Minimally Invasive Delivery of Percutaneous Ablation Agent via Magnetic Colloidal Hydrogel Injection for Treatment of Hepatocellular Carcinoma.

Percutaneous thermotherapy, a minimally invasive operational procedure, is employed in the ablation of deep tumor lesions by means of target-delivering heat. Conventional thermal ablation methods, such as radiofrequency or microwave ablation, to a certain extent, are subjected to extended ablation time as well as biosafety risks of unwanted overheating. Given its effectiveness and safety, percutaneous thermotherapy gains a fresh perspective, thanks to magnetic hyperthermia. In this respect, an injectable- and magnetic-hydrogel-construct-based thermal ablation agent is likely to be a candidate for the aforementioned clinical translation. Adopting a simple and environment-friendly strategy, a magnetic colloidal hydrogel injection is introduced by a binary system comprising super-paramagnetic Fe3O4 nanoparticles and gelatin nanoparticles. The colloidal hydrogel constructs, unlike conventional bulk hydrogel, can be easily extruded through a percutaneous needle and then self-heal in a reversible manner owing to the unique electrostatic cross-linking. The introduction of magnetic building blocks is exhibited with a rapid magnetothermal response to an alternating magnetic field. Such hydrogel injection is capable of generating heat without limitation of deep penetration. The materials achieve outstanding therapeutic results in mouse and rabbit models. These findings constitute a new class of locoregional interventional thermal therapies with minimal collateral damages.

Liquid exfoliation of ultrasmall zirconium carbide nanodots as a noninflammatory photothermal agent in the treatment of glioma.

Photothermal therapy (PTT), like other clinical translational tumor ablation techniques, requires a temperature increase above 50 °C to cause necrosis and death of tumor cells. Although the tumor can be eliminated rapidly by PTT, the inflammatory response is triggered by the large amounts of released reactive oxygen species (ROS). Therefore, liquid exfoliation was used to create ultrasmall zirconium carbide nanodots (NDs) with an average diameter of approximately 4.5 nm as noninflammatory/anti-inflammatory photosensitizers for PTT of glioma. Ultrasmall ZrC NDs showed excellent photothermal stability and biocompatibility but no obvious toxicity. Moreover, the ultrasmall ZrC NDs effectively ablated glioma at relatively low concentrations and inhibited tumor migration and proliferation in vitro and in vivo. Furthermore, the excellent ROS-scavenging ability of ultrasmall ZrC NDs suppressed the inflammatory response to PTT. Intriguingly, we found that ZrC had the capability of performing CT imaging. We demonstrated that the ultrasmall ZrC NDs created in this study could effectively and safely treat glioma without inflammation.

Ultrasmall zirconium carbide nanodots for synergistic photothermal-radiotherapy of glioma.

Glioma is characterized by highly invasive, progressive, and lethal features. In addition, conventional treatments have been poorly effective in treating glioma. To overcome this challenge, synergistic therapies combining radiotherapy (RT) with photothermal therapy (PTT) have been proposed and extensively explored as a highly feasible cancer treatment strategy. Herein, ultrasmall zirconium carbide (ZrC) nanodots were successfully synthesized with high near-infrared absorption and strong photon attenuation for synergistic PTT-RT of glioma. ZrC-PVP nanodots with an average size of approximately 4.36 nm were prepared by the liquid exfoliation method and modified with the surfactant polyvinylpyrrolidone (PVP), with a satisfactory absorption and photothermal conversion efficiency (53.4%) in the near-infrared region. Furthermore, ZrC-PVP nanodots can also act as radiosensitizers to kill residual tumor cells after mild PTT due to their excellent photon attenuating ability, thus achieving a significant synergistic therapeutic effect by combining RT and PTT. Most importantly, both in vitro and in vivo experimental results further validate the high biosafety of ZrC-PVP NDs at the injected dose. This work systematically evaluates the feasibility of ZrC-PVP NDs for glioma treatment and provides evidence of the application of zirconium-based nanomaterials in photothermal radiotherapy.

