Minnie Chan

Collective activation of MRI agents via encapsulation and disease-triggered release

An activation mechanism based on encapsulated ultrasmall gadolinium oxide nanoparticles (Gd oxide NPs) in bioresponsive polymer capsules capable of triggered release in response to chemical markers of disease (i.e., acidic pH, H2O2) is presented. Inside the hydrophobic polymeric matrices, the Gd oxide NPs are shielded from the aqueous environment, silencing their ability to enhance water proton relaxation. Upon disassembly of the polymeric particles, activation of multiple contrast agents generates a strong positive contrast enhancement of >1 order of magnitude.

Nanogels from metal-chelating crosslinkers as versatile platforms applied to copper-64 PET imaging of tumors and metastases

Metals are essential in medicine for both therapy and diagnosis. We recently created the first metal-chelating nanogel imaging agent, which employed versatile, reproducible chemistry that maximizes chelation stability. Here we demonstrate that our metal chelating crosslinked nanogel technology is a powerful platform by incorporating 64Cu to obtain PET radiotracers. Polyacrylamide-based nanogels were crosslinked with three different polydentate ligands (DTPA, DOTA, NOTA). NOTA-based nanogels stably retained 64Cu in mouse serum and accumulated in tumors in vivo as detected by PET/CT imaging. Measurement of radioactivity in major organs ex vivo confirmed this pattern, revealing a high accumulation (12.3% ID/g and 16.6% ID/g) in tumors at 24 and 48 h following administration, with lower accumulation in the liver (8.5% ID/g at 24 h) and spleen (5.5% ID/g). Nanogels accumulated even more efficiently in metastases (29.9% and 30.4% ID/g at 24 and 48 h). These metal-chelating nanogels hold great promise for future application as bimodal PET/MRI agents; chelation of β-emitting radionuclides could enable radiation therapy.

Metal Chelating Crosslinkers Form Nanogels with High Chelation Stability.

We present a series of hydrogel nanoparticles (nanogels) incorporating either acyclic or cyclic metal chelates as crosslinkers. These crosslinkers are used to formulate polyacrylamide-based nanogels (diameter 50 to 85 nm) yielding contrast agents with enhanced relaxivities (up to 6-fold greater than Dotarem®), because this nanogel structure slows the chelators tumbling frequency and allows fast water exchange. Importantly, these nanogels also stabilize Gd3+ within the chelator thermodynamically and kinetically against metal displacement through transmetallation, which should reduce toxicity associated with release of free Gd3+. This chelation stability suggests that the chelate crosslinker strategy may prove useful for other applications of metal-chelating nanoparticles in medicine, including other imaging modalities and radiotherapy.

Long-Lasting and Efficient Tumor Imaging Using a High Relaxivity Polysaccharide Nanogel Magnetic Resonance Imaging Contrast Agent.

Clinically approved small-molecule magnetic resonance imaging (MRI) contrast agents are all rapidly cleared from the body and offer weak signal enhancement. To avoid repeated administration of contrast agent and improve signal-to-noise ratios, agents with stronger signal enhancement and better retention in tumors are needed. Therefore, we focused on hydrogels because of their excellent water accessibility and biodegradability. Gadolinium (Gd)-chelating cross-linkers were incorporated into self-assembled pullulan nanogels to both impart magnetic properties and to stabilize this material that has been extensively studied for medical applications. We show that these Gd-chelating pullulan nanogels (Gd-CHPOA) have the highest reported relaxivity for any hydrogel-based particles and accumulate in the 4T1 tumors in mice at high levels 4 h after injection. This combination offers high signal enhancement and lasts up to 7 days to delineate the tumor clearly for longer imaging time scales. Importantly, this long-term accumulation does not cause any damage or toxicity in major organs up to three months after injection. Our work highlights the clinical potential of Gd-CHPOA as a tumor-imaging MRI contrast agent, permitting tumor identification and assessment with a high signal-to-background ratio.

An extracellular MRI polymeric contrast agent that degrades at physiological pH

Macromolecular contrast agents have the potential to assist magnetic resonance imaging (MRI) due to their high relaxivity, but are not clinically useful because of toxicity due to poor clearance. We have prepared a biodegradable ketal-based polymer contrast agent which is designed to degrade rapidly at physiological pH by hydrolysis, facilitating renal clearance. In vitro, the agent degraded more rapidly at lower pH, with complete fragmentation after 24 h at pH 7.4. In vitro relaxivity measurements showed a direct correlation between molecular weight and relaxivity. We compared our polymer contrast agent with commercially available Magnevist in vivo by MRI imaging, as well as measuring the Gd concentration in blood. Our results show that our polymer contrast agent gives a higher contrast and intensity in the same organs and areas as Magnevist and is cleared from the blood at a similar rate. We aim to improve our polymer contrast agent design to develop it for use as a MRI contrast agent, and explore its use as a platform for other imaging modalities.

Short Soluble Coumarin Crosslinkers for Light-Controlled Release of Cells and Proteins from Hydrogels

Materials that degrade or dissociate in response to low power light promise to enable on-demand, precisely localized delivery of drugs or bioactive molecules in living systems. Such applications remain elusive because few materials respond to wavelengths that appreciably penetrate tissues. The photocage bromohydroxycoumarin (Bhc) is efficiently cleaved upon low-power ultraviolet (UV) and near-infrared (NIR) irradiation through one- or two-photon excitation, respectively. We have designed and synthesized a short Bhc-bearing crosslinker to create light-degradable hydrogels and nanogels. Our crosslinker breaks by intramolecular cyclization in a manner inspired by the naturally occurring ornithine lactamization, in response to UV and NIR light, enabling rapid degradation of polyacrylamide gels and release of small hydrophilic payloads such as an ∼10 nm model protein and murine mesenchymal stem cells, with no background leakage.

Nanogels as imaging agents for modalities spanning the electromagnetic spectrum

An updated and detailed overview of nanogel imaging agents for various modalities spanning the electromagnetic (EM) spectrum.

Iron oxide nanoparticle-based magnetic resonance method to monitor release kinetics from polymeric particles with high resolution.

A new method to precisely monitor rapid release kinetics from polymeric particles using super paramagnetic iron oxide nanoparticles, specifically by measuring spin-spin relaxation time (T(2)), is reported. Previously, we have published the formulation of logic gate particles from an acid-sensitive poly-β-aminoester ketal-2 polymer. Here, a series of poly-β-aminoester ketal-2 polymers with varying hydrophobicities were synthesized and used to formulate particles. We attempted to measure fluorescence of released Nile red to determine whether the structural adjustments could finely tune the release kinetics in the range of minutes to hours; however, this standard technique did not differentiate each release rate of our series. Thus, a new method based on encapsulation of iron oxide nanoparticles was developed, which enabled us to resolve the release kinetics of our particles. Moreover, the kinetics matched the relative hydrophobicity order determined by octanol-water partition coefficients. To the best of our knowledge, this method provides the highest resolution of release kinetics to date.