King C. Li

Numerical investigation of heating of a gold nanoparticle and the surrounding microenvironment by nanosecond laser pulses for nanomedicine applications

We have modeled, by finite element analysis, the process of heating of a spherical gold nanoparticle by nanosecond laser pulses and of heat transfer between the particle and the surrounding medium, with no mass transfer. In our analysis, we have included thermal conductivity changes, vapor formation, and changes of the dielectric properties as a function of temperature. We have shown that such changes significantly affect the temperature reached by the particle and surrounding microenvironment and therefore the thermal and dielectric properties of the medium need to be known for a correct determination of the temperature elevation. We have shown that for sufficiently low intensity and long pulses, it is possible to establish a quasi-steady temperature profile in the medium with no vapor formation. As the intensity is increased, a phase-change with vapor formation takes place around the gold nanoparticle. As phase-transition starts, an additional increase in the intensity does not significantly increase the temperature of the gold nanoparticle and surrounding environment. The temperature starts to rise again above a given intensity threshold which is particle and environment dependent. The aim of this study is to provide useful insights for the development of molecular targeting of gold nanoparticles for applications such as remote drug release of therapeutics and photothermal cancer therapy.

The Knowledge-Integrated Network Biomarkers Discovery for Major Adverse Cardiac Events

The mass spectrometry (MS) technology in clinical proteomics is very promising for discovery of new biomarkers for diseases management. To overcome the obstacles of data noises in MS analysis, we proposed a new approach of knowledge-integrated biomarker discovery using data from Major Adverse Cardiac Events (MACE) patients. We first built up a cardiovascular-related network based on protein information coming from protein annotations in Uniprot, protein-protein interaction (PPI), and signal transduction database. Distinct from the previous machine learning methods in MS data processing, we then used statistical methods to discover biomarkers in cardiovascular-related network. Through the tradeoff between known protein information and data noises in mass spectrometry data, we finally could firmly identify those high-confident biomarkers. Most importantly, aided by protein-protein interaction network, that is, cardiovascular-related network, we proposed a new type of biomarkers, that is, network biomarkers, composed of a set of proteins and the interactions among them. The candidate network biomarkers can classify the two groups of patients more accurately than current single ones without consideration of biological molecular interaction.

Molecular Theranostics: A Primer for the Imaging Professional

OBJECTIVE A theranostic system integrates some form of diagnostic testing to determine the presence of a molecular target for which a specific drug is intended. Molecular imaging serves this diagnostic function and provides powerful means for noninvasively detecting disease. We briefly review the paradigms rooted in nuclear medicine and highlight recent advances in this field. We also explore how nanometer-sized complexes, called nanomedicines, present an excellent theranostic platform applicable to both drug discovery and clinical use. CONCLUSION For imagers, molecular theranostics represents a powerful emerging platform that intimately couples targeted therapeatic entities with noninvasive imaging that yields information on the presence of defined molecular targets before, during, and after cognate therapy.

Partially polymerized liposomes: stable against leakage yet capable of instantaneous release for remote controlled drug delivery

A critical issue for current liposomal carriers in clinical applications is their leakage of the encapsulated drugs that are cytotoxic to non-target tissues. We have developed partially polymerized liposomes composed of polydiacetylene lipids and saturated lipids. Cross-linking of the diacetylene lipids prevents the drug leakage even at 40 °C for days. These inactivated drug carriers are non-cytotoxic. Significantly, more than 70% of the encapsulated drug can be instantaneously released by a laser that matches the plasmon resonance of the tethered gold nanoparticles on the liposomes, and the therapeutic effect was observed in cancer cells. The remote activation feature of this novel drug delivery system allows for precise temporal and spatial control of drug release.

Augmentation of targeted delivery with pulsed high intensity focused ultrasound

This paper reviews the enhanced delivery of genes, drugs and therapeutics using ultrasound. It begins with a general overview of the field and the various techniques associated with it, including sonophoresis, hyperthermia (with ultrasound), sonoporation, and microbubble assisted transvascular and targeted delivery. Particular attention is then paid to pulsed high intensity focused ultrasound drug delivery without the use of ultrasound contrast agents. Feasibility and mechanistic studies of this technique are described in some detail. Conclusions are then drawn regarding possible mechanisms of this treatment, and to contrast with the better known treatments relying on injection of ultrasound contrast agents.

First results from the high-resolution mouseSPECT annular scintillation camera

High-resolution single-photon emission computed tomography (SPECT) imaging in small animals tends to use long imaging times and large injected doses due to the poor sensitivity of single pinhole gamma cameras. To increase sensitivity while maintaining spatial resolution, we designed and constructed a multi-pinhole collimator array to replace the parallel hole collimators of a Ceraspect human SPECT brain scanner. The Ceraspect scanner is composed of an annular NaI(Tl) crystal within which the eight pinhole collimators (1-mm-diameter holes) rotate while projecting nonoverlapping images of the object onto the stationary annular crystal. In this manner, only one-eighth of a collimator rotation is required to acquire a full circle orbit tomographic data set. The imaging field of view (FOV) has a diameter of 25.6 mm in the transverse direction, which is sufficient to encompass a mouse in the transverse direction. The axial FOV is 25.6 mm at the center of the FOV and 13.9 mm at the edge of the transverse FOV. Data are currently acquired in step-and-shoot mode; however, the system is capable of list mode acquisition with the collimator continuously rotating. Images are reconstructed using a cone-beam ordered subsets expectation maximization method. The reconstructed spatial resolution of the system is 1.7 mm and the sensitivity at the center of the FOV is 13.8 cps/microCi. A whole-body bone scan of a mouse injected with [Tc-99 m]MDP clearly revealed skeletal structures such as the ribs and vertebral bodies. These preliminary results suggest that this approach is a good tradeoff between resolution and sensitivity and, with further refinement, may permit dynamic imaging in living animals.