Injectable magnetic montmorillonite colloidal gel for the postoperative treatment of hepatocellular carcinoma.

Bioactive materials have been extensively developed for the adjuvant therapy of cancer. However, few materials can meet the requirements for the postoperative resection of hepatocellular carcinoma (HCC) due to massive bleeding and high recurrence. In particular, combination therapy for HCC has been highly recommended in clinical practice, including surgical resection, interventional therapy, ablation therapy and chemotherapy. Herein, an injectable magnetic colloidal gel (MCG) was developed by controllable electrostatic attraction between clinically available magnetic montmorillonites and amphoteric gelatin nanoparticles. The optimized MCG exhibited an effective magnetic heating effect, remarkable rheological properties, and high gel network stability, realizing the synergistic treatment of postoperative HCC by stimuli-responsive drug delivery, hemostasis and magnetic hyperthermia. Furthermore, a minimal invasive MCG-induced interventional magnetic hyperthermia therapy (MHT) under ultrasound guidance was realized on hepatic tumor rabbits, providing an alternative therapeutics to treat the postoperative recurrence. Overall, MCG is a clinically available injectable formulation for adjuvant therapy after HCC surgical resection.

Phototherapy Using a Fluoroquinolone Antibiotic Drug to Suppress Tumor Migration and Proliferation and to Enhance Apoptosis.

In this work, a fluoroquinolone antibiotic drug (sparfloxacin (SP)) was selected as a chemotherapy drug and photosensitizer for combined therapy. A facile chemical process was developed to incorporate SP and upconversion nanoparticles (UCNPs) into the thermally sensitive amphiphilic polymer polyethylene glycol-poly(2-hexoxy-2-oxo-1,3,2-dioxaphospholane). In vitro and in vivo experiments showed that 60% of the SP molecules can be released from the micelles of thermal-sensitive polymers using a 1 W cm-2 980 nm laser, and this successfully inhibits cell migration and metastasis by inhibiting type II topoisomerases in nuclei. Additionally, intracellular metal ions were chelated by SP to induce cancer cell apoptosis by decreasing the activity of superoxide dismutase and catalase. In particular, the fluoroquinolone molecules produced singlet oxygen (1O2) to kill cancer cells, and this was triggered by UCNPs when irradiation was performed with a 980 nm laser. Overall, SP retained a weak chemotherapeutic effect, achieved enhanced photosensitizer-like effects, and was able to repurpose old drugs to elevate the therapeutic efficacy against cancer, increase the specificity for suppressing tumor migration and proliferation, and enhance apoptosis.

Controlled CRISPR-Cas9 Ribonucleoprotein Delivery for Sensitized Photothermal Therapy.

Manipulation of CRISPR delivery for stimuli-responsive gene editing is crucial for cancer therapeutics through maximizing efficacy and minimizing side-effects. However, realizing controlled gene editing for synergistic combination therapy remains a key challenge. Here, a near-infrared (NIR) light-triggered thermo-responsive copper sulfide (CuS) multifunctional nanotherapeutic platform is constructed to achieve controlled release of CRISPR-Cas9 ribonucleoprotein (RNP) and doxorubicin for tumor synergistic combination therapy involving in gene therapy, mild-photothermal therapy (PTT), and chemotherapy. The semiconductor CuS serves as a "photothermal converter" and can stably convert NIR light (808 nm) into local thermal effect to provide photothermal stimulation. The double-strand formed between CuS nanoparticle-linked DNA fragments and single-guide RNA is employed as a controlled element in response to photothermal stimulation for controlled gene editing and drug release. Hsp90α, one subunit of heat shock protein 90 (Hsp90), is targeted by Cas9 RNP to reduce tumor heat tolerance for enhanced mild-PTT effects (≈43 °C). Significant synergistic therapy efficacy can be observed by twice NIR light irradiation both in vitro and in vivo, compared to PTT alone. Overall, this exogenously controlled method provides a versatile strategy for controlled gene editing and drug release with potentially synergistic combination therapy.

