Genevieve M. Fent

Bombesin functionalized gold nanoparticles show in vitro and in vivo cancer receptor specificity.

Development of cancer receptor-specific gold nanoparticles will allow efficient targeting/optimum retention of engineered gold nanoparticles within tumors and thus provide synergistic advantages in oncology as it relates to molecular imaging and therapy. Bombesin (BBN) peptides have demonstrated high affinity toward gastrin-releasing peptide (GRP) receptors in vivo that are overexpressed in prostate, breast, and small-cell lung carcinoma. We have synthesized a library of GRP receptor-avid nanoplatforms by conjugating gold nanoparticles (AuNPs) with BBN peptides. Cellular interactions and binding affinities (IC50) of AuNP–BBN conjugates toward GRP receptors on human prostate cancer cells have been investigated in detail. In vivo studies using AuNP–BBN and its radiolabeled surrogate 198AuNP–BBN, exhibiting high binding affinity (IC50 in microgram ranges), provide unequivocal evidence that AuNP–BBN constructs are GRP-receptor-specific showing accumulation with high selectivity in GRP-receptor-rich pancreatic acne in normal mice and also in tumors in prostate-tumor-bearing, severe combined immunodeficient mice. The i.p. mode of delivery has been found to be efficient as AuNP–BBN conjugates showed reduced RES organ uptake with concomitant increase in uptake at tumor targets. The selective uptake of this new generation of GRP-receptor-specific AuNP–BBN peptide analogs has demonstrated realistic clinical potential in molecular imaging via x-ray computed tomography techniques as the contrast numbers in prostate tumor sites are severalfold higher as compared to the pretreatment group (Hounsfield unit = 150).

Radioactive gold nanoparticles in cancer therapy: therapeutic efficacy studies of GA-198AuNP nanoconstruct in prostate tumor–bearing mice

UNLABELLED Biocompatibility studies and cancer therapeutic applications of nanoparticulate beta-emitting gold-198 (198Au; beta(max) = 0.96 MeV; half-life of 2.7 days) are described. Gum arabic glycoprotein (GA)-functionalized gold nanoparticles (AuNPs) possess optimum sizes (12-18 nm core diameter and 85 nm hydrodynamic diameter) to target individual tumor cells and penetrate through tumor vasculature and pores. We report the results of detailed in vivo therapeutic investigations demonstrating the high tumor affinity of GA-198AuNPs in severely compromised immunodeficient (SCID) mice bearing human prostate tumor xenografts. Intratumoral administration of a single dose of beta-emitting GA-198AuNPs (70 Gy) resulted in clinically significant tumor regression and effective control in the growth of prostate tumors over 30 days. Three weeks after administration of GA-198AuNPs, tumor volumes for the treated animals were 82% smaller as compared with tumor volume of control group. The treatment group showed only transitory weight loss in sharp contrast to the tumor-bearing control group, which underwent substantial weight loss. Pharmacokinetic studies have provided unequivocal evidence for the optimum retention of therapeutic payload of GA-198AuNPs within the tumor site throughout the treatment regimen with minimal or no leakage of radioactivity to various nontarget organs. The measurements of white and red blood cells, platelets, and lymphocytes within the treatment group resembled those of the normal SCID mice, thus providing further evidence on the therapeutic efficacy and concomitant in vivo tolerance and nontoxic features of GA-198AuNPs. FROM THE CLINICAL EDITOR In this study, the biocompatibility and cancer therapeutic applications of glycoprotein (GA) functionalized gold nanoparticles containing b-emitting Au-198 are described in SCID mice bearing human prostate tumor xenografts. The findings of significant therapeutic efficacy, good in vivo tolerance and non-toxic features make these particles ideal candidates for future human applications.

Evaluation of Small Arms Range Soils for Metal Contamination and Lead Bioavailability

Although small arms ranges are known to be contaminated with lead, the full extent of metal contamination has not been described, nor has the oral bioavailability of lead in these soils. In this work, soil samples from ranges with diverse geochemical backgrounds were sieved to <250 microm and analyzed for total metal content. Soils had consistently high levels of lead and copper, ranging from 4549 to 24 484 microg/g and 223 to 2936 microg/g, respectively, while arsenic, antimony, nickel, and zinc concentrations were 100-fold lower. For lead bioavailability measurements, two widely accepted methods were used: an in vivo juvenile swine relative bioavailability method measuring lead absorption from ingested soils relative to equivalent lead acetate concentrations and an in vitro bioaccessibility procedure which measured acid-extractable lead as a percent of total lead in the soil. For eight samples, the mean relative bioavailability and bioaccessibility of lead for the eight soils was about 100% (108 +/- 18% and 95 +/- 6%, respectively) showing good agreement between both methods. Risk assessment and/or remediation of small arms ranges should therefore assume high bioavailability of lead.

