Our lab is advancing a new multi-disciplinary field of research investigating the central role of the lymphatic system in disease, and developing novel drug delivery systems to target the lymphatics and treat disease. Specifically, we are:
1. Determining the impact of environment and disease factors on lymphatic function and composition
2. Defining the mechanisms by which the lymphatic system shapes metabolism and immunity to determine health and disease
3. Developing novel treatments that target the lymphatic system to ensure health and mitigate disease
Historically, lymphatic vessels were considered biologically inert and like a pipe that drains fluid, lipids and immune cells from tissues back to blood. In the last 10-15 years our group and others have discovered that the structure and composition of the lymphatics is dynamic and changes in response to the environment to have profound effects on health and disease. For example, lymph from the intestine communicates with the mesentery then bypasses the liver to empty into the blood circulation, directly influencing metabolism, immunity and organ function around the body (see Figure 1). Lymph is thus a new key factor that influences health and disease.
Our major projects include:
.
Developing novel drug delivery systems to target the lymphatics
After oral or parenteral administration, most drugs are absorbed into blood capillaries and transported to the systemic circulation. From here they distribute non-specifically to target tissues. We are interested in how specific uptake into the draining lymphatics can be achieved. This typically involves the administration of macromolecular constructs or in situ association with endogenous macromolecular constructs that are too large to enter the draining blood capillaries and are instead transported via the more permeable lymphatic vessels.
Our group is exploring various strategies to target lymph including administration of i) macromolecular drugs (proteins, antibodies, antigens, peptides etc.), ii) small molecule drugs in association with macromolecular delivery systems such as nanoparticles, polymers, liposomes and lipoprotein-mimetics, iii) lipid conjugated molecules that associate with albumin or lipoproteins to be transported via lymph. For example, we have developed lipid prodrugs that are assembled into lipoproteins and transported via the lymphatics after oral administration. These prodrugs have been patented and licensed to Puretech Health (Figure 2).
Key collaborators and staff: Prof Chris Porter, Dr Sifei Han, Dr Luojuan Hu, Ms Xiaotong Zhou, A/Prof Angus Johnston, Dr Orlagh Feeney, Prof Mike Whittaker, Prof John Quinn, A/Prof Joseph Nicolazzo, Prof Ray Norton, Dr Ian Styles, Mr Mohammad Abdallah, Mr Zijun Lu (all Monash University).
Pharmacokinetic and pharmacodynamic benefits of targeting lymph
Drug absorption and transport via the lymph (rather than the blood) provides benefits in increasing delivery to targets within the lymphatics such as immune cells, and increasing the oral bioavailability of drugs with high first-pass metabolism, since transport from the intestine via the lymph avoids passage through the liver. We are exploring these benefits, including targeting the lymph for vaccination and treatment of autoimmune diseases such as arthritis and multiple sclerosis. We are also profiling in detail the mechanisms that direct therapeutic and delivery system trafficking within lymph nodes and their interactions with local immune cells (Figure 3).
Key collaborators and staff: Prof Chris Porter, Prof Frank Caruso, A/Prof Stephen Kent, A/Prof Angus Johnston, Dr Orlagh Feeney, Ms Alina Lam, Dr Enyuan Cao, A/Prof Joseph Nicolazzo, Prof Ray Norton, Dr Ian Styles, Mr Mohammad Abdallah
Targeting lymph-fat interactions to treat metabolic disease
We have demonstrated that there are substantial changes to the intestinal lymphatics in obesity (Figure 4). We have found that these changes result in intestinal lymph leakage to fat that promotes insulin resistance in obesity, and that targeted treatment of lymphatic dysfunction with a celecoxib lipid prodrug reverses visceral obesity and insulin resistance. This represents a promising approach to treat and prevent type 2 diabetes.
Extending from this project we established a collaboration with Prof Axel Kallies and Dr Ajith Vasanthakumar to investigate sex differences in adipose tissue inflammation and metabolism. Our collaborative studies were published in the journal Nature in 2020.
We are also working with Dr Sarah Turpin-Nolan and Prof Mark Febbraio to determine the impact of ceramides, that traffic through intestinal lymph, in metabolic disease.
Key staff and collaborators: Dr Enyuan Cao, Ms Lena De Malo Ferreira, Prof Chris Porter, A/Prof Darren Creek, Dr Sarah Turpin-Nolan, Prof Mark Febbraio (Monash University), Prof Matthew Watt, Prof Axel Kallies and Dr Ajith Vasanthakumar (University of Melbourne), Prof Natasha Harvey (University of South Australia).
Developing novel treatment strategies for organ failure in acute and critical illnesses (ACI) based on the gut-lymph concept
Over 30% of patients in intensive care due to ACI die from organ dysfunction and failure for which there are currently no specific and effective treatments. According to the gut-lymph concept, toxic factors that enter lymph from the gut promote systemic inflammation, organ dysfunction and failure in ACIs (Figure 5). We are working on two approaches to mitigate the gut lymph toxicity – diversion of lymph out of the body and delivery of drugs into the lymph to inactivate the toxic factors prior to systemic entry. We have filed a provisional patent for our first lymph-targeted treatment for organ failure and are seeking industry partners to progress the technology.
Key collaborators and staff: Prof John Windsor, Prof Anthony Phillips and Dr Jiwon Hong (University of Auckland), Prof Chris Porter, Dr Sifei Han, Dr Given Lee, Dr Ian Styles, Mr Mohammad Abdallah, Mr Zijun Lu (Monash University).