2007 NSTI Nanotechnology Conference and Trade Show - Nanotech 2007 - 10th Annual

Hormone Peptide Conjugated Ironoxide Nanoparticles For Detection and Treatment of Metastases

C. Leuschner, C. Kumar, W. Hansel, R.T. Branca, G. Galiana, W. Warren and F. Hormes
Pennington Biomedical Research Center, US

metastases, nanoparticles, luteinizing hormone releasing hormone receptors, magnetic resonance imaging, lytic peptides, treatment monitoring

Hormone Peptide Conjugated Ironoxide Nanoparticles For Detection and Treatment of Metastases LEUSCHNER C1, KUMAR C2, Hansel W 1,BRANCA RT3, GALIANA G3, WARREN WS3, HORMES F2. 1Pennington Biomedical Research Center, Baton Rouge, LA, USA, 2Center for Advanced Microstructures and Devices, Baton Rouge, LA, USA, 3Duke University, Durham NC, USA. Background: Despite new discoveries of drugs for cancer the mortality rate did not improve over the last decades. In 2005 over 600,000 new cases of breast cancer were reported in the US; more than 41,000 deaths occurred due to metastatic disease. There is an urgent need to improve imaging and treatment to diagnose distant metastatic cancers. It has become evident that most cancers and their metastases overexpress functional receptors for luteinizing hormone releasing hormone (LHRH) (1). The treatment of cancers with conjugated lytic peptides (Hecate) has been very successful in xenograft models with minimal side effects (2). We have demonstrated the usefulness of nanoparticles for diagnosis of single cancer cells, by linking covalently a ligand molecule to superparamagnetic iron oxide nanoparticles (SPION) (3). A new nanoparticle construct has been developed for monitoring and treatment of tumors and metastases. Hypothesis: Targeted delivery of LHRH-SPION-Hecate facilitates and increases the accumulation of SPIONs in metastatic cancer cells, in peripheral tissues, lymph nodes, brain and bones, thus increasing the sensitivity of MR imaging and destroy the cancer cells. For imaging and monitoring treatment response LHRH and the lytic peptide hecate have been covalently linked to, SPIONs, (LHRH-SPION-Hecate). In this study we tested whether LHRH-SPION-Hecate specifically target and accumulate and destroy in metastatic cells from breast cancer xenografts. Methods: Female nude mice bearing human breast cancer xenografts (MDA-MB-435S.luc) were injected i.v. with 100 mg/kg LHRH-SPION-Hecate, LHRH-SPION with and without co-injections of LHRH. Mice were treated with a single injection once a week for three weeks and sacrificed in the fourth week. At necropsy, organs and tumors were collected for iron and metastasis analysis. Metastatic cells were determined by luciferase assays from organ homogenates; iron contents were determined spectrophotometrically by a Prussian blue reaction from organ homogenates and from paraffin embedded and sectioned tissues. Results: 1. LHRH-SPIONs were incorporated directly in the cancer cells of primary tumors and metastatic cells from peripheral tissues. 2. The amounts of LHRH-SPION accumulated were directly dependent on the number of metastatic cells, 3. repeated injection of LHRH-SPION increased the accumulation of nanoparticles in tumors and metastases and were retained over a period of 4 weeks, 4. LHRH-SPIONs did not reduce tumor volume or tumor weight, nor did it cause destruction of metastatic cells. 5. LHRH-SPION-Hecate accumulated in tumor tissue and metastases 6. LHRH-SPION-Hecate caused significant reduction in tumor volume, tumor weight and metastases. 7. Ironoxide nanoparticles were retained in diseased tissue. 8. Co-injection of LHRH inhibited the accumulation of LHRH-SPION and LHRH-SPION-Hecate in target tissue. Conclusion: LHRH conjugated SPION or in conjugation to a cytotoxic drug can serve as contrast agent and anticancer drug that specifically increased the sensitivity of detection of metastases and disseminated cells in lymph nodes, bones and peripheral organs in MRI and opens the possibility to monitor a treatment response in a non-invasive manner. Keywords: Metastases, nanoparticles, luteinizing hormone releasing hormone receptors, Magnetic Resonance Imaging lytic peptides, treatment monitoring References: 1. Nagy A, Schally AV. Targeting of cytotoxic luteinizing hormone-releasing hormone analogs to breast, ovarian, endometrial, and prostate cancers. Biol Reprod. 2005 Nov;73(5):851-9. 2. Leuschner C, Hansel W. (2005). Targeting breast and prostate cancers through their hormone receptors. Biology of Reproduction 73, 255-260. 3. Leuschner C, Kumar C, Hansel W, Zhou J, Soboyejo W, Hormes W: Ligand conjugated superparamagnetic iron oxide nanoparticles for early detection of metastases. Breast Cancer Res Treat. 2006 Sep;99(2):163-76. Presenting Author: Carola Leuschner, Ph.D., Assistant Professor Reproductive Biotechnology Pennington Biomedical Research Center 6400 Perkins Road Baton Rouge, LA, 70808 USA Tel. (work): USA-225-763-3197 (home): USA-225-927-6116 Fax: USA-225-763-2525 E-mail: Leuschc@pbrc.edu

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