Light-Responsive Nanoparticles for Highly Efficient Cytoplasmic Delivery of Anticancer Agents

Stimuli-responsive nanostructures have shown great promise for intracellular delivery of anticancer compounds. A critical challenge remains in the exploration of stimuli-responsive nanoparticles for fast cytoplasmic delivery. Herein, near-infrared (NIR) light-responsive nanoparticles were rationally designed to generate highly efficient cytoplasmic delivery of anticancer agents for synergistic thermo-chemotherapy. The drug-loaded polymeric nanoparticles of selenium-inserted copolymer (I/D-Se-NPs) were rapidly dissociated in several minutes through reactive oxygen species (ROS)-mediated selenium oxidation upon NIR light exposure, and this irreversible dissociation of I/D-Se-NPs upon such a short irradiation promoted continuous drug release. Moreover, I/D-Se-NPs facilitated cytoplasmic drug translocation through ROS-triggered lysosomal disruption and thus resulted in highly preferable distribution to the nucleus even in 5 min postirradiation, which was further integrated with light-triggered hyperthermia for achieving synergistic tumor ablation without tumor regrowth

Gadolinium-Bisphosphonate Nanoparticle-Based Low-Dose Radioimmunotherapy for Osteosarcoma

Osteosarcoma is a malignant osteogenic tumor with a high metastatic rate commonly occurring in adolescents. Although radiotherapy is applied to treat unresectable osteosarcoma with radiation resistance, a high dose of radiotherapy is required, which may weaken the immune microenvironment. Therefore, there is an urgent need to develop novel agents to maximize the radiotherapeutic effects by eliciting immune activation effects. In this study, we synthesized therapeutic gadolinium-based metal-bisphosphonate nanoparticles (NPs) for osteosarcoma treatment that can be combined with radiotherapy. The gadolinium ion (Gd) was chelated with zoledronic acid (Zol), a commonly used drug to prevent/treat osteoporosis or bone metastases from advanced cancers, and stabilized by ovalbumin (OVA) to produce OVA-GdZol NPs. OVA-GdZol NPs were internalized into K7M2 osteosarcoma cells, showing a high sensitization effect under X-ray irradiation. Cell pretreatment of OVA-GdZol NPs significantly enhanced the radiation therapeutic effect in vitro by reducing the cell colonies and increased the signal of γH2AX-positive cells. More importantly, OVA-GdZol NPs promoted the maturation of bone marrow-derived dendritic cells (BMDCs) and M1 polarization of macrophages. The inhibitory effect on K7M2 osteosarcoma of OVA-GdZol NPs and X-ray radiation was evident, indicated by a significantly reduced tumor volume, high survival rate, and decreased lung metastasis. Meanwhile, both innate and adaptive immune systems were activated to exert a strong antitumor effect. The above results highly suggest that OVA-GdZol NPs serve as both radiosensitizers and immune adjuvants, suitable for the sequential combination of vaccination and radiotherapy

Ultrasensitive GSH-Responsive Ditelluride-Containing Poly(ether-urethane) Nanoparticles for Controlled Drug Release

A novel ultrasensitive redox-responsive system for the controlled release of doxorubicin (DOX) was fabricated by ditelluride-containing poly­(ether-urethane) copolymers. In this study, the ditelluride group was introduced for the first time into water-soluble copolymers used for drug delivery. Doxorubicin loaded in the copolymer nanoparticles can be released in a controlled manner through the cleavage of ditelluride bonds by glutathione (GSH). The ditelluride-containing poly­(ether-urethane) nanoparticles were demonstrated to be biocompatible as drug delivery vehicles, therefore opening a new avenue in drug delivery systems for chemotherapy. Furthermore, the in vitro and in vivo studies revealed that the DOX-loaded ditelluride-containing poly­(ether-urethane) nanoparticles exhibited efficient uptake in cancer cells, specific tumor targeting and antitumor activity, indicating their excellent potential as novel nanocarriers for drug delivery and cancer therapy

Noninvasive Multimodal Imaging of Osteosarcoma and Lymph Nodes Using a ^99mTc-Labeled Biomineralization Nanoprobe

The accurate imaging of the lymph nodes represents a critical indicator for tumor staging and surgical planning (e.g., osteosarcoma). Clinically, nodal tracing using a radio-nanocolloid is often limited by the inaccessibility of real-time images and inadequate anatomical information. Herein, we present a ^99mTc-labeled biomineralization nanoprobe for the advanced detection of osteosarcoma and lymph nodes with multimodal imaging. Through the exploitation of the complementary strengths of MRI/SPECT/NIR fluorescence, the fabricated nanoprobe exhibited suitable stability and biocompatibility characteristics and was shown to be able to be located in osteosarcoma. The lymphatic drainage and network in healthy mice were imaged in real-time using NIR fluorescence and SPECT/CT. Furthermore, we demonstrated that our ^99mTc-biomineralization nanoprobe could be used for the high-resolution and high-sensitivity imaging analysis of lymphatic drainage in an orthotopic osteosarcoma model. Overall, the ^99mTc-labeled biomineralization nanoprobe features promising characteristics to be used as an intraoperative visualization tool to aid in precise tumor imaging and nodal resection

Injectable and Biodegradable pH-Responsive Hydrogels for Localized and Sustained Treatment of Human Fibrosarcoma

