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 (198)Au 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 (198)AuNPs 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 (198)AuNP-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 (198)AuNP-EGCg nanotherapeutic agent may provide significant advances in oncology for use as an effective treatment for prostate and other solid tumors.

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 (IC 50 ) 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 198 AuNP–BBN, exhibiting high binding affinity (IC 50 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).

1538 Objectives In this study we investigated Au-198 nanoparticles (198AuNP) that were rapidly produced using (-)-Epigallocatechin gallate (EGCG) an antioxidant reducing agent derived from green tea. Methods The 198Au was produced at MURR and provided as H198AuCl4 in a final concentration of 0.05 M HCl. EGCG was dissolved in Milli-Q water, and the H198AuCl4 and carrier HAuCl4 (0.1 M Au) were added and stirred at room temperature for 5 min to generate the nanoparticles. The UV/Vis spectrum showed the expected Plasmon peak at 529-535 nm. TLC confirmed that over 99% of the gold was present in the nanoparticle form. SCID mice bearing human prostate cancer derived from PC-3 cells were used for pharmacokinetic and therapy studies. On day 6, 30 µL of EGCG 198AuNP (136 µCi) was injected into the tumor (IT) to deliver an estimated 70 Gy. Control animals received 30 µL of Dulbecco’s PBS. A further set of animals were injected IT with 30 µL of solution containing only EGCG. Tumors were measured twice weekly. Results Previous results indicated IT injections result in the highest retention of activity in the tumor and lowest dose to normal tissues. In the pharmacokinetic studies animals injected with EGCG 198AuNP showed 77.8 ± 12.3 % ID was retained in the tumor at 30 min and 72.4 ± 13.0 % ID after 24 hr. Based on these results radiotherapy evaluations were conducted. No differences were noted between the controls and animals injected IT with EGCG. By day 18, tumors in the control group were 4-fold larger than those of the treatment group (p=0.04). By day 28, tumors in the control group were over 5-fold larger than those of the treatment group (p=0.01). An end of study biodistribution on day 42 showed 34.1 ± 19.8 %ID remained in the residual tumor. Conclusions Using EGCG, 198AuNP can be formulated at room temperature to treat prostate cancer. The formed 198AuNP showed very good tumor retention and significantly inhibited tumor growth compared to saline controls and EGCG alone. Research Support R01CA119412-0

Introduction: A variety of (bis)thiosemicarbazone-based ligand systems have been investigated as chelating agents for Au(III) complexes with potential radiotherapeutic applications. Ligand systems containing an ethyl, propyl or butyl backbone between the two imine N donors have been synthesized to evaluate chelate ring size effects on the resultant Au(Ill) complex stability at the macroscopic and radiotracer levels.Methods: The Au(III) complexes were synthesized and characterized by NMR, electrospray ionization mass spectra, elemental analysis and X-ray crystallography. The Au-198 complexes were evaluated in vitro at the tracer level for stability in phosphate-buffered saline at pH 7.4 and 37 degrees C. One of these complexes [Au-198(3,4-HxTSE)] showed high in vitro stability and was further evaluated in vivo in normal mice.Results: [Au(ATSM)]AUCl(4)center dot 2CH(3)OH, (ATSM=diacetyl-bis(N-4-methylthiosemicarbazone)) H14C8N6O2S2Cl4Au2 center dot 2CH(3)OH, crystallized from methanol in the monoclinic space group P21/n with a=14.7293(13) angstrom, b=7.7432(7) angstrom, c=20.4363(18) angstrom, beta=100.140(2)degrees, V=2294.4 (4) angstrom(3), Z=4; [Au(3,4-HxTSE)]Cl center dot CH3CH2OH/AuCl2, (3,4-HxTSE=3,4-hexanedione-bis(N-4-ethylthiosemicarbazone)) H26C13.6N6O0.8S2Cl1.2Au1.2, crystallized from ethanol in the monoclinic space group P21/c with a=10.1990(10) angstrom, b=13.8833(14) angstrom, c=15.1752(15) angstrom, beta=99.353(2)degrees, V=2120.2 (4) angstrom, Z=4.Conclusions: These studies revealed poor stability of the [Au-198][Au(3,4-HxTSE)](+) complex; however, crystal structure data suggest potential alterations to the ligand backbone may increase stability. (C) 2010 Elsevier Inc. All rights reserved.

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.

3164 The American Cancer Society estimates that 1.4 million people will be diagnosed with cancer in 2007. Men have a 45% probability of developing some form of cancer in their lifetime. Of men diagnosed with cancer, 1-in-3 will be prostate cancer. Current detection methods for prostate cancer involve determining the concentration of prostate specific antigen (PSA) in blood serum. Medications, certain herbs, and genetics can increase PSA levels, thus providing inaccurate results. Current treatment options for prostate cancer include surgery, irradiation, immunotherapy, hormone therapy and chemotherapy. Gold nanoparticles provide an attractive alternative to treating cancer by delivering high irradiation payloads. Gold-198 (Au-198) radiolabeled nanoparticles stabilized with gum Arabic, a natural additive used in everyday food products and thus non-toxic in-vivo , are described. These nanoparticles are rapidly produced by using the non-toxic, amino acid derived reducing agent tris-hydroxymethyl phosphine alanine (THPAL). The nuclear properties of Au-198 are well suited for radiotherapy (t 1/2 = 2.7 days, E βmax = 1.37 MeV). The 411 keV gamma emission (95%) allows tracking of the Au-198 radiolabeled nanoparticles using Single Photon Emission Computed Tomography (SPECT). The high thermal (98.6 barns) and epithermal (1550 barns) nuclear cross-section of natural, monoisotopic Au-197 allows for relatively rapid irradiation to achieve reasonable specific activity. If carrier-free radioactive Au is needed, Au-199 (t 1/2 = 3.1 days, E βmax = 0.45 MeV, 158 and 208 keV γ-rays) can be obtained from the β - decay of Pt-199 (t 1/2 = 30.9 min; produced from an enriched Pt-198 target). Three different routes of administering Au-198 radiolabeled gold nanoparticles (Au-198-GA-AuNP), prepared as described above, were compared using a PC-3 (human prostate cancer) xenograft tumor model in immunocompromised mice. Radiotracer uptake and retention were determined after 30 min, 1 h, 2 h, 4 h, and 24 h. Tumor uptake after 24 h was 1.79 + 0.32% D/g by intravenous (IV) injection, 5.75 + 1.49% D/g by intraperitoneal (IP) injection, and 87.73 + 37.61% D/g by intratumoral (IT) injection. The IV injection also showed high liver (65.2 + 2.30% D/g), lungs (17.9 + 4.92% D/g), and spleen (8.52 + 1.12% D/g) uptake over time. After IP injection, tumor uptake increased steadily over the time course. IT administration showed little to no leakage of Au-198-GA-AuNP from the tumor over the first 4 hr, while 60% of the injected dose was retained at 24 hr, indicating potential as a radiotherapeutic agent.