Layered Double Hydroxide‐Based Micro “Chemical Factory” with Arsenic Processing and Screening Functions on Nitinol for Gallbladder Cancer Treatment

Abstract

deaths with 220 000 new cases diagnosed annually. [7,8] Gallbladder cancer is additionally characterized by concealed onset, rapid development, and poor prognosis. [9] Therefore, the majority (90%) of patients are diagnosed at an advanced stage. [3] Most deaths from gallbladder cancer are caused by malignant obstruction. The insertion of Ni-Ti stents to alleviate obstructive jaundice is the gold standard of life prolongation. [10] However, Ni-Ti stents are vulnerable to tumor invasion and bacterial infection, leading to a high reocclusion rate. [11] Drug-eluting stents (DESs) that load antitumor or antibacterial drugs are considered to prevent in-stent restenosis, but their clinical efficacy is low because most of the commercially available DESs are derived from cardiovascular stents. [12][13][14][15] Therefore, the loaded drugs, such as rapamycin, [16] aspirin, [17] and statins, [18] are intended to reduce inflammation and promote endothelialization rather than kill bacteria and gallbladder cancer cells. The design of specialized Ni-Ti DESs is urgently needed for the palliative treatment of gallbladder cancer.Recent studies have shown a good inhibitory effect of As(III) on gallbladder cancer. As(III) can effectively kill gallbladder cancer cells within a certain concentration range. [19,20] However, in clinical applications, the killing effect of highly toxic trivalent arsenic must be limited to the gallbladder cancer cells; reducing the toxic side effects of arsenic on normal tissue is a critical problem. Among 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

“…The LDH spectrum showed diffraction peaks around 11.2° and 22.7° corresponding to its (003) and (006) crystal planes, respectively, and this result indicated the successful construction of the LDHs . After heat treatment, the diffraction peaks at 11.2° and 22.7° disappeared, indicating that the lamellar structure of LDHs was damaged because the heat treatment caused the removal of interlayer anions and water molecules, and the lamellar structure gradually disappeared . The XPS elemental analysis (Figure d) results revealed that the surface elements of the samples were Ni, Ti, and O elements, which corroborated the EDS results.…”

“…Due to good biocompatibility, stable mechanical properties, and unique shape memory effect, nickel–titanium alloys are extensively used in the manufacture of luminal self-expanding stents. − For specific applications such as gallbladder cancer, bile duct cancer, and liver cancer combined with portal vein thrombosis, self-expanding stents need to have excellent mechanical properties to keep the lumen open to ensure blood and digestive fluid flow. − On the other hand, they should also have good antibacterial and antitumor properties to avoid malignant obstruction caused by tumor invasion and bacterial colonization. − At present, the existing bare-metal nickel–titanium alloy stents cannot meet both of these requirements. Therefore, it is scientifically important to develop new nickel–titanium alloy stents with anticancer and antibacterial functions based on bare-metal stents.…”