conjugate, HES-SS-DOX, with diameter of 19.9 ± 0.4 nm was successfully prepared for tumor targeted drug delivery and GSH-mediated intracellular drug release. HES-SS-DOX was relatively stable under extracellular GSH level (∼2 μM) but released DOX quickly under intracellular GSH level (2–10 mM). In vitro cell study confirmed the GSH-mediated cytotoxicity of HES-SS-DOX. HES-SS-DOX exhibited prolonged plasma half-life time and enhanced tumor accumulation in comparison to free DOX. As a consequence, HES-SS-DOX exhibited better antitumor efficacy and reduced toxicity as compared to free DOX in the in vivo antitumor activity study. The redox-sensitive HES-SS-DOX was proved to be a promising prodrug of DOX, with clinical potentials, to achieve tumor targeted drug delivery and timely intracellular drug release for effective and safe cancer chemotherapy

α‑Amylase- and Redox-Responsive Nanoparticles for Tumor-Targeted Drug Delivery

Paclitaxel (PTX) is an effective antineoplastic agent and shows potent antitumor activity against a wide spectrum of cancers. Yet, the wide clinical use of PTX is limited by its poor aqueous solubility and the side effects associated with its current therapeutic formulation. To tackle these obstacles, we report, for the first time, α-amylase- and redox-responsive nanoparticles based on hydroxyethyl starch (HES) for the tumor-targeted delivery of PTX. PTX is conjugated onto HES by a redox-sensitive disulfide bond to form HES–SS-PTX, which was confirmed by results from NMR, high-performance liquid chromatography-mass spectrometry, and Fourier transform infrared spectrometry. The HES–SS-PTX conjugates assemble into stable and monodispersed nanoparticles (NPs), as characterized with Dynamic light scattering, transmission electron microscopy, and atomic force microscopy. In blood, α-amylase will degrade the HES shell and thus decrease the size of the HES–SS-PTX NPs, facilitating NP extravasation and penetration into the tumor. A pharmacokinetic study demonstrated that the HES–SS-PTX NPs have a longer half-life than that of the commercial PTX formulation (Taxol). As a consequence, HES–SS-PTX NPs accumulate more in the tumor compared with the extent of Taxol, as shown in an in vivo imaging study. Under reductive conditions, the HES–SS-PTX NPs could disassemble quickly as evidenced by their triggered collapse, burst drug release, and enhanced cytotoxicity against 4T1 tumor cells in the presence of a reducing agent. Collectively, the HES–SS-PTX NPs show improved in vivo antitumor efficacy (63.6 vs 52.4%) and reduced toxicity in 4T1 tumor-bearing mice compared with those of Taxol. These results highlight the advantages of HES-based α-amylase- and redox-responsive NPs, showing their great clinical translation potential for cancer chemotherapy

Synergizing Upconversion Nanophotosensitizers with Hyperbaric Oxygen to Remodel the Extracellular Matrix for Enhanced Photodynamic Cancer Therapy

Photodynamic therapy (PDT) holds great promise as a noninvasive and selective cancer therapeutic treatment in preclinical research and clinical practice; however, it has limited efficacy in the ablation of deep-seated tumor because of hypoxia-associated circumstance and poor penetration of photosensitizers to cancer cells away from the blood vessels. To tackle the obstacles, we propose a therapeutic strategy that synergizes upconversion nanophotosensitizers (UNPSs) with hyperbaric oxygen (HBO) to remodel the extracellular matrix for enhanced photodynamic cancer therapy. The UNPSs are designed to have an Nd³⁺-sensitized sandwiched structure, wherein the upconversion core serves as light transducers to transfer energy to the neighboring photosensitizers to produce reactive oxygen species (ROS). With HBO, photodynamic process can generate abundant ROS in the intrinsically hypoxic tumor. It is revealed for the first time that HBO-assisted PDT decomposes collagen in the extracellular matrix of tumor and thus facilitates the diffusion of oxygen and penetration of UNPSs into the deeper area of tumor. Such a synergic effect eventually results in a significantly enhanced therapeutic efficacy at a low laser power density as compared with that using UNPSs alone. In view of its good biosafety, the HBO-assisted and UNPSs-mediated PDT provides new possibilities for treatment of solid tumors