Catalytic rhodium (Rh)-based (mesoporous polydopamine) MPDA nanoparticles with enhanced phototherapeutic efficiency for overcoming tumor hypoxia.

Catalytic nanomedicine with high oxygen-generation efficiency may find applications in alleviating tumor hypoxia and improving the efficiency of photodynamic therapy (PDT). In this study, a catalytic nanosystem (Ce6-Rh@MPDA) was developed using mesoporous polydopamine nanoparticles (MPDA) to encapsulate catalase-like rhodium nanoparticles (Rh NPs) and photosensitizer chlorine6 (Ce6) for photoacoustic/fluorescence dual imaging-guided tumor therapy. The Rh NPs can catalyze the production of O2 from tumor-enriched H2O2in situ, in which the mesoporous structure of MPDA plays an important role via improving the catalytic efficiency of Rh NPs. Moreover, the hyperthermia generated by both MPDA and Rh NPs under laser irradiation accelerates the O2 generation to promote the PDT. The Ce6-Rh@MPDA nanoparticles described herein represent a multifunctional metal-based catalytic nanomedicine which not only alleviates tumor hypoxia but also enables a synergistic antitumor treatment using PTT and PDT.

Rod-based urchin-like hollow microspheres of Bi2S3: Facile synthesis, photo-controlled drug release for photoacoustic imaging and chemo-photothermal therapy of tumor ablation.

Hollow nanostructures have been evoked considerable attention owing to their intriguing hollow interior for important and potential applications in drug delivery, lithium battery, catalysis and etc. Herein, Bi2S3 hollow microspheres with rod-based urchin-like nanostructures (denoted as U-BSHM) were synthesized through a facile and rapid ion exchanging method using a particular hard template. The growth mechanism of the U-BSHM has been investigated and illustrated by the morphological evolution of the different samples at early stages. The obtained U-BSHM exhibited strong and wide UV-vis-NIR absorption ability and outstanding photothermal conversion efficiency. Thus, the U-BSHM can be used as spatio-temporal precisely controlled carrier by loading the mixture of 1-tetradecanol (phase change material, PCM) with melting point around 38 °C and hydrophilic chemotherapeutic doxorubicin hydrochloride (denoted as DOX) into the hollow interior to form (PCM + DOX)@Bi2S3 nanocomposites (denoted as PD@BS) for photoacoustic (PA) imaging and chemo-photothermal therapy of the tumors. When exposed to 808 nm near infrared light (NIR) laser irradiation, this nanocomposites could elevate the temperature of the surroundings by absorption and conversion of the NIR photons into heat energy, which inducing the triggered release of DOX from the hollow interior once the temperature reach up to the melting point of PCM. The killing efficiency of the chemo-photothermal therapy was systematically validated both in vitro and in vivo. In the meanwhile, the implanted tumor was completely restrained through PA imaging and combined therapies. Therefore, this kind of urchin-like hollow nanostructures would be used as important candidates for the multimodal bioimaging and therapy of tumors.

Liquid Exfoliation of Atomically Thin Antimony Selenide as an Efficient Two-Dimensional Antibacterial Nanoagent.

