A clinical trial of super-stable homogeneous lipiodol-nanoICG formulation-guided precise fluorescent laparoscopic hepatocellular carcinoma resection.

BACKGROUND: Applying traditional fluorescence navigation technologies in hepatocellular carcinoma is severely restricted by high false-positive rates, variable tumor differentiation, and unstable fluorescence performance. RESULTS: In this study, a green, economical and safe nanomedicine formulation technology was developed to construct carrier-free indocyanine green nanoparticles (nanoICG) with a small uniform size and better fluorescent properties without any molecular structure changes compared to the ICG molecule. Subsequently, nanoICG dispersed into lipiodol via a super-stable homogeneous intermixed formulation technology (SHIFT&nanoICG) for transhepatic arterial embolization combined with fluorescent laparoscopic hepatectomy to eliminate the existing shortcomings. A 52-year-old liver cancer patient was recruited for the clinical trial of SHIFT&nanoICG. We demonstrate that SHIFT&nanoICG could accurately identify and mark the lesion with excellent stability, embolism, optical imaging performance, and higher tumor-to-normal tissue ratio, especially in the detection of the microsatellite lesions (0.4 × 0.3 cm), which could not be detected by preoperative imaging, to realize a complete resection of hepatocellular carcinoma under fluorescence laparoscopy in a shorter period (within 2 h) and with less intraoperative blood loss (50 mL). CONCLUSIONS: This simple and effective strategy integrates the diagnosis and treatment of hepatocellular carcinoma, and thus, it has great potential in various clinical applications.

A super-stable homogeneous Lipiodol-hydrophilic chemodrug formulation for treatment of hepatocellular carcinoma.

Background: Though lipiodol formulations are major options in transcatheter arterial chemoembolization (TACE) of advanced unresectable hepatocellular carcinoma (HCC) in the clinic, their application is severely limited by insufficient physical stability between the hydrophobic lipiodol and hydrophilic drugs; thus, most chemotherapeutic drugs are quickly released into systemic circulation resulting in poor therapeutic outcomes and serious side effects. Methods: The typical hydrophilic drug doxorubicin hydrochloride (DOX) was prepared as a pure nanomedicine and then stably and homogeneously dispersed in lipiodol (SHIFT&DOX) via slightly ultrasonic dispersion. The drug release profiles of SHIFT&DOX were defined in a decellularized liver model. In vivo therapeutic studies were performed in rat-bearing N1S1 orthotopic HCC models and rabbit-bearing VX2 orthotopic HCC models. Results: SHIFT&DOX features an ultrahigh homogeneous dispersibility over 21 days, which far surpassed typical Lipiodol-DOX formulations in clinical practice (less than 0.5 h). SHIFT&DOX also has excellent sustained drug release behavior to improve the local drug concentration dependence and increase the time dependence, leading to remarkable embolic and chemotherapeutic efficacy, and eminent safety in all of the orthotopic HCC models. Conclusions: The carrier-free hydrophilic drug nanoparticle technology-based lipiodol formulation provides a promising approach to solve the problem of drug dispersion in TACE with the potential for a translational pipeline.

A pure nanoICG-based homogeneous lipiodol formulation: toward precise surgical navigation of primary liver cancer after long-term transcatheter arterial embolization.

PURPOSE: To surmount the critical issues of indocyanine green (ICG), and thus achieving a precise surgical navigation of primary liver cancer after long-term transcatheter arterial embolization. METHODS: In this study, a facile and green pure-nanomedicine formulation technology is developed to construct carrier-free indocyanine green nanoparticles (nanoICG), and which subsequently dispersed into lipiodol via a super-stable homogeneous lipiodol formulation technology (SHIFT nanoICG) for transcatheter arterial embolization combined near-infrared fluorescence-guided precise hepatectomy. RESULTS: SHIFT nanoICG integrates excellent anti-photobleaching capacity, great optical imaging property, and specific tumoral deposition to recognize tumor regions, featuring entire-process enduring fluorescent-guided precise hepatectomy, especially in resection of the indiscoverable satellite lesions (0.6 mm × 0.4 mm) in rabbit bearing VX2 orthotopic hepatocellular carcinoma models. CONCLUSION: Such a simple and effective strategy provides a promising avenue to address the clinical issue of clinical hepatectomy and has excellent potential for a translational pipeline.

