Evan Boote

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).

Laminin receptor specific therapeutic gold nanoparticles (198AuNP-EGCg) show efficacy in treating prostate cancer

Systemic delivery of therapeutic agents to solid tumors is hindered by vascular and interstitial barriers. We hypothesized that prostate tumor specific epigallocatechin-gallate (EGCg) functionalized radioactive gold nanoparticles, when delivered intratumorally (IT), would circumvent transport barriers, resulting in targeted delivery of therapeutic payloads. The results described herein support our hypothesis. We report the development of inherently therapeutic gold nanoparticles derived from the Au-198 isotope; the range of the 198Au β-particle (approximately 11 mm in tissue or approximately 1100 cell diameters) is sufficiently long to provide cross-fire effects of a radiation dose delivered to cells within the prostate gland and short enough to minimize the radiation dose to critical tissues near the periphery of the capsule. The formulation of biocompatible 198AuNPs utilizes the redox chemistry of prostate tumor specific phytochemical EGCg as it converts gold salt into gold nanoparticles and also selectively binds with excellent affinity to Laminin67R receptors, which are over expressed in prostate tumor cells. Pharmacokinetic studies in PC-3 xenograft SCID mice showed approximately 72% retention of 198AuNP-EGCg in tumors 24 h after intratumoral administration. Therapeutic studies showed 80% reduction of tumor volumes after 28 d demonstrating significant inhibition of tumor growth compared to controls. This innovative nanotechnological approach serves as a basis for designing biocompatible target specific antineoplastic agents. This novel intratumorally injectable 198AuNP-EGCg nanotherapeutic agent may provide significant advances in oncology for use as an effective treatment for prostate and other solid tumors.

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.

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.

Functionalized radioactive gold nanoparticles in tumor therapy

The development of new treatment modalities that offer clinicians the ability to reduce sizes of tumor prior to surgical resection or to achieve complete ablation without surgery would be a significant medical breakthrough in the overall care and treatment of prostate cancer patients. The goal of our investigation is aimed at validating the hypothesis that Gum Arabic-functionalized radioactive gold nanoparticles (GA-(198) AuNP) have high affinity toward tumor vasculature. We hypothesized further that intratumoral delivery of the GA-(198) AuNP agent within prostate tumor will allow optimal therapeutic payload that will significantly or completely ablate tumor without side effects, in patients with hormone refractory prostate cancer. In order to evaluate the therapeutic efficacy of this new nanoceutical, GA-(198) AuNP was produced by stabilization of radioactive gold nanoparticles ((198) Au) with the FDA-approved glycoprotein, GA. This review will describe basic and clinical translation studies toward realization of the therapeutic potential and myriad of clinical applications of GA-(198) AuNP agent in treating prostate and various solid tumors in human cancer patients.

Accurate depth‐independent determination of acoustic backscatter coefficients with focused transducers

The accuracy of a method of data reduction for determining acoustic backscatter coefficients was tested using focused transducers and narrow-band pulses. Two phantoms with well-defined scattering properties were the bases of the tests, one having low attenuation and one with tissue-mimicking attenuation. The experimentally determined backscatter coefficients were found to be independent of transducer-to-scattering-volume distance and to agree very well with theoretical values, typically within 10%.

Anthropomorphic 1H MRS head phantom

An anthropomorphic 1H MRS head phantom has been developed which mimics the in vivo structure, metabolite concentrations, and relaxation times (for both water and metabolites) of human brain tissue. Different brain regions and two tumor types, fluid-containing ventricles, and air-filled sinus, and subcutaneous fat are all simulated. The main tissue-mimicking materials are gelatin/agar mixtures with metabolites and several other ingredients added. Their composition and method of production are thoroughly described. T1s and T2s of water in the phantom are very close to in vivo values, and metabolite T1s and T2s are considerably more realistic than those in aqueous solutions. Spectra and relaxation times for the pig brain were also acquired and compare well with those of the phantom. The realistic properties of this phantom should be useful for testing spectral quantitation and localization.

Backscatter coefficient imaging using a clinical scanner

A clinical ultrasound scanner has been integrated with a digital data acquisition system to record echo signals for off-line processing of quantitative acoustic backscatter images. The method used to determine backscatter coefficients accounts for experimental factors related to the beam directivity function, the transmitting and receiving electronics, and the attenuation path of the beam. After characterization and calibration of the ultrasound scanner according to the data processing requirements, the quantitative backscatter coefficient for tissue-mimicking phantoms are within 14% of a value predicted by scattering theory. On five normal volunteers, preliminary in vivo liver images of the acoustic backscatter coefficient are obtained. Results from this study are compared to previously published in vitro results.

WE‐D‐M100J‐01: Enhancement of Cell Killing by X‐Ray Irradiation in the Presence of Gold Nanoparticles

Purpose: This investigation was initiated to determine the radiobiologic enhancement for x‐ray irradiation of cells in the presence of citrate‐stabilized goldnanoparticles.Method and materials: Citrate‐stabilized goldnanoparticles were added to a strain of lymphoma cells in suspension at a concentration of 0.017 mg of gold per ml. Cell suspensions prepared included a two sham controls, and two samples with goldnanoparticles. One sham and one goldnanoparticle based sample were irradiated with x‐ray photons from a clinical x‐ray device (120 kVp, 6.67 mm Al equivalent beam). A total dose of 0.91 Gy was delivered in two approximately equal parts (24 hour separation). The non‐irradiated cell suspensions were treated identically. Cell survival for non‐irradiated cell suspensions and irradiated cell suspensions were determined over 72 hours using methylene blue dye exclusion. Results: The ratio of live:dead cells for all cell suspensions was 7.5:1 at the start of the experiment. After 72 hours, the irradiated cells exhibited a ratio approximately 50% lower than the non‐irradiated cells. The irradiated cell suspension with goldnanoparticles showed enhanced cell killing. Conclusions: Even at the low gold concentration and low x‐ray energy, goldnanoparticles exhibit some enhancement of cell killing. Further studies are ongoing using increasing gold concentrations and varying radiationdoses. It is likely that the presence of higher Z materials contributes to secondary electrondose in a way that may be described only through microdosimetry methods. Goldnanoparticle‐enhancedradiation therapy is a possible outcome of this work. Additional effort is directed toward functionalized goldnanoparticles using targeting moieties for specific cancers. This work contributes toward an understanding of the therapeutic enhancement that may be expected with specific concentrations of goldnanoparticles. Supported by: NIH R01 CA119412‐01.