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

https://doi.org/10.1016/j.nano.2009.11.001Get rights and content

Abstract

Biocompatibility studies and cancer therapeutic applications of nanoparticulate β-emitting gold-198 (198Au; βmax = 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 β-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.

Section snippets

Synthesis and characterization of GA-AuNPs and GA-198AuNPs

University of Missouri Research Reactor irradiation facilities were used for the production of 198Au. The radioactive and nonradioactive GA-conjugated AuNPs were synthesized using synthetic procedures already established in our laboratory.31, 41 Briefly, H198AuCl4 in 0.05 M HCl was added to aqueous solutions of GA followed by the addition of trimeric alanine conjugate, P(CH2NHCH(CH3)COOH)3. The color change from yellow to a red-purple was observed to yield nanoparticles stabilized by GA. The

Synthesis and characterization of GA-198AuNPs

The synthesis and characterization of GA-198AuNPs and GA-AuNPs were performed by following the procedure established in our laboratory.31, 41. Physicochemical properties such as size, charge, and morphology of GA-AuNPs were determined by TEM and DLS. TEM images of GA-AuNPs indicate that the nanoparticles are spherical with core size range of 12–18 nm. DLS measurements revealed that GA-AuNPs have the hydrodynamic diameter of 85 nm; these data suggest that AuNPs are wrapped with glycoprotein

Discussion

As part of our long-standing interest in the development of nanoparticle-based therapeutic agents, synthetic protocols for stabilizing AuNPs via labeling with biocompatible vectors (including GA glycoprotein) have been optimized.31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 45, 46, 47, 48, 51 Traditional methods use NaBH4 (and other reducing chemicals) for the production of AuNPs at macroscopic levels. However, such methods fail when used at tracer levels to produce 198Au nanoparticulate

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    This research was supported by grants from the National Institutes of Health–National Cancer Institute under the Cancer Nanotechnology Platform Program: 5R01CA119412-01, NIH-1R21CA128460-01, NIH-SBIR-Contract No. 241, and University of Missouri Research Board Program: C8761 RB 06-030.

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