Clinical translation of a novel cancer nanothereapeutic agent : bench to bedside from a small company perspective [abstract]

Nanoparticles of gold are inherently multifunctional in their diagnostic and therapeutic capabilities. 198Au, provides a desirable beta energy emission and half-life for effective destruction of tumor cells/ tissue(?max = 0.96 MeV; half -life of 2.7 days). The range of the 198Au [beta]-particle is sufficiently long to provide cross-fire effects of radiation dose delivered to cells within the prostate gland and short enough to minimize significant radiation dose to critical tissues near the periphery of the capsule. In order to capitalize on the well known tumor affinity of gold nanoparticles to tumor vasculature, Nanoparticle Biochem Inc (NBI), has developed proprietary technology that allows efficient conversion of radioactive gold-198 to its corresponding therapeutic nanoparticles with subsequent stabilization via conjugation with Gum Arabic protein matrix. As part of the SBIR Phase I effort, Nanoparticle Bicohem Inc (NBI) has successfully completed detailed therapeutic efficacy studies in prostate tumor bearing mice and toxicity studies of the non radioactive surrogate of NBI 29 in pigs. Intratumoral injection of NBI's proprietary gold nanoparticle based injectable agent: 198AuNP-GA (NBI-29), has unequivocally demonstrated that over 90% of the injected dose remains in the tumor over a 24 hour (and longer) time period and that the agent effectively shrinks and suppresses the growth of prostate tumors in mice to such levels that are not commonly observed with any chemo or radiotherapeutic agent (Katti, Kannan and others in Nanomedicine Volume 6, Issue 2, Pages 201-209 April 2010; featured article on the cover page in April 2010 issue). No toxic side effects were noted for over 40 days of studies in mice and for over 120 days investigation in pigs (using the non radioactive surrogate). Limited Phase I clinical trial studies in client owned dogs with naturally occurring prostate tumors, which mimic androgen independent prostate tumors in men, have already provided unequivocal evidence on the realistic clinical potential of NBI 29 as a new generation nanotherapeutic agent for treating inoperable solid tumors. In order to clinically translate the therapeutic potential of NBI 29 for treating prostate tumor human patients, Nanoparticle Biochem Inc has recently entered into a joint product development effort with Shasun Pharmaceutical Company of India. Shasun-NBI LLC will focus product development efforts aimed at completion of toxicity/therapeutic efficacy in dogs to allow filing of an IND application with the US FDA to commence Phase I clinical trials in human prostate cancer patients. Product development efforts, incorporating platform nanotechnology of Shasun-NBI LLC, as outlined above, will be carried out in collaboration with internationally reputed group of interdisciplinary scientists, consultants and cancer therapy experts within the University of Missouri and chosen from other locations with expertise in (i) therapeutic isotope production; (ii) nanotechnology as it relates to applications in nanomedicine; (ii) tumor biology (iii) radiation/clinical and surgical oncology; (iii) medical physics and dosimetry; (iv) veterinarians with strong comparative oncology track record; and (v) conducting Phase I-III clinical trials leading to final approval by the US FDA Implications for prospective investors in terms of the pontifical of Shasun-NBI LLC's 'Platform Nanotechnology' for the development of sophisticated therapy agents for treating hepatocellular and pancreatic cancers will be presented

Green nantocehnology in dual medical and national defense applications : global perspectives on formal training and education

This presentation was part of the Sensing: Biomarkers, Biometrics, and CBRNE Platforms Panel in which experts addressed the challenge of sensing, and sense-making in support of the national security analytic process. Perspectives emphasized the technology strengths, limitations, and operational relevance

Nanomedicine approach for sustained release delivery of Avastin : treatment for PXE and AMD [abstract]

Gold nanoparticles possess unique properties including preferential binding to leaky blood vessels, ability to bind to a variety of ligands, with no evidence of cellular toxicity, making them an excellent platform for targeted sustained release of drugs. Avastin (Bevacizumab) is a humanized monoclonal antibody specifically targeting vascular endothelial growth factor (VEGF) that has found widespread use in inhibiting intraocular neovascularization manifested in macular degeneration and proliferative diabetic retinopathy. The conjugation of gold nanoparticles (AuNP) with Avastin (Av) yields AvAuNP nanoconjugates. Avastin conjugated gold nanoparticles (AvAuNP) can be used as therapeutic agents in the treatment of ophthalmic neovascular disorders, such as macular degeneration, PXE and proliferative diabetic retinopathy. AvAuNP nanoconjugate is a potential clinical therapeutic agent and has demonstrated excellent ability to deliver Avastin for sustained release of therapeutic dose within the eye. The design and development of AvAuNP conjugate would help in the initiation and completion of preclinical evaluations aimed at determining the ability to achieve long-term suppression of intraocular neovascularization in large animals. INVENTOR(S): Ravi Shukla; Kavita K. Katti; Raghuraman Kannan; Dean Hainsworth and Kattesh V. Katti CONTACT INFO: Paul Hippenmeyer, Ph.D., M.B.A.; [email protected]; (573)-882-047