Injectable hydrogels are an important class of biomaterials, and they have been widely used for controlled drug release. This study evaluated an injectable hydrogel formed <i>in situ</i> system by the reaction of a polyethylene glycol derivative with α,β-polyaspartylhydrazide for local cancer chemotherapy. This pH-responsive hydrogel was used to realize a sol–gel phase transition, where the gel remained a free-flowing fluid before injection but spontaneously changed into a semisolid hydrogel just after administration. As indicated by scanning electron microscopy images, the hydrogel exhibited a porous three-dimensional microstructure. The prepared hydrogel was biocompatible and biodegradable and could be utilized as a pH-responsive vector for drug delivery. The therapeutic effect of the hydrogel loaded with doxorubicin (DOX) after intratumoral administration in mice with human fibrosarcoma was evaluated. The inhibition of tumor growth was more obvious in the group treated by the DOX-loaded hydrogel, compared to that treated with the free DOX solution. Hence, this hydrogel with good syringeability and high biodegradability, which focuses on local chemotherapy, may enhance the therapeutic effect on human fibrosarcoma

Long-Circulating Iodinated Albumin–Gadolinium Nanoparticles as Enhanced Magnetic Resonance and Computed Tomography Imaging Probes for Osteosarcoma Visualization

Multimodal imaging probes represent an extraordinary tool for accurate diagnosis of diseases due to the complementary advantages of multiple imaging modalities. The purpose of the work was to fabricate a simple dual-modality MR/CT probe for osteosarcoma visualization in vivo. Protein-directed synthesis methods offer a suitable alternative to MR/CT probe produced by synthetic chemistry. Bovine serum albumin (BSA) bound to gadolinium nanoparticles (GdNPs) was first prepared via a biomimetic synthesis method and was subsequently iodinated by chloramine-T method. The final iodinated BSA-GdNPs (I-BSA-GdNPs) showed excellent chemical stability and biocompatibility, intense X-ray attenuation coefficient, and good MR imaging ability. However, an iodinated protein nanoparticles synthesis for MR/CT imaging, as well as its useful application, has not been reported yet. Intravenous injection of I-BSA-GdNPs into orthotopic osteosarcoma-bearing rats led to its accumulation and retention by the tumor, allowing for a noninvasive tumor dual-modality imaging through the intact thigh. The long-circulating dual-model I-BSA-GdNPs probes possess potential application for image-guided drug delivery and image-guided surgery. Our study is therefore highlighting the properties of albumin in this field combined with its useful use in dual-model MR/CT osteosarcoma visualization, underlining its potential use as a drug carrier for a future therapy on cancer

The protective role of autophagy in nephrotoxicity induced by bismuth nanoparticles through AMPK/mTOR pathway

<p>Bismuth is widely used in metallurgy, cosmetic industry, and medical diagnosis and recently, bismuth nanoparticles (NPs) (BiNP) have been made and proved to be excellent CT imaging agents. Previously, we have synthesized bovine serum albumin based BiNP for imaging purpose but we found a temporary kidney injury by BiNP. Due to the reported adverse events of bismuth on human health, we extended our studies on the mechanisms for BiNP induced nephrotoxicity. Blood biochemical analysis indicated the increase in creatinine (CREA) and blood urea nitrogen (BUN), and intraluminal cast formation with cell apoptosis/necrosis was evident in proximal convoluted tubules (PCTs) of mice. BiNP induced acute kidney injury (AKI) was associated with an increase in LC3II, while the autophagic flux indicator p62 remained unchanged. Chloroquine and rapamycin were used to evaluate the role of autophagy in AKI caused by BiNP. Results showed that BiNP induced AKI was further attenuated by rapamycin, while AKI became severe when chloroquine was applied. <i>In vitro</i> studies further proved BiNP induced autophagy in human embryonic kidney cells 293, presented as autophagic vacuole (AV) formation along with increased levels of autophagy-related proteins including LC3II, Beclin1, and Atg12. Specifically, reactive oxygen species (ROS) generated by BiNP could be the major inducer of autophagy, because ROS blockage attenuated autophagy. Autophagy induced by BiNP was primarily regulated by AMPK/mTOR signal pathway and partially regulated by Akt/mTOR. Our study provides fundamental theory to better understand bismuth induced nephrotoxicity for better clinical application of bismuth related compounds.</p

Dually pH/Reduction-Responsive Vesicles for Ultrahigh-Contrast Fluorescence Imaging and Thermo-Chemotherapy-Synergized Tumor Ablation

Smart nanocarriers are of particular interest as nanoscale vehicles of imaging and therapeutic agents in the field of theranostics. Herein, we report dually pH/reduction-responsive terpolymeric vesicles with monodispersive size distribution, which are constructed by assembling acetal- and disulfide-functionalized star terpolymer with near-infrared cyanine dye and anticancer drug. The vesicular nanostructure exhibits multiple theranostic features including on-demand drug releases responding to pH/reduction stimuli, enhanced photothermal conversion efficiency of cyanine dye, and efficient drug translocation from lysosomes to cytoplasma, as well as preferable cellular uptakes and biodistribution. These multiple theranostic features result in ultrahigh-contrast fluorescence imaging and thermo-chemotherapy-synergized tumor ablation. The dually stimuli-responsive vesicles represent a versatile theranostic approach for enhanced cancer imaging and therapy