Layered Double Hydroxide-Based Micro "Chemical Factory" with Arsenic Processing and Screening Functions on Nitinol for Gallbladder Cancer Treatment.

Gallbladder cancer is a common malignant tumor of the biliary system with a high fatality rate. Nitinol (Ni-Ti) stents, a standard treatment for prolonging patients' lives, are susceptible to reocclusion and cannot inhibit tumor recurrence because they lack antitumor and antibacterial activity. Herein, an arsenic-loaded layered double-hydroxide film is constructed on Ni-Ti, forming a micro "chemical factory." The LDH plays the role of a "processer" which absorbs highly toxic trivalent arsenic (As(III)) and processes it into lowly toxic pentavalent arsenic (As(V)). It also acts as a "quality-inspector," confining As(III) in the interlayer and releasing only As(V) (the finished product) to the outside. This control mechanism minimizes the toxicity during contact with normal tissue. The acidic microenvironment and overexpression of glutathione in tumor tissues not only accelerates the release of arsenic from the platform but also triggers the in situ transformation of arsenic from lowly toxic As(V) to highly toxic As(III), exerting a strong arsenic-mediated antineoplastic effect. Such a microenvironment-responsive "chemical factory" with arsenic processing and screening functions is expected to prevent tumor overgrowth, metastasis, and bacterial infection and provide new insights into the design of Ni-Ti drug-eluting stents for gallbladder cancer treatment.

Selective Tumor Inhibition Effect of Drug-Free Layered Double Hydroxide-Based Films via Responding to Acidic Microenvironment.

Nickel-titanium alloy stents are widely used in the interventional treatment of various malignant tumors, and it is important to develop nickel-titanium alloy stents with selective cancer-inhibiting and antibacterial functions to avoid malignant obstruction caused by tumor invasion and bacterial colonization. In this work, an acid-responsive layered double hydroxide (LDH) film was constructed on the surface of a nickel-titanium alloy by hydrothermal treatment. The release of nickel ions from the film in the acidic tumor microenvironment induces an intracellular oxidative stress response that leads to cell death. In addition, the specific surface area of LDH nanosheets could be further regulated by heat treatment to modulate the release of nickel ions in the acidic microenvironment, allowing the antitumor effect to be further enhanced. This acid-responsive LDH film also shows a good antibacterial effect against S. aureus and E. coli. Besides, the LDH film prepared without the introduction of additional elements maintains low toxicity to normal cells in a normal physiological environment. This work offers some guidance for the design of a practical nickel-titanium alloy stent for the interventional treatment of tumors.

NIR-triggered arsenic-loaded layered double hydroxide-based films for localized thermal synergistic chemotherapy.

Portal vein tumor thrombus (PVTT) formed by cancer cell invasion is a major cause of high mortality in hepatocellular carcinoma (HCC), and the formation of thrombus will be accelerated by bacterial colonization on the surface of the implant after surgery. In this work, Polypyrrole-coated arsenic-loaded layered double hydroxide films were in situ constructed on the nickel-titanium alloy for the efficient killing of tumour cells by thermo-therapeutic synergistic chemotherapy. The good near-infrared photothermal conversion ability of polypyrrole enables the sample surface temperature to be raised to about 51 °C at a low photothermal power (0.5 w/cm2), while the elevated temperature could further accelerate the release of drug arsenic. In addition, when NIR light is not applied, the polypyrrole coating also cleverly acts as a "barrier layer" to reduce the natural release of arsenic in normal tissues to avoid toxicity issues. In vivo and in vitro experiments have demonstrated that the platform exhibits excellent antitumor and antibacterial abilities. In contrast to the systemic toxicity issues associated with systemic circulation of nanotherapeutic drugs, this in situ functional film is expected to be used in localised interventions for precise drug delivery, and is also more suitable for surgical treatment scenarios in PVTT surgeries.

Fusible and Radiopaque Microspheres for Embolization.

In this work, fusible microspheres loaded with radiopaque agents as an embolic agent for transcatheter arterial embolization (TAE) are developed. A poly(ethylene glycol) (PEG) and poly(ε-caprolactone) (PCL) multi-block copolymer basing polyurethane (PCEU) is synthesized and fabricated into blank microspheres (BMs). The microspheres are elastic in compression test. A clinical contrast agent lipiodol is encapsulated in the microspheres to receive fusible radiopaque microspheres (FRMs). The sizes of FRMs are uniform and range from 142.2 to 343.1 µm. The encapsulated lipiodol acts as the plasticizer to reduce the melting temperature point (Tm) of PECU microspheres, thus, leading to the fusion of microspheres to exhibit efficient embolization in vivo. The performance of FRMs is carried out on a rabbit ear embolization model. Serious ischemic necrosis is observed and the radiopacity of FRMs sustains much longer time than that of commercial contrast agent Loversol in vivo. The fusible and radiopaque microsphere is promising to be developed as an exciting embolic agent.

