Gadolinium(III)-Chelated Silica Nanospheres Integrating Chemotherapy and Photothermal Therapy for Cancer Treatment and Magnetic Resonance Imaging

The combination of therapy and diagnosis has been emerging as a promising strategy for cancer treatment. To realize chemotherapy, photothermal therapy, and magnetic resonance imaging (MRI) in one system, we have synthesized a new magnetic nanoparticle (Gd@SiO₂-DOX/ICG-PDC) integrating doxorubicin (DOX), indocyanine green (ICG), and gadolinium­(III)-chelated silica nanospheres (Gd@SiO₂) with a poly­(diallyl­dimethyl­ammonium chloride) (PDC) coating. PDC coating serves as a polymer layer to protect from quick release of drugs from the nanocarriers and increase cellular uptake. The DOX release from Gd@SiO₂-DOX/ICG-PDC depends on pH and temperature. The process will be accelerated in the acidic condition than in a neutral pH 7.4. Meanwhile, upon laser irradiation, the photothermal effects promote DOX release and improve the therapeutic efficacy compared to either DOX-loaded Gd@SiO₂ or ICG-loaded Gd@SiO₂. Moreover, MRI results show that the Gd@SiO₂-PDC nanoparticles are safe T₁-type MRI contrast agents for imaging. The Gd@SiO₂-PDC nanoparticles loaded with DOX and ICG can thus act as a promising theranostic platform for multimodal cancer treatment

Summary of SCNT results.

<p>Summary of SCNT results.</p

Transgene integration and expression analysis in three cloned lambs.

<p>PCR analysis using primers specific for the shRNA expression cassette (A) and Neo (B). (C) Expression of the shRNA targeting MSTN in muscle tissues of transgenic sheep M17, M18 and M23. Negative control (NC): control sheep; positive control (PC): ploxP-shMSTN3 vector. M: Maker; TF-s2: Transgenic cell clone TF-s2; TF-s19: Transgenic cell clone TF-s19. (D) Western blot analysis of MSTN protein expression in muscle tissues of transgenic sheep M17, M18 and M23 and control sheep (Ctr1, Ctr2 and Ctr3).</p

Schematic illustration representing ploxP-shMSTN3 vector used in this study.

<p>Loxp: recombination site of Cre recombinase for bacteriophage P1; CMV: CMV promoter; Neo: neomycin gene; U6: polymerase III U6-RNA gene promoter, shRNA: short hairpin RNA. Arrowhead indicated localization of the primers specific for shRNA expression cassette and Neo gene. The size of the PCR amplicons is indicated.</p

Morphometric analysis of muscles.

<p>(A) H&E staining displayed myofiber hypertrophy in muscles of M17 compared with control sheep. (B) Distribution of muscle fiber sizes in M17 and control sheep. A total of 500 fibers from each sheep were measured. (C) Mean myofiber diameter for M17 and controls.</p

Expression levels of MHCII, MyoD, Myogenin and Smad2 in the muscle tissues of transgenic sheep.

<p>mRNA expression of MHCII (A), MyoD (B), Myogenin (C) and Smad2 (D) were determined using Real-time RT-PCR and normalized to GAPDH expression. * P<0.05, ** P<0.01.</p

Body weight of transgenic sheep and controls.

<p>M17, M18, M23 and three control sheep were weighted at 1, 20, 40, 60 and 90 days after birth. Control values are average weights of three control sheep.</p

Using Hollow Carbon Nanospheres as a Light-Induced Free Radical Generator To Overcome Chemotherapy Resistance

Under evolutionary pressure from chemotherapy, cancer cells develop resistance characteristics such as a low redox state, which eventually leads to treatment failures. An attractive option for combatting resistance is producing a high concentration of produced free radicals <i>in situ</i>. Here, we report the production and use of dispersible hollow carbon nanospheres (HCSs) as a novel platform for delivering the drug doxorubicine (DOX) and generating additional cellular reactive oxygen species using near-infrared laser irradiation. These irradiated HCSs catalyzed sufficiently persistent free radicals to produce a large number of heat shock factor-1 protein homotrimers, thereby suppressing the activation and function of resistance-related genes. Laser irradiation also promoted the release of DOX from lysosomal DOX@HCSs into the cytoplasm so that it could enter cell nuclei. As a result, DOX@HCSs reduced the resistance of human breast cancer cells (MCF-7/ADR) to DOX through the synergy among photothermal effects, increased generation of free radicals, and chemotherapy with the aid of laser irradiation. HCSs can provide a unique and versatile platform for combatting chemotherapy-resistant cancer cells. These findings provide new clinical strategies and insights for the treatment of resistant cancers

Rapid Degradation and High Renal Clearance of Cu₃BiS₃ Nanodots for Efficient Cancer Diagnosis and Photothermal Therapy <i>in Vivo</i>

A key challenge for the use of inorganic nanomedicines in clinical applications is their long-term accumulation in internal organs, which raises the common concern of the risk of adverse effects and inflammatory responses. It is thus necessary to rationally design inorganic nanomaterials with proper accumulation and clearance mechanism <i>in vivo</i>. Herein, we prepared ultrasmall Cu₃BiS₃ nanodots (NDs) as a single-phased ternary bimetal sulfide for photothermal cancer therapy guided by multispectral optoacoustic tomography (MSOT) and X-ray computed tomography (CT) due to bismuth’s excellent X-ray attenuation coefficient. We then monitored and investigated their absorption, distribution, metabolism, and excretion. We also used CT imaging to demonstrate that Cu₃BiS₃ NDs can be quickly removed through renal clearance, which may be related to their small size, rapid chemical transformation, and degradation in an acidic lysosomal environment as characterized by synchrotron radiation-based X-ray absorption near-edge structure spectroscopy. These results reveal that Cu₃BiS₃ NDs act as a simple but powerful “theranostic” nanoplatform for MSOT/CT imaging-guided tumor ablation with excellent metabolism and rapid clearance that will improve safety for clinical applications in the future

Use of Synchrotron Radiation-Analytical Techniques To Reveal Chemical Origin of Silver-Nanoparticle Cytotoxicity

To predict potential medical value or toxicity of nanoparticles (NPs), it is necessary to understand the chemical transformation during intracellular processes of NPs. However, it is a grand challenge to capture a high-resolution image of metallic NPs in a single cell and the chemical information on intracellular NPs. Here, by integrating synchrotron radiation-beam transmission X-ray microscopy (SR-TXM) and SR-X-ray absorption near edge structure (SR-XANES) spectroscopy, we successfully capture the 3D distribution of silver NPs (AgNPs) inside a single human monocyte (THP-1), associated with the chemical transformation of silver. The results reveal that the cytotoxicity of AgNPs is largely due to the chemical transformation of particulate silver from elemental silver (Ag⁰)_<i>n</i>, to Ag⁺ ions and Ag–O–, then Ag–S– species. These results provide direct evidence in the long-lasting debate on whether the nanoscale or the ionic form dominates the cytotoxicity of silver nanoparticles. Further, the present approach provides an integrated strategy capable of exploring the chemical origins of cytotoxicity in metallic nanoparticles