Stimulus-responsive nanoparticles for intraoperative NIR imaging and treatment of pancreatic cancer

Patients with pancreatic cancer are usually diagnosed at late stage, when the disease has progressed and is difficult to treat. Surgery is the primary treatment after diagnosis of pancreatic cancer. Surgical treatment aims to remove all or as much of the cancerous tissue as possible. However, it is difficult to identify the borders between cancerous and normal tissue and, often, fragments of the disease are left behind without being removed. This residual cancer tissue after surgical procedure will lead to further cancer progression and will reduce survival of the patient.
Current methods used to distinguish different tissue structures, such as lymph nodes, during surgery are based on fluorescence and this procedure is termed fluorescence-guided surgery or intraoperative fluorescence imaging. Indocyanine green (ICG) is an agent that can emit fluorescence when exposed to high-wavelength light, which can transmit efficiently through tissue. This agent is safe to administer through blood circulation and it has already been used in fluorescence-guided surgery. However, ICG is very unstable in the body, it loses its fluorescence within minutes after injection in the blood and most of the agent accumulates in the liver. In this project, ICG, as well as similar cyanine molecule with improved optical properties, will be incorporated inside nanosised particles and this will consequently increase blood circulation time of these agents, it will temporarily quench their fluorescence emission and it will increase their accumulation in pancreatic tumours. In addition, based on preliminary experiments, once the agent is gathered within the cancerous mass, certain molecules present in the area, such as proteolytic enzymes, will break the particles apart releasing the cyanine molecules and the fluorescence emission of the agent will be recovered only inside the tumour. This will enable surgeons to identify the borders of the cancerous tissue and improve surgical removal of the disease.
In recent work, it has been discovered that when the size of these particles is decreased under exposure to conditions similar to those in pancreatic cancer tissue, more cyanine agent can accumulate inside cancerous cells. It is also been shown that when cancer cells contain cyanine dye and are exposed to laser light, these cells are destroyed. On the basis of these findings, the nanosized particles are intended to be used, not only for fluorescence-guided surgery, but also to destroy any residual cancer tissue left behind by irradiating the surgical resection area with laser light. This intraoperative treatment will improve the outcome of surgical procedures and will improve survival of patients.
The research proposed herein includes a series of experiments for characterizing the properties of the nanosized particles that contain ICG and the improved cyanine agent. Early work will establish how these particles respond to conditions similar to those of pancreatic tumours and we will examine the efficiency of the particles in highlighting cancer tissue and in destroying the latter, using cell-based systems. A subsequent series of experiments will be conducted using experimental animals that carry pancreatic tumours. These experiments will establish the safety and the efficiency of the cyanine-containing particles in fluorescence-guided surgical removal of pancreatic tumours and in the destruction of residual cancer at the resection site. Analysis will also be performed to investigate the effect of the treatment in the biology of the cancer.
The proposed approach will improve the prognosis for patients that undergo surgery for pancreatic tumour resection and will also provide new insights for the development of combined fluorescence-guided surgery and intraoperative treatment of cancer.

The aim of the proposed project is to exploit nanotechnology for developing a system that has significant potential to increase the efficacy of surgical treatment in pancreatic cancer, and subsequently improve prognosis. The aspect of intraoperative treatment can also reduce the need for extensive post-operative radiotherapy and exposure to ionizing radiation. The proposed theranostic system has the potential to be adopted for the combined near infra-red guided surgical resection and intraoperative treatment of different cancers overexpressing cathepsin B, such as breast cancer and head and neck cancers. Importantly, the formulation described here is adaptable and different carriers can be exploited in the future for developing systems that are responsive to varying, disease-specific proteolytic enzymes. Such an approach has the potential to stimulate the initiation of research for the exploitation of similar intraoperative theranostic approaches in a broad spectrum of cancers. The system will provide a valuable means of improving the surgical treatment of highly diffuse cancers, extend the limits of resectability and eliminate any residual microscopic disease in the tumour bed after resection.
The simplicity and versatility of this system will maximize the efficacy of surgical treatment at affordable cost. The afore-mentioned will undoubtedly present economic benefit to the National Health Service provider. The simplicity and the cost-effectiveness of this intraoperative theranostic approach will also allow the affordable and feasible adoption of this technology in hospitals. Importantly, the proposed research fits in very well with key research theme strategies of the Research Council, within the spectrum of research from exploration of physical phenomena and molecular mechanisms, through to more translational medical research that can facilitate the development of new health interventions.
The implementation of the proposed study will contribute to the efforts aiming to bring research in the UK at the forefront of therapeutic and technological advances for cancer and trigger innovative projects. The potential clinical translation of the system described in this study will be a pioneering development in pancreatic cancer treatment, with the UK having a leading role in this advancement. We have proposed a theranostic system that will involve the opportunity for new product development, both in terms of formulation and automation equipment. This opportunity will eventually improve innovation performance, which plays a catalytic role in facilitating competitiveness and national progress.