The ever-growing global crisis of multidrug-resistant bacteria has triggered a tumult of activity in the design and development of antibacterial formulations. Here, atomically thin antimony selenide nanosheets (Sb2Se3 NSs), a minimal-toxic and low-cost semiconductor material, were explored as a high-performance two-dimensional (2D) antibacterial nanoagent via a liquid exfoliation strategy integrating cryo-pretreatment and polyvinyl pyrrolidone (PVP)-assisted exfoliation. When cultured with bacteria, the obtained PVP-capped Sb2Se3 NSs exhibited intrinsic long-term antibacterial capability, probably due to the reactive oxygen species generation and sharp edge-induced membrane cutting during physical contact between bacteria and nanosheets. Upon near-infrared laser irradiation, Sb2Se3 NSs achieved short-time hyperthermia sterilization because of strong optical absorption and high photothermal conversion efficiency. By virtue of the synergistic effects of these two broad-spectrum antibacterial mechanisms, Sb2Se3 NSs exhibited high-efficiency inhibition of conventional Gram-negative Escherichia coli, Gram-positive methicillin-resistant Staphylococcus aureus, and wild bacteria from a natural water pool. Particularly, these three categories of bacteria were completely eradicated after being treated with Sb2Se3 NSs (300 µM) plus laser irradiation for only 5 min. In vivo wound healing experiment further demonstrated the high-performance antibacterial effect. In addition, Sb2Se3 NSs depicted excellent biocompatibility due to the biocompatible element constitute and bioinert PVP modification. This work enlightened that atomically thin Sb2Se3 NSs hold great promise as a broad-spectrum 2D antibacterial nanoagent for various pathogenic bacterial infections.

Mesoporous NiS2 nanospheres as a hydrophobic anticancer drug delivery vehicle for synergistic photothermal-chemotherapy.

To overcome the unfavorable effects of the hydrophobicity of drugs and cancer resistance, mesoporous NiS2 nanospheres (mNiS2 NSs) have been successfully developed here to package hydrophobic camptothecin (CPT) and realize the synergistic photothermal-chemotherapy of cancer. The mNiS2 NSs which were prepared through a facile solvothermal method here exhibited not only considerable near-infrared (NIR) absorption and good photothermal conversion efficiency as high as 44.6%, but also achieved a NIR light induced CPT release property which were both beneficial for improving the cancer cell-killing efficacy. After a short period of NIR light illumination, a significant intensified cell killing efficacy was observed when 4T1 or HepG2 cancer cells were incubated with CPT@mNiS2 NSs. Thus, mNiS2 NSs have been demonstrated here to have potential as a novel NIR light-responsive hydrophobic drug delivery nanoplatform for realizing synergistic cancer treatment.

Ambient Aqueous Synthesis of Ultrasmall Ni0.85Se Nanoparticles for Noninvasive Photoacoustic Imaging and Combined Photothermal-Chemotherapy of Cancer.

Large-size-induced long-term retention in the body has hampered the translational applications of many reported nanomedicines. Herein, we reported a multifunctional theranostic agent composed of ultrasmall poly(acrylic acid)-functionalized Ni0.85Se nanoparticles (PAA-Ni0.85Se NPs), which were successfully obtained through a facile ambient aqueous precipitation strategy. Without exhibiting any noticeable toxicity, the as-prepared PAA-Ni0.85Se NPs (average diameter of 6.40 ± 1.89 nm) showed considerable absorption in near-infrared (NIR) region and high photothermal conversion efficiency of 54.06%, which could induce remarkable photoacoustic signals for tumor imaging and heat for localized ablation of cancerous cells upon exposure to NIR light. Notably, the ultrasmall PAA-Ni0.85Se NPs, unlike conventional nanomaterials with larger sizes, showed reasonable body clearance within 8 h after intravenous injection. Furthermore, ascribed to protonation process of amino groups in DOX molecules and carboxyl groups in PAA molecules in an acidic microenvironment, the drug-loaded (doxorubicin hydrochloride, DOX·HCl) PAA-Ni0.85Se NPs (PAA-Ni0.85Se-DOX NPs) revealed promoted drug release at acidic pH, which could be useful for acidic tumor microenvironment responsive drug delivery. Evident from the results of cell-killing assay in vitro and tumor treatment study in vivo, PAA-Ni0.85Se-DOX NPs exhibited evident synergistic effects on killing 4T1 breast cancer cells. Thus, this study presents a multifunctional theranostic agent composed of ultrasmall PAA-Ni0.85Se NPs for potential cancer treatment without long-term toxicity concerns.

