Most cancer patients receive chemotherapy at some stage of their treatment which makes improving the efficacy of cytotoxic drugs an ongoing and important goal. Despite large numbers of potent anti-cancer agents being developed, a major obstacle to clinical translation remains the inability to deliver therapeutic doses to a tumor without causing intolerable side effects. To address this problem, there has been intense interest in nanoformulations and targeted delivery to improve cancer outcomes. The aim of this work was to demonstrate how vascular endothelial growth factor receptor 2 (VEGFR2)-targeted, ultrasound-triggered delivery with therapeutic microbubbles (thMBs) could improve the therapeutic range of cytotoxic drugs.

Mouse models of human diseases are an essential part of the translational pipeline. Orthotopic tumour mouse models are increasingly being used in cancer research due to their increased clinical relevance over subcutaneous xenograft models, particularly in relation to metastatic disease. In this study, we have developed orthotopic colorectal cancer liver metastases (CRCLM) and primary cholangiocarcinoma (CCA) models in BALB/c nude mice using minimally invasive ultrasound-guided intrahepatic injection. Due to its minimally invasive nature, the method reduced risk from surgical complications whilst being fast and easy to perform and resulted in measurable tumour volumes 1 to 3 weeks post-injection. Tumour volumes were monitored in vivo by weekly high-frequency ultrasound (HF-US) and/or twice weekly bioluminescence imaging (BLI) and confirmed with end-point histology. Take rates were high for human CRC cells (>73%) and for CCA cells (90%). We have demonstrated that this method reliably induces CRCLM and CCAs, in which tumour volume can be monitored throughout using HF-US and/or BLI. This provides a promising experimental tool for future testing of cancer therapeutics in an orthotopic model.

Lung cancer is responsible for over one million deaths worldwide each year. Smoking cessation for lung cancer prevention remains key, but it is increasingly acknowledged that prevention strategies also need to focus on high-risk groups, including ex-smokers, and patients who have undergone resection of a primary tumor. Models for chemoprevention of lung cancer often present conflicting results, making rational design of lung cancer chemoprevention trials challenging. There has been much focus on use of dietary bioactive compounds in lung cancer prevention strategies, primarily due to their favorable toxicity profile and long history of use within the human populace. One such compound is curcumin, derived from the spice turmeric. This review summarizes and stratifies preclinical evidence for chemopreventive efficacy of curcumin in models of lung cancer, and adjudges the weight of evidence for use of curcumin in lung cancer chemoprevention strategies.

Cholangiocarcinoma (CCA) is a rare disease with poor outcomes and limited research efforts into novel treatment options. A systematic review of CCA biomarkers was undertaken to identify promising biomarkers that may be used for theranosis (therapy and diagnosis). MEDLINE/EMBASE databases (1996–2019) were systematically searched using two strategies to identify biomarker studies of CCA. The PANTHER Go-Slim classification system and STRING network version 11.0 were used to interrogate the identified biomarkers. The TArget Selection Criteria for Theranosis (TASC-T) score was used to rank identified proteins as potential targetable biomarkers for theranosis. The following proteins scored the highest, CA9, CLDN18, TNC, MMP9, and EGFR, and they were evaluated in detail. None of these biomarkers had high sensitivity or specificity for CCA but have potential for theranosis. This review is unique in that it describes the process of selecting suitable markers for theranosis, which is also applicable to other diseases. This has highlighted existing validated markers of CCA that can be used for active tumor targeting for the future development of targeted theranostic delivery systems. It also emphasizes the relevance of bioinformatics in aiding the search for validated biomarkers that could be repurposed for theranosis.

Advanced drug delivery systems, such as ultrasound-mediated drug delivery, show great promise for increasing the therapeutic index. Improvements in delivery by altering the ultrasound parameters have been studied heavily in vitro but relatively little in vivo. Here, the same therapeutic microbubble and tumour type are used to determine whether altering ultrasound parameters can improve drug delivery. Liposomes were loaded with SN38 and attached via avidin: biotin linkages to microbubbles. The whole structure was targeted to the tumour vasculature by the addition of anti-vascular endothelial growth factor receptor 2 antibodies. Tumour drug delivery and metabolism were quantified in SW480 xenografts after application of an ultrasound trigger to the tumour region. Increasing the trigger duration from 5 s to 2 min or increasing the number of 5 s triggers did not improve drug delivery, nor did changing to a chirp trigger designed to stimulate a greater proportion of the microbubble population, although this did show that the short tone trigger resulted in greater release of free SN38. Examination of ultrasound triggers in vivo to improve drug delivery is justified as there are multiple mechanisms at play that may not allow direct translation from in vitro findings. In this setting, a short tone burst gives the best ultrasound parameters for tumoural drug delivery.