A multifunctional cascade bioreactor based on a layered double oxides composite hydrogel for synergetic tumor chemodynamic/starvation/photothermal therapy.

The field of nanomedicine-catalyzed tumor therapy has achieved a lot of progress; however, overcoming the limitations of the tumor microenvironment (TME) to achieve the desired therapeutic effect remains a major challenge. In this study, a nanocomposite hydrogel (GH@LDO) platform combining the nanozyme CoMnFe-layered double oxides (CoMnFe-LDO) and natural enzyme glucose oxidase (GOX) was engineered to remodel the TME to enhance tumor catalytic therapy. The CoMnFe-LDO is a nanozyme that can convert endogenous H2O2 into reactive oxygen species (ROS) and O2 to achieve chemodynamic therapy (CDT) and alleviate the hypoxic microenvironment. Meanwhile, GOX can catalyze the conversion of glucose and O2 to gluconic acid and H2O2, which not only represses the ATP production of tumor cells to achieve starvation therapy (ST), but also decreases the pH value of TME and supplies extra H2O2 to enhance the CDT effect. Furthermore, this well-designed CoMnFe-LDO possessed a high photothermal conversion efficiency of GH@LDO (66.63%), which could promote the generation of ROS to enhance the CDT effect and achieve photothermal therapy (PTT) under near-infrared light irradiation. The GH@LDO hydrogel performes cascade reaction which overcomes the limitation of the TME and achieves satisfactory CDT/ST/PTT synergetic effects in vitro and in vivo. This work provides a new strategy for remodeling the TME using nanomedicine to achieve precise tumor cascaded catalytic therapy. STATEMENT OF SIGNIFICANCE: At present, the focus of tumor therapy has begun to shift from monotherapy to combination therapy for improving the overall therapeutic effect. In this study, we synthesized a CoMnFe-LDO nanozyme composed of multiple transition metal oxides, which demonstrated improved peroxidase and oxidase activities as well as favorable photothermal conversion capability. The CoMnFe-LDO nanozyme was compounded with an injectable GH hydrogel crosslinked by GOX and horseradish peroxidase (HRP). This nanocomposite hydrogel overcame the limitations of weak acidity, H2O2, and O2 levels in the TME and achieved synergetic CDT, ST, and PTT effects based on the cascaded catalytic actions of CoMnFe-LDO and GOX to H2O2 and glucose.

Poly(styrenesulfonate)-Modified Ni-Ti Layered Double Hydroxide Film: A Smart Drug-Eluting Platform.

Drug-eluting stents (DESs) are widely used in the palliative treatment of many kinds of cancers. However, the covered polymers used in DESs are usually associated with stent migration and acute cholecystitis. Therefore, developing noncovered drug-loading layers on metal stents is of great importance. In this work, Ni-Ti layered double hydroxide (Ni-Ti LDH) films were prepared on the surface of nitinol via hydrothermal treatment, and the LDH films were further modified by poly(styrenesulfonate) (PSS). The anticancer drug doxorubicin could be effectively loaded onto the modified films, and drug release could be smartly controlled by the pH. Besides, the drug absorption amounts of cancer cells cultured on the films could be effectively improved. These results indicate that the PSS-modified LDH film may become a promising drug-loading platform that can be used in the design of DESs.

Selective Tumor Cell Inhibition Effect of Ni-Ti Layered Double Hydroxides Thin Films Driven by the Reversed pH Gradients of Tumor Cells.

Nitinol is widely fabricated as stents for the palliation treatment of many kinds of cancers. It is of great importance to develop nitinol stents with selective tumor cell inhibition effects. In this work, a series of pH sensitive films composed of Ni(OH)2 and Ni-Ti layered double hydroxide (Ni-Ti LDH) with different Ni/Ti ratios were prepared on the surface of nitinol via hydrothermal treatment. The films with specific Ni/Ti ratios would release a large amount of nickel ions under acidic environments but were relatively stable in neutral or weak alkaline medium. Cell viability tests showed that the films can effectively inhibit the growth of cancer cells but have little adverse effects to normal cells. Besides, extraordinarily high intracellular nickel content and reactive oxygen species (ROS) level were found in cancer cells, indicating the death of cancer cells may be induced by the excessive intake of nickel ions. Such selective cancer cell inhibition effect of the films is supposed to relate with the reversed pH gradients of tumor cells.