One-pot solution synthesis of shape-controlled copper selenide nanostructures and their potential applications in photocatalysis and photothermal therapy.

Developing a facile and reliable method for the fabrication of transition metal chalcogenides is a vital and endless pursuit of scientific and technological disciplines. In this work, we develop a one-pot solution approach to obtain copper selenide nanostructures with different morphologies and crystal structures (Cu2Se nanoparticles, CuSe nanoplates and CuSe2 nanosheets). In comparison to previously reported methods, our method did not use expensive and very toxic raw materials. After detailed studies of reaction conditions, including temperature, reaction time, and feeding amount of surfactants and precursors, we found that the feeding ratio of precursors played a key role in the crystal structures and morphologies of the final products. Moreover, as a proof-of-concept study, the potential applications of the as-prepared copper selenide nanostructures in the photocatalytic discoloration of aqueous methylene blue (MB) under visible light irradiation and near-infrared (NIR) light induced photothermal therapy for cancer treatment were investigated. Encouraged by their strong photocatalytic activities and high photothermal conversion efficiencies (calculated to be 51.0%, 49.5% and 48.9% for Cu2Se nanoparticles, CuSe nanoplates and CuSe2 nanosheets, respectively), we believe that copper selenide nanostructures fabricated from the one-pot solution approach developed in this work would be promising candidates for a wide variety of emerging applications.

Novel doxorubicin loaded PEGylated cuprous telluride nanocrystals for combined photothermal-chemo cancer treatment.

Recently, combined photothermal-chemo therapy has attracted great attention due to its enhanced anti-tumor efficiency via synergistic effects. Herein, PEGylated cuprous telluride nanocrystals (PEGylated Cu2Te NCs) were developed as novel drug nanocarriers for combined photothermal-chemo treatment of cancer cells. PEGylated Cu2Te NCs were fabricated through a simple two-step process, comprised of hot injection and thin-film hydration. The as-prepared PEGylated Cu2Te NCs (average diameter of 5.21±1.05nm) showed a noticeable photothermal conversion efficiency of 33.1% and good capacity to load hydrophobic anti-cancer drug. Due to the protonated amine group at low pH, the doxorubicin (DOX)-loaded PEGylated Cu2Te NCs (PEGylated Cu2Te-DOX NCs) exhibited an acidic pH promoted drug release profile. Moreover, a three-parameter model, which considers the effects of drug-carrier interactions on the initial burst release and the sustained release of drug from micro- and nano-sized carriers, was used to gain insight into how pH and laser irradiation affect drug release from PEGylated Cu2Te-DOX NCs. Based on the results from in vitro cell study, PEGylated Cu2Te-DOX NCs revealed remarkably photothermal-chemo synergistic effect to HeLa cells, attributed to both the PEGylated Cu2Te NCs mediated photothermal ablation and enhanced cellular uptake of the drug. Thus, our results encourage the usage of Cu2Te-DOX drug nanocarriers for enhanced treatment of cancer cells by combined photothermal-chemo therapy.

Encapsulating tantalum oxide into polypyrrole nanoparticles for X-ray CT/photoacoustic bimodal imaging-guided photothermal ablation of cancer.

A nanotheranostic agent has been readily fabricated by encapsulating tantalum oxide (TaOx) nanoparticles (NPs) into polypyrrole (PPy) NPs via a facile one-step chemical oxidation polymerization for bimodal imaging guided photothermal ablation of tumor. It was proved that the obtained composite nanoparticles (TaOx@PPy NPs) with an average diameter around 45 nm could operate as an efficient bimodal contrast agent to simultaneously enhance X-ray CT and photoacoustic (PA) imaging greatly in vivo. Systemically administered TaOx@PPy NPs could passively accumulate at the tumor site during the blood circulation, which was proved by both CT and PA imaging. In addition, the in vivo therapeutic examinations showed that TaOx@PPy NPs exhibited significant photothermal cytotoxicity under near infrared laser irradiation. The tumor growth inhibition was evaluated to be 66.5% for intravenously injection and 100% for intratumoral injection, respectively. This versatile agent can be developed as a smart and promising nanoplatform that integrates multiple capabilities for both accurate diagnosing and precise locating of cancerous tissue, as well as effective photoablation of tumor.

