Thermal ablation of ultrasound and non-contrast computed tomography invisible primary and secondary liver tumors: targeting by selective intra-arterial lipiodol injection.

PURPOSE: To evaluate the technical feasibility and outcomes of thermal ablation following selective intra-arterial lipiodol injection (SIALI) for targeting primary and secondary liver tumors invisible on ultrasound (US) and non-contrast computed tomography (CT). METHODS: This retrospective study included 18 patients with 20 tumors (67% male, mean age 60.8 ± 12.1 years). The 20 tumors included 15 liver metastases and 5 hepatocellular carcinomas. All patients underwent single-session SIALI and subsequent CT-guided thermal ablation. The primary outcome was a technical success, defined as visualization of the tumor after SIALI and successful thermal ablation. Secondary outcomes were local recurrence rate and procedure-related complications. RESULTS: The median tumor size was 1.5 (1-2.5) cm. In addition, SIALI was performed with a median volume of 3 (1-10) mL of lipiodol resulting in intra-tumoral iodized oil accumulation in 19 tumors and negative imprint with iodized oil accumulation of the surrounding liver parenchyma in 1 tumor. The technical success rate was 100%. No local occurrence was observed at a mean follow-up time of 3 ± 2.5 years. CONCLUSION: SIALI to tag liver tumors not visible with US and non-contrast CT before percutaneous ablation is highly feasible and has a high success rate for the treatment of both primary and secondary liver tumors.

Thermal ablation in the management of oligometastatic colorectal cancer.

PURPOSE: To review available evidence on thermal ablation of oligometastatic colorectal cancer. METHODS: Technical and cancer specific considerations for percutaneous image-guided thermal ablation of oligometastatic colorectal metastases in the liver and lung were reviewed. Ablation outcomes are compared to surgical and radiation therapy literature. RESULTS: The application of thermal ablation varies widely based on tumor burden, technical expertise, and local cancer triage algorithms. Ablation can be performed in combination or in lieu of other cancer treatments. For surgically non-resectable liver metastases, a randomized trial has demonstrated the superiority of thermal ablation combined with chemotherapy compared to systemic chemotherapy alone in term of progression-free survival and overall survival (OS), with 5-, and 8-year OS of 43.1% and 35.9% in the combined arm vs. 30.3% and 8.9% in the chemotherapy alone arm. As ablation techniques and technology improve, the role of percutaneous thermal ablation may expand even into surgically resectable disease. Many of the prognostic factors for better OS after local treatment of lung metastases are the same for surgery and thermal ablation, including size and number of metastases, disease-free interval, complete resection/ablation, negative carcinoembryonic antigen, neoadjuvant chemotherapy, and controlled extra-pulmonary metastases. When matched for these factors, thermal ablation for lung and liver metastases appears to provide equivalent overall survival as surgery, in the range of 50% at 5 years. Thermal ablation has limitations that should be respected to optimize patient outcomes and minimize complications including targets that are well-visualized by image guidance, measure <3cm in diameter, and be located at least 3mm distance from prominent vasculature or major bronchi. CONCLUSIONS: The routine incorporation of image-guided thermal ablation into the therapeutic armamentarium for the treatment of oligometastatic colorectal cancer can provide long survival and even cure.

Pickering emulsions with ethiodized oil and nanoparticles for slow release of intratumoral anti-CTLA4 immune checkpoint antibodies.