Green nanotechnology from cumin phytochemicals : generation of biocompatible gold nanoparticles

Published in final edited form as: Int J Green Nanotechnol Biomed. 2009 January 1; 1(1): B39-B52. doi:10.1080/19430850902931599.The powerful antioxidant characteristics of various phytochernicals within cumin prompted us to test their efficacy in reducing sodium tetrachloroaurate to corresponding gold nanoparticles. We, herein, report an unprecedented synthetic route that involves the production of well-defined spherical gold nanoparticles by simple mixing of cumin to an aqueous solution of sodium tetrachloro aurate. Production of gold nanoparticles in this cumin-mediated Green Nanotechnological process is achieved under biologically benign conditions. The gold nanoparticles generated through cumin-mediated process did not aggregate suggesting that the cocktail of phytochemicals including proteins serve as excellent coatings on nanoparticles and thus, provide robust shielding from aggregations. In addition, the phytochemical coatings on nanoparticles have rendered nontoxic features to these 'Green Gold Nanoparticles' as demonstrated through detailed MTT assays performed on 'normal fibroblast cells. Results of our studies presenting a new 'Nano-Naturo' connection for the production and utility of gold nanoparticles for potential applications in nanomedicine and nanotechnology are discussed in this paper.This work has been supported by the generous support from the National Institutes of Health/National Cancer Institute under the Cancer Nanotechnology Platform program (grant number: 5R01CA119412-01), NIH - 1R21CA128460-01 and University of Missouri-Research Board - Program C8761 RB 06-030

Production and optimization of 198/199 gold nanoparticles for potential use in cancer therapy [abstract]

Abstract only availableRadiopharmaceuticals are used to diagnose and treat a number of diseases such as bone cancer and non-Hodgkin's lymphoma. A radiopharmaceutical typically consists of a targeting molecule that selectively targets certain tumors. The targeting molecule is labeled with a radioactive atom(s) that delivers a dose of radiation to the tumor. The radioactive properties of Au-198 ([beta]- = 0.96 MeV; [gamma] = 411 KeV) and Au-199 ([beta]- = 0.45 MeV; [gamma] = 158 KeV) with their beta (therapeutic) and gamma (imaging) emission make them valuable candidates for both therapeutic and imaging applications. Gold nanoparticles have several properties that make them particularly interesting for use in radiopharmaceuticals. They are stable in vivo, have multiple atoms per particle and are small enough in size to deliver a radioactive dose directly to cancer cells. The purpose of this study was to gain a better understanding of the binding properties of the nanoparticles with reducing and stabilizing agents. This knowledge will aid in future attempts to label the particles with various antibodies and peptides for tumor targeted delivery of the drug. Next, investigate the relationship between particle size and the amount of reducing agent used was studied with varying amounts and types of carbohydrate stabilizers. Our goal is to establish a library of nanoparticles with varying sizes that can be conjugated with different biomolecules that are selective for receptors over expressed by the diseased tissue. In future studies we also plan to pursue an indirect method of preparing radioactive Au-199 nanoparticles at carrier free levels from beta decay of Pt-199.Life Sciences Undergraduate Research Opportunity Progra

A Comparative Study between Antibody and Peptide Conjugated Gold Nanoparticles for In Vivo Targeting of EGFR in Pancreatic Cancer Bearing Mice Models [abstract]

Nanoscience Poster SessionPancreatic cancer is the fourth leading cause of cancer related deaths in the United States due to its severe aggressiveness and lethal malignancy. Epidermal Growth Factor Receptor (EGFR) is over expressed in more than 95% of human pancreatic cancer patients. A number of peptides and monoclonal antibodies have been developed to target the EGFR in pancreatic cancer. Our research has focused on developing EGFR targeting biomolecule conjugated gold nanoparticles for the diagnosis and staging of various cancers. In this study, we synthesized a series of Antibody EGFR and EGFR-peptide conjugated AuNPs. We investigated the in vivo EGFR targeting characteristics of these conjugates in pancreatic tumor bearing SCID mice models. Our investigation establishes that the peptide conjugated AuNPs have high in vivo mobility and targets pancreatic tumor effectively. We have also established that EGFR-peptide -AuNP conjugates act as better X-ray contrast agents for early detection of pancreatic cancer in mice models. The details of this comparative study will be presented in this poster

Relative study between anti-EGFR and GE-11 peptide conjugated gold nanoparticles for in vivo targeting in pancreatic cancer [abstract]