Gold Nanoparticle Contrast in a Phantom and Juvenile Swine : Models for Molecular Imaging of Human Organs using X-ray Computed Tomography

RATIONALE AND OBJECTIVES The purpose of this study was to demonstrate the application of gold nanoparticles (AuNP) as a contrast agent for a clinical x-ray computed tomography (CT) system using a phantom and juvenile swine. MATERIALS AND METHODS A tissue-mimicking phantom with spherical inclusions containing known concentrations of Au was scanned. Swine were injected with gum Arabic stabilized Au nanoparticles (GA-AuNP), up to 85 mg kg(-1) body weight. CT scans were performed before and after the injections. Changes in Hounsfield unit (HU) values between pre- and post- injection scans were evaluated and compared to postmortem determinations of Au uptake. Average uptake of GA-AuNP in the liver of the swine was 380 microg per gram of liver and 680 microg per gram of spleen. RESULTS Concentrations of Au in tissues increased the CT numbers in liver by approximately 22 HU per mg Au concentration at 80 kVp and 27 HU per mg Au concentration at 140 kVp. These data were consistent with HU changes observed for similar concentrations in the phantom. CONCLUSIONS AuNP-based contrast agents may be useful in x-ray based CT. This study provides data for determining concentrations of AuNP in comparison to other contrast materials.

An Effective Strategy for the Synthesis of Biocompatible Gold Nanoparticles Using Cinnamon Phytochemicals for Phantom CT Imaging and Photoacoustic Detection of Cancerous Cells

ABSTRACTPurposeThe purpose of the present study was to explore the utilization of cinnamon-coated gold nanoparticles (Cin-AuNPs) as CT/optical contrast-enhancement agents for detection of cancer cells.MethodsCin-AuNPs were synthesized by a “green” procedure, and the detailed characterization was performed by physico-chemical analysis. Cytotoxicity and cellular uptake studies were carried out in normal human fibroblast and cancerous (PC-3 and MCF-7) cells, respectively. The efficacy of detecting cancerous cells was monitored using a photoacoustic technique. In vivo biodistribution was studied after IV injection of Cin-AuNPs in mice, and also a CT phantom model was generated.ResultsBiocompatible Cin-AuNPs were synthesized with high purity. Significant uptake of these gold nanoparticles was observed in PC-3 and MCF-7 cells. Cin-AuNPs internalized in cancerous cells facilitated detectable photoacoustic signals. In vivo biodistribution in normal mice showed steady accumulation of gold nanoparticles in lungs and rapid clearance from blood. Quantitative analysis of CT values in phantom model revealed that the cinnamon-phytochemical-coated AuNPs have reasonable attenuation efficiency.ConclusionsThe results indicate that these non-toxic Cin-AuNPs can serve as excellent CT/ photoacoustic contrast-enhancement agents and may provide a novel approach toward tumor detection through nanopharmaceuticals.

Lead distribution in rats following respiratory exposure to lead-contaminated soils

Two preliminary experiments were performed to explore the use of an intratracheal instillation technique as a cost-effective method of determining the biokinetics of lead (Pb) following respiratory exposure to Pb-contaminated soils. A novel intratracheal instillation procedure was refined and used to deliver a defined dose of Pb-contaminated soil or PbAc to the lower respiratory tract of rats. In the first experiment, rats were sacrificed at numerous time intervals post-dosing, and liver, kidney, blood, and bone tissues were collected for Pb analysis. In the second experiment, rats were dosed with Pb-contaminated soil or PbAc via intratracheal instillation or gastric gavage. All rats were sacrificed 96 h after dose administration and tissues were collected for lead analysis. Data from these experiments indicate Pb is well-absorbed following intratracheal instillation of Pb-contaminated soil, and the intratracheal instillation technique could be used as a cost effective method for exploring the biokinetics of Pb in Pb-contaminated soils following respiratory tract exposure.