BACKGROUND: Intratumorous immunotherapy for cancer is currently thriving. The aim of such local strategy is to improve the therapeutic index of these treatments, for higher on-target/on-tumor activity and less on-target/off-tumor adverse events. Strategies allowing for slow release of anti-CTLA4 in the tumor microenvironment could improve their clinical efficacy.The purpose of the study was to develop a radiopaque delivery platform to improve the targeting and exposure of intratumorous anti-CTLA4 antibodies for cancer immunotherapy. METHODS: Pickering emulsions of anti-CTLA4 antibodies were formulated with radiopaque ethiodized oil and poly-lactic-co-glycolic acid (PLGA) nanoparticles. We characterized the microscopic aspect and stability of such emulsions using Turbiscan. We monitored the release of anti-CTLA4 over time from these emulsions and evaluated their structure using mass spectrometry. We then tested the functionality of the released antibodies by preforming ex vivo competitive binding assays. Finally, we assessed the in vivo efficacy of intratumorous anti-CTLA4 Pickering emulsions. RESULTS: Pickering emulsions of ethiodized oil and PLGA nanoparticles (PEEPs) resulted in a radiopaque water-in-oil emulsion with average internal phase droplet size of 42±5 µm at day 7. Confocal microscopy showed that anti-CTLA4 antibodies were effectively encapsulated by ethiodized oil with PLGA nanoparticles located at the interface between the aqueous and the oily phase. Turbiscan analysis showed that emulsions were stable with continuous and progressive release of anti-CTLA4 antibodies reaching 70% at 3 weeks. Structural and functional analysis of the released antibodies did not show significant differences with native anti-CTLA4 antibodies. Finally, intratumorous anti-CTLA4 PEEPs were able to eradicate tumors and cure mice in a syngeneic immunocompetent preclinical tumor model. CONCLUSION: Pickering emulsions of ethiodized oil and PLGA is an innovative radiopaque delivery platform that does not alter the functionality of anti-CTLA4 immune checkpoint antibodies. Beyond local anti-CTLA4 applications, these emulsions might be used with other therapeutic molecules for optimal intratumorous or intra-arterial delivery of novel cancer immunotherapies.

Biodegradable Pickering emulsions of Lipiodol for liver trans-arterial chemo-embolization.

Water-in-oil (W/O) Lipiodol emulsions remain the preferable choice for local delivery of chemotherapy in the treatment of hepatocellular carcinoma. However, their low stability severely hampers their efficiency. Here, remarkably stable W/O Lipiodol emulsion stabilized by biodegradable particles was developed thanks to Pickering technology. The addition of poly(lactide-co-glycolide) nanoparticles (NPs) into the aqueous-phase of the formulation led to W/O Pickering emulsion by a simple emulsification process through two connected syringes. Influence of nanoparticles concentration and water/oil ratio on emulsion stability and droplet size were studied. All formulated Pickering emulsions were W/O type, stable for at least one month and water droplets size could be tuned by controlling nanoparticle concentration from 24 µm at 25 mg/mL to 69 µm at 5 mg/mL. The potential of these emulsions to efficiently encapsulate chemotherapy was studied through the internalization of doxorubicin (DOX) into the aqueous phase with a water/oil ratio of 1/3 as recommended by the medical community. Loaded-doxorubicin was released from conventional emulsion within a few hours whereas doxorubicin from stable Pickering emulsion took up to 10 days to be completely released. In addition, in vitro cell viability evaluations performed on the components of the emulsion and the Pickering emulsion have shown no significant toxicity up to relatively high concentrations of NPs (3 mg/mL) on two different cell lines: HUVEC and HepG2. STATEMENT OF SIGNIFICANCE: We present an original experimental research in the field of nanotechnology for biomedical applications. In particular, we have formulated, thanks to Pickering technology, a new therapeutic emulsion stabilized with biodegradable PLGA nanoparticles. As far as we know, this is the first therapeutic Pickering emulsion reported in the literature for hepatocellular carcinoma. Such a new emulsion allows to easily prepare a predictable and stable lipiodolized emulsion having all the required characteristics for optimum tumor uptake. As demonstrated throughout our manuscript, emulsions stabilized with these nanoparticles have the advantage of being biodegradable, biocompatible and less toxic compared to usual emulsions stabilized with synthetic surfactants. These findings demonstrate the plausibility of the use of Pickering emulsions for chemoembolization as a therapeutic agent in extended release formulations.

