Liposome-Coated Arsenic–Manganese Complex for Magnetic Resonance Imaging-Guided Synergistic Therapy Against Carcinoma

PURPOSE: A liposome-coated arsenic–manganese complex, denoted as LP@MnAs(x) was constructed for the targeted delivery of arsenic trioxide (ATO) against carcinoma. METHODS: Arsenite, the prodrug of ATO, was encapsulated within a liposome via electrostatic interaction with the manganese ions. The as-prepared material was characterized with dynamic light scattering and transmission electron microscopy. The entrapment efficiency and drug loading of arsenic in the carrier were measured using inductively coupled plasma spectrometry. The in vitro release of arsenic was evaluated by using the dialysis bag method. Furthermore, the Fenton-like activity and in vitro cytodynamics research of LP@MnAs(x) were monitored in this work. And the cellular uptake study was used to investigate the in vitro entry mechanism. Furthermore, the cytotoxicity, cell apoptosis and cell cycle study were performed to evaluate the tumor-killing efficiency. Also, the pharmacokinetic and antitumor studies were investigated in HepG2 tumor-bearing nude mice. RESULTS: The as-prepared LP@MnAs(x) possessed a spherical morphology, uniformly distributed hydrodynamic diameter, and excellent drug-loading efficiency. LP@MnAs(x) displayed robust stability and sustained-release profile under physiological environments. LP@MnAs(x) could degrade with high sensitivity to the pH variation in the tumor microenvironment. As such, this could lead to a burst release profile of Mn(2+) and arsenite to achieve a synergistic therapy of chemodynamic therapy and chemotherapy. When compared to the carrier-free arsenate, in vitro experiments revealed that LP@MnAs(x) exhibited enhanced cellular uptake and tumor-killing efficiency. LP@MnAs(x) also demonstrated significantly enhanced tumor-specific in vivo distribution of arsenic, prolonged systemic circulation lifetime, and increased accumulation at the tumor site. CONCLUSION: Based on the experimental results, LP@MnAs(x) is an ideal arsenic-based nanodelivery system, whereby it can improve the non-specific distribution of NaAsO(2) in vivo. Thus, this work can expand the research and application of arsenic trioxide against solid tumors.