Agents of change: 'painting' cancer for easy removal

Early diagnosis is crucial for effective cancer management and treatment. While conventional methods have relied on tissue biopsies, new approaches using contrast agents and biofluid samples make screening far less invasive.

While a tissue biopsy only provides a snapshot of cancer heterogeneity – and is often limited by sampling bias – liquid techniques use easily accessible samples, such as blood or urine, and provide deep molecular insights. This approach also has valuable clinical applications such as early cancer screening, treatment monitoring, drug-resistance evaluation and residual disease quantitation.

There are immunotherapies emerging for enhanced cancer management, meaning that liquid biopsy tests will also play a significant role in predicting the efficacy of such targeted therapies in the future. With this in mind, liquid tests look set to have an increasing role in cancer management.

Rapid advances in nanotechnology have fuelled enhanced cancer-imaging applications and are improving early tumour detection. Nanoscale devices are being developed that can be conjugated with functional molecules, such as tumour-specific ligands and antibodies for nanoscale imaging applications across personalised cancer therapy.

As nanoprobes can be up to 1,000 times smaller than cancer cells, they can be easily transported through the blood to interact with antigens on or inside growths. As a result, nanoscale contrast agents are being developed for imaging applications that use PET-CT, MRI and ultrasound.

Dr Cristina Zaveleta, who has almost 20 years’ experience in medical imaging at some of the most advanced university research centres in the US, discusses the most exciting emerging trendsin her field.

Can you explain the field of nano and your role in the current research?

Dr Cristina Zavaleta: I majored in the nuclear medicine programme at the University of Incarnate Word. My interest in nano came when I joined the University of Texas Health Science Center in San Antonio, where my coordinator – who was an expert in liposomal fabrication – introduced me to the advantages that nanoparticles had over smallmolecule- based contrast agents.

The imaging contrast agents used in the clinic today are mostly small molecules ranging 1–2nm. Our lab was developing liposomal nanoparticles on the order of 100nm that could act as therapeutic and imaging agents. Nanoparticles of this size range have very different properties and biodistribution characteristics to typical clinical small-molecule imaging agents.

In fact, there are several advantages of using nanoparticles as opposed to small molecules for imaging contrast agents. Their size is ideal for interacting with cellular/ molecular targets, and enables them to passively accumulate in tumours and be retained. They are also great carriers of either diagnostic or therapeutic agents; thousands of drug or imaging molecules can be encapsulated in a single nanoparticle; and they are easily directed to specific target cells by conjugating their surface with specific targeting ligands.

Also, hundreds of targeting peptides or antibodies can be conjugated to the surface, thereby increasing binding affinity/avidity; specific targeting can reduce toxic effects and improve therapeutic efficacy; and various routes of administration are possible, including IV, oral, nasal, intraperitoneal and topical.

Can you explain the basics around contrast agents and what their uses are, especially around nanoscale?

These factors are important because the main purpose of imaging contrast agents is to alert the doctor to a particular area of interest in the body, whether that is a disease process, such as cancer, or a compromised blood brain barrier, or even a stress fracture.

The imaging agent needs to get to the area of interest and provide the image with enough signal to distinguish it from normal healthy tissue. They act as little homing beacons, telling us where they are and what they have found.

Your work “focuses on developing novel diagnostic molecular imaging strategies that have potential for clinical translation”. Can you tell us more about this?

I trained as a postdoctoral fellow on the molecular imaging programme at Stanford. This field focuses on using and developing new techniques to image what is going on at the cellular/ molecular level, providing important physiological information.

This type of work played an integral role in developing an entirely new molecular imaging strategy that uses a different kind of nanoparticle and different imaging platform. We were the first to produce a Raman image using surface enhanced Raman scattering (SERS) nanoparticles as contrast agents. Our Raman imaging strategy is an optical imaging technique that uses SERS nanoparticles to look at the inelastic scattering properties of light.

Your work also talks about the fabrication of new nano-based contrast agents. What does this mean and how can it be used?

Nanoparticles have several advantages over small molecules and we are trying to develop new nano-based contrast agents to exploit these to give us better images. Using nanoparticles could potentially offer physicians images with better sensitivity and disease specificity. The lab is especially interested in developing biodegradable nanoparticles so that their clinical translation is easier when approaching regulatory agencies.

Nanoscale agents are being developed for imaging applications that use several different types of technology to help find disease. What does this entail?

Another great advantage of nanoparticles over small-molecule imaging agents is that you can use a multimodal approach, which means that you can use several different types of imaging techniques to image (localise) the nanoparticle’s accumulation within the body. There are multitudes of imaging tools available and each imaging modality has its own advantages and disadvantages.

Using multiple imaging techniques together allows one to overcome the limitations that some of these techniques face. For instance, some of the imaging tools are more depthlimited, whereas others are more sensitive, and some may have other unique properties like multiplexing capabilities. Bringing the imaging techniques together can provide the physician with the best possible functional and structural information.

Time is a critical factor in cancer diagnosis and early detection has been shown to radically reduce mortality. We can easily modify the surface of our nanoparticles to express tumour targeting ligands specific for dysplastic (precancerous) lesions to improve early cancer detection.

The imaging technique also enables scientists to ‘paint’ cancers so that they can be removed more easily. How does this work, and what sort of technology does it involve?

We can direct our nanoparticles to various disease processes by modifying the surface of the nanoparticles with targeting ligands that specifically bind to biomarkers that are overexpressed on various diseases. We are particularly active in researching cancer in the lab. Identifying tumour margins during therapeutic surgical resection is a critical determinant of patient outcome.

The first line of treatment for several cancer patients is surgery, which suffers from poor tumour margin delineation that often results in lengthy surgeries and repeat visits. One of the biggest challenges faced by oncologic surgeons in the operating rooms is determining where the tumour they are resecting begins and ends. Obtaining negative tumour margins can be essential to a patient’s survival.

Current intraoperative surgical guidance depends largely on visual cues and tactile feedback, which may be highly subjective and distorted in diseased tissues. Failure to fully remove cancerous cells leads to rapid tumour regrowth and may necessitate reoperation, which increases patient morbidity and healthcare costs, such as imaging, anaesthesia and pathology.

Our goal is to provide surgeons with a new molecular imaging tool that offers objective, actionable information in real time to guide tumour resection, thereby improving patient outcomes. The imaging strategy we are further developing in the lab involves delivering a nanoparticle imaging agent that would essentially ‘paint’ the tumour and can be sensitively detected using real time optical imaging technologies like fluorescence and Raman imaging.

What developments are you excited about within your field?

The important functional information that various molecular imaging techniques offer can greatly improve personalised cancer therapy. Nanoparticle-based imaging techniques have great potential to help determine which therapies are best suited to patients, as well as determining their therapeutic response over time. With recent advances in personalised cancer therapy, having effective molecular imaging tools to help determine and assess the most effective treatments will be essential.