Pickering-Emulsion for Liver Trans-Arterial Chemo-Embolization with Oxaliplatin.

PURPOSE: Biodegradable polylactic-co-glycolic acid (PLGA) nanoparticles can adsorb at the water/oil interface to stabilize the emulsion (forming Pickering-emulsion). The purpose of this study was to compare the release profiles of oxaliplatin from Pickering-emulsion and Lipiodol-emulsion. MATERIALS/METHODS: Pickering-emulsions and Lipiodol-emulsions were both formulated with oxaliplatin (5 mg/mL) and Lipiodol (water/oil ratio: 1/3). For Pickering-emulsion only, PLGA nanoparticles (15 mg/mL) were dissolved into oxaliplatin before formulation. In vitro release of oxaliplatin from both emulsions was evaluated. Then, oxaliplatin was selectively injected into left hepatic arteries of 18 rabbits bearing VX2 liver tumors using either 0.5 mL Pickering-emulsion (n = 10) or 0.5 mL Lipiodol-emulsion (n = 8). In each group, half of the rabbits were killed at 1 h and half at 24 h. Mass spectrometry was used to quantify drug pharmacokinetics in blood and resulting tissue (tumors, right, and left livers) oxaliplatin concentrations. RESULTS: Pickering-emulsion demonstrated a slow oxaliplatin release compared to Lipiodol-emulsion (1.5 ± 0.2 vs. 12.0 ± 6% at 1 h and 15.8 ± 3.0 vs. 85.3 ± 3.3% at 24 h) during in vitro comparison studies. For animal model studies, the plasmatic peak (Cmax) and the area under the curve (AUC) were significantly lower with Pickering-emulsion compared to Lipiodol-emulsion (Cmax = 0.49 ± 0.14 vs. 1.08 ± 0.41 ng/mL, p = 0.01 and AUC = 19.8 ± 5.9 vs. 31.8 ± 14.9, p = 0.03). This resulted in significantly lower oxaliplatin concentrations in tissues at 1 h with Pickering-emulsion but higher ratio between tumor and left liver at 24 h (43.4 vs. 14.5, p = 0.04). CONCLUSION: Slow release of oxaliplatin from Pickering-emulsion results in a significant decrease in systemic drug exposure and higher ratio between tumor and left liver oxaliplatin concentration at 24 h.

Intra-arterial therapies for colorectal cancer liver metastases (radioembolization excluded).

During the past 20 years, advances in systemic therapies have improved overall survival of patients with Colorectal cancer Liver metastases (CRLM) from 6 to 24 months. By reaching CRLM via their preferential arterial vascularization, hepatic arterial infusion of chemotherapy (HAIC) has demonstrated improvement in response rate and deepness of response. Improvement in deepness of response is potentially helpful to convert no surgical patient to surgery. Recent HAIC regimens, including HAIC-FUDR plus systemic oxaliplatin/irinotecan, or HAIC-oxaliplatin plus systemic 5FU and cetuximab yielded a 92% and 90% response rate respectively, and conversion to R0 surgery in 47% and 42% of patients, respectively. When HAIC delivered a drug ineffective through intravenous delivery, this rechallenge provided 62% response rate for HAIC. Nowadays, port-catheter implanted percutaneously by radiologists has 95% feasibility with primary patency equivalent to that of surgically implanted catheters, and secondary patency superior after radiologic revision. Retrospective studies demonstrated prolonged DFS of HAIC over IV chemotherapy in the adjuvant setting after surgery of CRLM. Drug eluting beads loaded with irinotecan (DEBIRI) were developed as drug carrier and embolization platform for treatment of CRLM by chemoembolization. DEBIRI allows for a very high level of SN-38 (SN-38 is the active compound of irinotecan) and a very high rate of complete l response at pathologic studies of treated metastases. DEBIRI was compared to systemic FOLFIRI in a phase III randomized trial including 74 patients with benefit in overall survival and disease-free survival.