Hendrik Engelbrecht

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.

Comparison of Systemic Toxicities of 177Lu-DOTMP and 153Sm-EDTMP Administered Intravenously at Equivalent Skeletal Doses to Normal Dogs

Bone-seeking radiopharmaceuticals have been used to effectively treat cancer arising from and metastasizing to bone in humans and dogs. The rate of complete tumor control is low, and the geographic distribution of available compounds is limited by their half-lives. This experiment was done to evaluate in normal dogs the toxicity of 177Lu-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetramethylene phosphonate (177Lu-DOTMP) used as a potential therapeutic radiopharmaceutical. Methods: Four normal purpose-bred dogs were administered 177Lu-DOTMP at a dose of 8.14 MBq/kg and monitored for 84 d for evidence of toxicity in the bone marrow and vital organs. Results: No statistically significant alterations in the biochemical profile, white blood cell count, or platelet count were observed in any dog. Very mild decreases in the red cell count were seen on day 84. No microscopic evidence of toxicity was present at necropsy. Conclusion: The dogs receiving 177Lu-DOTMP tolerated the administration and the effects of the compound without apparent clinical toxicity. The results of this experiment support the further evaluation in tumor-bearing dogs of 177Lu-DOTMP as a potential therapy for metastatic bone cancer and primary bone tumors in humans and dogs.

Substitution and Intramolecular Rearrangement of trans‐[ReO(X)(acac2en/pn)]0/+ (X = OH2 or Cl−) to Yield Asymmetric cis‐[ReO(Y)(acac2en/pn)] Complexes with Cyanide and Thiocyanate

Asymmetric Re(V) oxo complexes of the type cis‐[ReO(Y)(acac2en/pn)] (Y = CN−, NCS−) were generated from the symmetric precursors trans‐[ReO(X)(acac2en/pn)]0/+ (X = H2O, Cl−) by reaction with cyanide and thiocyanate. The products were characterized using standard spectroscopic methods, elemental analyses and single crystal X‐ray diffraction. The crystallographic data for the structures reported are as follows: cis‐[ReO(NCS)(acac2pn)] (H20C14N3O3SRe), 1, monoclinic (P21/n), a = 8.0047(6) Å, b = 13.6118(10) Å, c = 30.597(2) Å, β = 96.571(1)°, V = 3311.9(4) Å3, Z = 8; cis‐[ReO(CN)(acac2pn)] (H20C14N3O3Re), 2, monoclinic (P21/n), a = 9.5139(12) Å, b = 14.0625(18) Å, c = 12.2343(3) Å, = 107.286(2)°, V = 1562.9(3) Å3, Z = 4; cis‐[ReO(NCS)(acac2en)] (H18C13N3O3SRe), 3, monoclinic (P21/c), a = 17.1965(19) Å, b = 12.7416(14) Å, c = 15.7270(17) Å, = 110.589(2)°, V = 3225.9(6) Å3, Z = 8. The authors would like to gratefully acknowledge financial support from DOE grants DE‐FG02‐93ER61661 (JLG) and DE‐FG2‐01ER63192 (HPE) from the Radiochemistry Education Award Program administered by the South Carolina Universities Research and Education Foundation (under U.S. Department of Energy Cooperative Agreement #DE‐FC09SR18262), Mallinckrodt Medical, Inc. (St. Louis, MO) and the National Science Foundation NSF CHE 9221835 (250 MHz NMR).