Vascular-targeted molecular imaging using functionalized polymerized vesicles.

In this review we will discuss the use of multivalent polymerized vesicles (PVs) combined with magnetic resonance imaging (MRI) and gamma scintigraphy to image expression of vascular molecular receptors in vivo. Specifically, we will present our data on the use of this technology to design imaging agents toward specific vascular receptors in both a mouse and rabbit tumor model and in the EAE mouse, a model for human multiple sclerosis (MS). Examples will be shown where the in vivo specificity of the targeted molecular imaging agents was validated in the animal models. Since the PVs are designed to carry either contrast or therapeutic agents or both, we can potentially use vascular‐targeted imaging for selecting patients and guiding vascular‐targeted therapies in these patients. Using this combined vascular‐targeted imaging and therapy approach, personalized treatment can potentially be delivered, maximizing efficacy and minimizing side effects. J. Magn. Reson. Imaging 2002;16:388–393. Published 2002 Wiley‐Liss, Inc.

Vascular-Targeted Nanoparticles for Molecular Imaging and Therapy

Publisher Summary This chapter describes the vascular-targeted nanoparticles for molecular imaging and therapy. Molecular imaging involves the noninvasive real-time observation of in vivo biologic events at the molecular level. In nearly all cases, molecular imaging will require the delivery of a probe to the tissue site of interest. The design of probes for molecular imaging target two basic classes of biologic events, including alteration in metabolic processes and changes in receptor expression. In the case of metabolic probes, small molecules are used that can perfuse most tissues and pathologic regions in the body. The integrins are one of the best characterized members of the adhesion molecule family that is upregulated in angiogenic endothelial cells found in tumors and certain inflammatory injuries. The integrins are transmembrane molecules that favor the anchorage of endothelial cells to a wide variety of extracellular matrix proteins with an exposed arginine, glycine, aspartate amino acid sequence. The in vivo imaging of angiogenic tumors using anti-avb3-targeted polymerized vesicles comprised of the murine antibody LM609 attached to PVs labeled with the MR contrast agent gadolinium in the V2 carcinoma model in rabbits is also elaborated.

MR imaging of Pelizaeus-Merzbacher disease.

Pelizaeus–Merzbacher disease (PMD) is a rare, slowly progressive, sex-linked dysmyelinating disorder generally classified with the sudanophilic leukodystrophies. The onset is most often in the pediatric age group and may be diagnosed as cerebral palsy because of the subtle onset. Cranial magnetic resonance (MR) imaging of two patients with PMD showed reversal of the normal gray/white matter signal relationships, consistent with dysmyelination, as well as low intensity lentiform nuclei and thalami possibly suggesting pathologic iron deposition. Magnetic resonance also better demonstrated low volume brain without the beam hardening limitations of X-ray CT. Although our MR findings correlate well with the pathophysiology of PMD, the MR characteristics are not specific. The diagnosis of PMD remains one of clinical and laboratory exclusion.

Enhanced MRI relaxivity of Gd3+-based contrast agents geometrically confined within porous nanoconstructs

Gadolinium chelates, which are currently approved for clinical MRI use, provide relaxivities well below their theoretical limit, and they also lack tissue specificity. Recently, the geometrical confinement of Gd(3+) -based contrast agents (CAs) within porous structures has been proposed as a novel, alternative strategy to improve relaxivity without chemical modification of the CA. Here, we have characterized and optimized the performance of MRI nanoconstructs obtained by loading [Gd(DTPA)(H(2) O)](2-) (Magnevist®) into the pores of injectable mesoporous silicon particles. Nanoconstructs with three different pore sizes were studied, and at 60 MHz, they exhibited longitudinal relaxivities of ~24 m m(-1)  s(-1) for 5-10 nm pores and ~10 m m(-1)  s(-1) for 30 - 40 nm pores. No enhancement in relaxivity was observed for larger pores sizes. Using an outer-sphere compound, [GdTTHA](3-) , and mathematical modeling, it was demonstrated that the relaxivity enhancement is due to the increase in rotational correlation times (CA adsorbed on the pore walls) and diffusion correlation times (reduced mobility of the water molecules), as the pore sizes decreases. It was also observed that extensive CA adsorption on the outer surface of the silicon particles negates the advantages offered by nanoscale confinement. Upon incubation with HeLa cells, the nanoconstructs did not demonstrate significant cytotoxicity for up to 3 days post incubation, at different particle/cell ratios. In addition, the nanoconstructs showed complete degradation after 24 h of continuous agitation in phosphate-buffered saline. These data support and confirm the hypothesis that the geometrical confinement of Gd(3+) -chelate compounds into porous structures offers MRI nanoconstructs with enhanced relaxivity (up to 6 times for [Gd(DTPA)(H(2) O)](2-) , and 4 times for [GdTTHA](3-) ) and, potentially, improved stability, reduced toxicity and tissue specificity.