Research Highlights

Magnetic Particle Imaging or MPI is a very new imaging modality that was first introduced by Gleich and Weizenecker and developed in the USA at UC Berkeley by Prof Steven Conolly (co-founder of Magnetic Insights Inc) & Dr. Patrick Goodwill (Founder and Executive Member of Magnetic Insights Inc). I was fortunate to work with prototype scanners at UC Berkeley and developed some of the key biomedical applications using MPI. I conducted a pioneering study using MPI to track inflammatory cells (neutrophils and monocytes) in vivo in collaboration with Dr Lawrence Fong from UCSF. With antibody-based tracers with high specificity towards inflammatory cells, we developed a non-radioactive method for labeling and tracking these cells to infection sites. This approach offers high contrast and minimal cell disruption, making it promising for tracking antibody-based drugs and diagnostics, as well as useful for detecting early-stage inflammatory-related cancer. I'm currently expanding this research to evaluate immunotherapies.

In a collaborative study with Dr. Spencer Behr and Dr. Jonathan Carter at UCSF, I pioneered the use of MPI for non-radioactive diagnosis of bleeding pathology in patients with abdominal trauma. By employing tracer kinetic modeling and digital subtraction algorithms, we successfully detected GI bleeds as small as 1 and 5 μL/min in a genetically predisposed mouse model. This innovative approach enables rapid intervention for hemorrhages in cases of abdominal trauma.

Figure References: (a) Chandrasekharan et al. Nanotheranostics 5(3): 240-255. (b) Chandrasekhara P et al., The British journal of radiology. 91: 20180326.

MRI contrast agent sensitivity is currently limited to millimolar concentrations. A key research focus has been to enhance the r1 relaxivity of Gadolinium (a T1 agent). By increasing r1, we can reduce the required Gadolinium dose, mitigating toxicity. I contributed to the development of both Gd-DOTA constructs and nanoparticle agents that exhibited significantly higher r1 relaxivity (3-fold compared to commercial agents). These agents also demonstrated prolonged circulation times and albumin binding properties, making them promising for glioma imaging. Due to their lower dosage requirements, they are safer for use in patients with chronic kidney disease. These projects were part of a Commercialization of Technology (COT) grant funded by Exploit Technologies Pte Ltd of Singapore and led by Dr. Chang-Tong Yang (a renowned radiochemist and assistant professor at Duke-NUS Medical School) and Associate Professor Kai-Hsiang Chuang (Queensland Brain Institute).

Furthermore, I expanded these tracers for molecular imaging by employing a nanoparticle-based polymer carrier system. This system can prolong the circulation time and enhance the binding efficiency of targeting ligands, such as the somatostatin analog used in this study. Additionally, it can carry a payload of drugs, imaging reporters (Gd-157, Ga-68, Tc-99m, or In-111), or molecular alpha-particle theranostics (Lu-177, Ac-225). The nanoparticle construct indeed improved the interaction with the target ligand.

Many of these projects were carried out in collaboration with A*STAR institutes (IMCB, ICES and IMRE), the National University of Singapore (NUS) and the Nanyang Technological University (NTU) of Singapore.

Figure References: (a) Chandrasekharan et al. Contrast Med & Mol Img 10(3): 237-244. (b) Chandrasekharan P et al., Biomacromolecules 17(12): 3902-3910.

For my Ph.D. thesis under the supervision of nanomedicine leader Prof Feng Si Shen at the department of chemical and biomolecular engineering (ChBE), National University of Singapore, I worked on developing biocompatible iron oxide nanoparticle tracers. Carboxydextran-coated iron oxide nanoparticles have been linked to anaphylactic reactions. I developed iron oxide nanoparticles encapsulated in biodegradable Vitamin E and Polyethylene glycol polymers. The tracer development involved careful manipulation of the organic/inorganic phase (based on the Hildebrand solubility parameter) to achieve isotropic distribution of the iron oxide in the polymer core. I used the tracers to evaluate enhanced-permeation and retention (EPR) in breast cancer xenograft preclinical models. Furthermore, I surface-functionalized them with folic acid for targeted delivery to Fr-alpha positive tumors and for therapeutic cell tracking. The particles allowed for enhanced delivery of therapeutics and payload and can double as a gene/macromolecular delivery system.

Figure References: (a) Chandrasekharan et al. Biomaterials 31 (21), 5588-5597. (b) Chandrasekhara P et al., Biomaterials 32 (24), 5663-5672. (c) Maity D & Chandrasekharan P, Nanomedicine (UK), 1571-1584.

Multimodal imaging employs multiple imaging modalities for both imaging and diagnosis. In a classic example, Prof. David Townsend and his colleagues pioneered the development of the combined PET/CT scanner. This scanner revolutionized cancer care by providing complementary anatomical (CT) and functional (PET) imaging. In one such multimodal imaging project, I had the privilege of working with Prof. Townsend and Dr. Jeffrey Steinberg as a co-investigator, developing a new imaging approach called Cerenkov Luminescence Imaging (CLI) using 68Ga PET tracers. CLI simplifies radioisotope imaging by using modern, highly sensitive CCD cameras. CLI does have limitations, especially the depth to which it can be imaged.

In another approach, under the  guidance of Prof. Kai-Hsiang Chuang (MRI) and Prof. Malini Olivo (Optical Imaging), we developed a combined MRI and photoacoustic imaging tool. Quantifying tumor oxygenation or hypoxia is crucial for assessing treatment response and overall survival in glioma patients. In a work presented at ISMRM 2016, I correlated tumor oxygenation and blood perfusion, and evaluated changes induced by a vascular disruptive agent. Multimodal molecular imaging using MRI and optoacoustic tomography can provide quantitative information on macroscopic changes during treatment response assessment. Vascular parameters like perfusion (Arterial Spin Labeling) and tissue parameters like mean diffusivity were measured using endogenous water without contrast agents, while saturation index was measured using PAT. Correlation enabled us to understand treatment response, treatment-associated angiogenesis, and vessel reactivity.

Figure References: Chandrasekharan P et al. ISMRM 2016;  Jeffrey D Steinberg, Chandrasekharan P, Journal of Nuclear Medicine, 2013.