Rajesh R. Kulkarni

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.

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.

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.

SU-E-T-384: Dosimetry Studies for Radioactive Gold Nanoparticles

Purpose: This investigation was initiated to determine the absorbed dose and radioactivity distribution of radioactive goldnanoparticles.Methods:Polymergel dosimeter was prepared using about 12% gelatin (Sigma Aldrich, 300 bloom type A), 9% methacrylic acid(Sigma Aldrich), 10mM THPC (Sigma Aldrich), 18mM hydroquinone (Sigma Aldrich) in deionized water. These dosimeters are used for calibration purpose and meant to estimate the absorbed dose in the medium from the radiation emitted by the radioactive goldnanoparticles. The high energy gamma dose, activity distribution were measured using SPECTimaging and the phantom used was the ball of play‐doh made by Hasbro Toys. A previously constructed acrylic cast of beagle dogs head was used in this study to place the phantom. The radioactive goldnanoparticles were synthesized at the University owned nuclear reactor with the high neutron flux of ∼10e14 neutrons/cm2/sec.Results: Carbohydrate suspended radioactive nanoparticles with approximately 200 microCuries were injected in a play doh ball, depicting the prostate gland of beagle dog, approximately 1 inch diameter (8–10ml) in size. The phantom was placed on the SPECTimaging table near the isocenter of the imaging plane. The Gamma camera was peaked for the 411keV photon and equipped with a high energy (Iodine collimator). The phantom was then imaged using SPECTimaging protocol. The activity imaged at various planes and count rates was evenly distributed as predicted Conclusions: The activity distribution as seen in the SPECTimaging indicated active hot and cold spots of radioactive goldnanoparticles. The use of play‐doh determines the activity distribution but uneven diffusion. To compensate for that polymergel dosimeters, equivalent to the tissue densities may be considered, besides there is also an advantage of estimating the absorbed doses.