With rapid advances in modern imaging, minimally invasive ablative procedures have emerged as popular alternatives to surgical removal of tumors. Tumor ablation modalities currently offered in clinical practice include microwave ablation, radiofrequency ablation, cryoablation, high-intensity focused ultrasound, and irreversible electroporation. Cryoablation, a non-heat-based method of ablation, is increasingly being used for treating various solid tumors. Accumulated comparative data of cryoablation versus heat-based ablation techniques (e.g., radiofrequency and microwave ablation) shows superior tumor response and quicker recovery time. Evolving research has demonstrated that nanocarriers may serves as excellent catalysts for the cryoablation therapy, imaging guidance, and the co-delivery of therapeutics for minimally invasive, precise, and complete treatment of cancer with immune modulation. This review article focuses on the current status of cryoablation in clinical practice, considers opportunities for enhancing therapeutic outcomes from cryoablation, and discusses new research in the field, including theranostic nanoparticles-mediated cryotherapy and combinational cryo-based immunotherapies.

An overlay of local ablation and immunotherapies could be one of the promising approaches to treat solid tumors, but finding the synergistic combination is still challenging with immune tolerance. Herein, electric pulse responsive iron-oxide-nanocube clusters (IONCs) loaded with indoleamine 2,3-dioxygenase inhibitors (IDOi) are prepared for the enhancement of irreversible electroporation (IRE) cell killing and modulation of the tumor immunosuppressive microenvironment (TIM). IDOi-loaded-IONCs (IDOi-IONCs) show highly responsive movement upon the application of IRE electric pulses inducing local magnetic fields. In vitro and in vivo IRE cell-killing efficiency are significantly enhanced by the IDOi-IONCs. The IRE with IDOi-IONCs also triggers IDOi release from IONCs for TIM modulation. The enhanced cell death and local IDOi release of the IRE with IDOi-IONCs demonstrate a synergistic anticancer effect in vivo with overturning the TIM. The increased infiltration of CD8+ T cells and the elevated ratio of CD8+ T cells to regulatory T cells are confirmed after the IRE with IDOi-IONCs. Further, synergistic interaction between IRE and IDOi-modulated TIM resulted in enhanced elimination of primary and secondary tumors. This proof-of-concept work illustrates a robust modality to guide immune-modulating nanoparticle-mediated immuno-ablation cancer therapies that can be easily tailored to improve its therapeutic outcome.

Purpose: To develop bile acid stabilized multimodal MRI and CT visible doxorubicin eluting Lipiodol emulsion for the transarterial chemoembolization of hepatocellular carcinoma (HCC). Materials and Methods:Ferumoxytol, an FDA approved magnetic resonance imaging (MRI) visible iron oxide nanoparticle, was electrostatically complexed with doxorubicin (DOX). An amphiphilic bile acid, sodium cholate (SC), was used to form a stable dispersion of Ferumoxytol-DOX complex in Lipiodol emulsion. The properties of fabricated emulsion were characterized in various component ratios. DOX release kinetics were evaluated for the chemoembolization applications. Finally, in vivo multimodal MRI/CT imaging properties and potential therapeutic effects upon intra-arterial (IA) infusion bile acid stabilized Ferumoxytol-DOX-Lipiodol emulsion were evaluated in orthotopic McA-Rh7777 HCC rat models.Results: DOX complexed with Ferumoxytol through electrostatic interaction. Amphiphilic sodium cholate bile acid at the interface between the aqueous Ferumoxytol-DOX complexes and Lipiodol enabled a sustained DOX release (17.2 ± 1.6% at 24 hr) at an optimized component ratio. In McA Rh7777 rat HCC model, IA infused emulsion showed a significant contrast around tumor in both T2W MRI and CT images (P = 0.044). H&E and Prussian-blue staining confirmed the local deposition of IA infused SC bile acid stabilized emulsion in the tumor. The deposited emulsion induced significant increases in TUNEL positive cancer cell apoptosis compared to a group treated with the non-stabilized emulsion. Conclusion: SC bile acid stabilized Ferumoxytol-DOX-Lipiodol emulsion demonstrated sustained drug release and multimodal MRI/CT imaging capabilities. The new Lipiodol based formulation may enhance the therapeutic efficacy of chemoembolization in HCC.

Purpose: Immiscible lipiodol and doxorubicin (Dox) emulsion limited their therapeutic efficacy of TACE. Here we developed bile acid-stabilized ferumoxytol-Dox nanocomplexes-lipiodol emulsion. This study aimed to evaluate whether our nanocomplex-lipiodol emulsion can serve as a multimodal TACE agent for the treatment of hepatocellular carcinoma. Materials: Ferumoxytol (feru), approved by the FDA as an iron replacement therapy was used to form nanocomplexes with doxorubicin. Various concentration of sodium cholic acid (primary form of bile acid) was used to form the feru-Dox nanocomplexes-lipiodol emulsion. A time-dependent stability of emulsion was investigated under confocal laser scanning microscope (CLSM). Dox release kinetics from the samples were determined. In vitro T2 MRI and CT contrast effect of the bile acid stabilized feru-Dox nanocomplex lipiodol emulsion were investigated. 6 HCC rats (McA model) were treated with IA infusion of bile acid stabilized feru-Dox nanocomplex lipiodol emulsion (group A, n¼3) and Dox-Lipiodol (group B, n¼3). MRI T2 and CT scans were performed pre-and 7 day-post IA infusion. At 7 day-post, animals were euthanized for the pathological examination. Results: Feru readily complexed with Dox by electrostatic interaction. Facially amphiphilic bile acid allowed stable aqueous feru-Dox nanocomplexes droplets in lipiodol. An optimized emulsion (1:5¼nanocomplexes:lipiodol at bile acid: 0.5 mg/ml) showed no visible separation during 1-month period. The bile acid-stabilized nanocomplex lipiodol emulsion demonstrated a sustained Dox release. Dox release rates were controlled by adjusting the component ratio of sample. In animal study, MRI T2 images and CT revealed an enhanced contrast in the tumor region right after IA infusion and post 7day IA infusion. A group of IA infused bile acid-stabilized feru-Dox nanocomplex lipiodol emulsion resulted in remarkable apoptosis rate increases. Conclusions:Our developed bile acid-stabilized feru-Dox nanocomplexes lipiodol emulsion demonstrated controlled drug release and MRI-CT visibility and resulted better therapeutic efficacy than conventional lipiodol TACE. It is promising for potential clinical translation with further studies.Purpose: The understanding of long-term hepatotoxicity from transarterial chemoembolization (TACE) and transarterial radioembolization (TARE) is currently evolving. We compared the manifestations of liver injury following TACE and TARE in patients with neuroendocrine tumor (NET). Materials: IRB-approved single-institution retrospective analysis of all NET patients receiving TACE from 2006 -2016 and TARE from 2005 -2014 and surviving at least one year from the initial treatment. Patients receiving only TACE (n¼63) or TARE (n¼28) were evaluated for the presence or absence of durable hepatic toxicities occurring at least 6 months after the initial treatment. The definition and grading of liver injury was adapted from the Common Terminology Criteria for Adverse Events Version 4.0 and was characterized by the presence of Grade...