A superstable homogeneous lipiodol-ICG formulation for locoregional hepatocellular carcinoma treatment.

Accurate identification of surgical margins for malignancy remains a challenge in the surgical therapy of cancer, and this encountered interoperative difficulties which directly contribute to the prognosis of patients. In recent years, indocyanine green (ICG) has been approved and applied in clinical settings for lesions detection, especially for the precise surgical resection. However, rapid clearance and poor stability greatly limit its clinical practicality. Herein, a super-stable homogeneous iodinated formulation technology (SHIFT) is designed to realize sufficient dispersion of ICG into lipiodol (SHIFTs) for transcatheter embolization (TAE) synergistic fluorescence-guided resection. Particularly, SHIFTs is prepared in a green physical mixture via a carrier-free manner, which possesses controlled morphology, long-term stability, and improved optical characteristics of ICG (fluorescence/photoacoustic/photothermal activities). Furthermore, the viscosity of the synthetic solvent is comparable to lipiodol, and further assessment demonstrated the same efficacy in computed tomography. The performance of SHIFTs in the fluorescence navigation was further evaluated in vivo by TAE therapy to the rabbit VX2 tumor model for a two-week monitor. The integration of near-infrared fluorescence surgery navigation and TAE could effectively guarantee the precise resection for hepatocellular carcinoma. This SHIFT system provides good potentials for ameliorating the dilemma of precise fluorescent navigation for surgical resection after arterial embolization in clinical practice.

Bio-engineered cell membrane nanovesicles as precision theranostics for perihilar cholangiocarcinoma.

Perihilar cholangiocarcinoma (PHCC) presents a formidable challenge due to its occult anatomic location, aggressive growth, insensitivity to conventional chemotherapy, and poor prognosis. Herein, we engineered a human epidermal growth factor receptor 2 (HER2) affibody to the surface of cell membrane nanovesicles (A-NVs) in a ligand-oriented manner and loaded them with indocyanine green (ICG) as precision theranostics for PHCC treatment. The A-NVs@ICG were prepared and exhibited satisfactory targeting effects in HER2-overexpressing PHCC cells. In vivo fluorescence and photoacoustic imaging demonstrated that A-NVs@ICG promoted the accumulation of ICG in PHCC tissue, leading to enhanced tumor regression and improved anti-cancer effects when combined with photoirradiation. Therefore, bio-engineered A-NVs@ICG represent a promising nanotheranostic agent for PHCC with potential for clinical translation.

Highly stable microwave susceptible agents via encapsulation of Ti-mineral superfine powders in urea-formaldehyde resin microcapsules for tumor hyperthermia therapy.

In this study, Ti-mineral superfine powders (Ti-MSP) encapsulated in urea-formaldehyde resin microcapsules (Ti-MSP@UF-MC) were successfully prepared via a one-step microemulsion method for the first time. Because of the strong confinement effects, the Ti-MSP@UF-MC possessed perfect microwave heating effects. The temperature was 9.3 °C higher than that of the saline solution, superior to UF-MC (no significant microwave heating effect, 0 °C) and Ti-MSP (5.1 °C). The Ti-MSP@UF-MC showed low toxicity and good biocompatibility via a series of studies, including a hemolysis study and the MTT assay in vitro and in vivo. When the concentration was below 1000 µg mL(-1), the hemolysis rate was lower than 5% (hemolysis study). When the concentration was below 400 µg mL(-1), the cell activity was higher than 80% (MTT assay). Moreover, the Ti-MSP@UF-MC exhibited an ideal CT imaging effect in vivo owing to the large molecular weight of Ti-MSP. The Ti-MSP@UF-MC showed a favorable microwave therapy effect in vivo. Using mice bearing H22 tumor cells as an animal model, the tumor suppression rate could reach 100%.