Pancreatic cancer is the fourth leading cause of cancer related deaths in the United States due to its severe aggressiveness and lethal malignancy. Epidermal Growth Factor Receptor (EGFR) is over expressed in more than 95% of human pancreatic cancer patients. A number of peptides and monoclonal antibodies have been developed to target the EGFR in pancreatic cancer. Our research has focused on developing EGFR targeting biomolecule conjugated gold nanoparticles for the diagnosis and staging of various cancers. In this study, we have synthesized a series of Antibody EGFR and EGFR-peptide (GE-11) conjugated AuNPs. We investigated the in vivo EGFR targeting characteristics of these conjugates in pancreatic tumor bearing SCID mice models. Our investigation has provided evidence that the peptide conjugated AuNPs have high in vivo mobility and targets pancreatic tumor effectively. We have also established that the EGFR-peptide-AuNP conjugates serve as better X-ray contrast agents for early detection of pancreatic cancer in mice models. The details of this comparative study will be presented in this poster

Photoacoustic Detection of Circulating Prostate, Breast and Pancreatic Cancer cells using targeted Gold Nanoparticles: Implications of Green Nanotechnology in Molecular Imaging

Nanoscience Poster SessionCirculating tumor cells are hallmarks of metastasis cancer. The presence of circulating tumor cells in blood stream correlates with the severity of disease. Photoacoustic imaging (PA) of tumor cells is an attractive technique for potential applications in diagnostic imaging of circulating tumor cells. However, the sensitivity of photoacoustic imaging of tumor cells depends on their photon absorption characteristics. In this context, gold nanoparticle embedded tumor cells offer significant advantages for diagnostic PA of single cells. As the PA absorptivity is directly proportional to the number of nanoparticles embedded within tumor cells, the propensity of nanoparticles to internalize within tumor cells will dictate the sensitivity for single cell detection. We are developing biocompatible gold nanoparticles to use them as probes as part of our ongoing effort toward the application of X ray CT Imaging, Ultra Sound (US) and photoacoustic imaging of circulating breast, pancreatic and prostate tumor cells. We, herein report our latest results which have shown that epigallocatechin gallate (EGCG)-conjugated gold nanoparticles (EGCG-AuNPs) internalize selectively within cancer cells providing threshold concentrations required for photo acoustic signals. In this presentation, we will describe, our recent results on the synthesis and characterization of EGCG gold nanoparticles, their cellular internalization and photo acoustic imaging of PC-3 prostate cancer cells and PANC-1 pancreatic cancer cells

Green nanotechnology of MGF‑AuNPs for immunomodulatory intervention in prostate cancer therapy

Abstract Men with castration-resistant prostate cancer (CRPC) face poor prognosis and increased risk of treatment-incurred adverse effects resulting in one of the highest mortalities among patient population globally. Immune cells act as double-edged sword depending on the tumor microenvironment, which leads to increased infiltration of pro-tumor (M2) macrophages. Development of new immunomodulatory therapeutic agents capable of targeting the tumor microenvironment, and hence orchestrating the transformation of pro-tumor M2 macrophages to anti-tumor M1, would substantially improve treatment outcomes of CRPC patients. We report, herein, Mangiferin functionalized gold nanoparticulate agent (MGF-AuNPs) and its immunomodulatory characteristics in treating prostate cancer. We provide evidence of immunomodulatory intervention of MGF-AuNPs in prostate cancers through observations of enhanced levels of anti-tumor cytokines (IL-12 and TNF-α) with concomitant reductions in the levels of pro-tumor cytokines (IL-10 and IL-6). In the MGF-AuNPs treated groups, IL-12 was elevated to ten-fold while TNF-α was elevated to about 50-fold, while IL-10 and IL-6 were reduced by two-fold. Ability of MGF-AuNPs to target splenic macrophages is invoked via targeting of NF-kB signaling pathway. Finally, therapeutic efficacy of MGF-AuNPs, in treating prostate cancer in vivo in tumor bearing mice, is described taking into consideration various immunomodulatory interventions triggered by this green nanotechnology-based nanomedicine agent

Cryphonectria nitschkei chrysovirus 1 with unique molecular features and a very narrow host range

Cryphonectria nitschkei chrysovirus 1 (CnCV1), was described earlier from an ascomycetous fungus, Cryphonectria nitschkei strain OB5/11, collected in Japan; its partial sequence was reported a decade ago. Complete sequencing of the four genomic dsRNA segments revealed molecular features similar to but distinct from previously reported members of the family Chrysoviridae. Unique features include the presence of a mini-cistron preceding the major large open reading frame in each genomic segment. Common features include the presence of CAA repeats in the 5′-untranslated regions and conserved terminal sequences. CnCV1-OB5/11 could be laterally transferred to C. nitschkei and its relatives C. radicalis and C. naterciae via coculturing, virion transfection and protoplast fusion, but not to fungal species other than the three species mentioned above, even within the genus Cryphonectria, suggesting a very narrow host range. Phenotypic comparison of a few sets of CnCV1-infected and -free isogenic strains showed symptomless infection in new hosts