Engineering of perfluorooctylbromide polypyrrole nano-/microcapsules for simultaneous contrast enhanced ultrasound imaging and photothermal treatment of cancer.

A versatile oil-in-water emulsion method has been explored for constructing water-dispersible polypyrrole (PPy) nano-/microcapsules with a soluble PPy complex as multifunctional photothermal agents for tumor ablation. In this work, both PPy nanocapsules (280.4 ± 79.0 nm) and microcapsules (1.31 ± 0.45 µm) with liquid perfluorooctylbromide (PFOB) core could be obtained by simply tuning the process energy for emulsion formation from ultrasonication to homogenization. Owing to the encapsulated liquid PFOB and strong near-infrared (NIR) absorption of PPy shell, the resulted PPy capsules showed great promise in ultrasound imaging guided photothermal ablation of tumor cells without inducing any significant side effect. Thus, it is anticipated that fine-tuning of the other encapsulated drugs or functional materials in PPy capsules would foster avenues for the development of multifunctional platforms for cancer treatments.

Polypyrrole hollow microspheres as echogenic photothermal agent for ultrasound imaging guided tumor ablation.

Ultrasound (US) imaging provides a valuable opportunity to administer photothermal therapy (PTT) of cancer with real-time guidance to ensure proper targeting, but only a few theranostic agents were developed by physically grafting near infrared (NIR)-absorbing inorganic nanomaterials to ready-made ultrasound contrast agents (UCAs) for US imaging guided PTT. In this paper, NIR absorbing hollow microspheres were generated from polypyrrole merely using a facile one-step microemulsion method. It was found that the obtained polypyrrole hollow microspheres (PPyHMs) can act as an efficient theranostic agent not only to enhance US imaging greatly, but also exhibit excellent photohyperthermic effects. The contrast consistently sustained the echo signals for no less than 5 min and the NIR laser light ablated the tumor completely within two weeks in the presence of PPyHMs. More importantly, no use of additional NIR absorber substantially minimizes an onetime dose of the theranostic agent.

Gadolinium-chelate functionalized copper sulphide as a nanotheranostic agent for MR imaging and photothermal destruction of cancer cells.

The gadolinium chelate functionalized copper sulphide nanoparticles have been developed for simultaneous magnetic resonance imaging contrast enhancement and effective hyperthermal therapeutics.

Enzyme-responsive copper sulphide nanoparticles for combined photoacoustic imaging, tumor-selective chemotherapy and photothermal therapy.

Gelatin-stabilized copper sulphide nanoparticles with conjugated doxorubicin have been developed for combined photoacoustic imaging, enzyme-responsive drug release and photothermal therapy.

Targeted delivery of CuS nanoparticles through ultrasound image-guided microbubble destruction for efficient photothermal therapy.

Novel "soft" microbubbles have been fabricated to show outstanding ultrasound imaging capability, and triggered CuS nanoparticles delivery through ultrasound-targeted microbubble destruction for efficient photothermal ablation of cancer cells.

Uniform polypyrrole nanoparticles with high photothermal conversion efficiency for photothermal ablation of cancer cells.

Uniform polypyrrole (PPy) nanoparticles are fabricated from a facile one-step aqueous dispersion polymerization. Owing to their high photothermal conversion efficiency and photostability compared with the well-known Au nanorods, as well as their good colloidal stability and biocompatibility, the resulting PPy nanoparticles can used as a novel promising photothermal ablation coupling agent for targeted treatment of cancer.