Wednesday, June 4, 2014

Nanoparticles and Prostate Cancer

Amarnath Mukherjee, PhD
Nanoparticles are small objects having a diameter in the nano-meter range (10-9 m) which behave as small individual particles. Over the last two decades, nanoparticles have made its impact in every area of science and technology. This is because they possess distinct properties (attributed to their small size and high surface to volume ratio) which can be explored for unique use. For example, iron-oxide based nanoparticles have been simultaneously used both in imaging (as MRI contrast agents) and therapy (through hyperthermia or drug delivery). [1] Amarnath Mukherjee, PhD, is a researcher in the Brady Urological Insitute at Johns Hopkins, who is studying the use of nanoparticle for potential cancer therapy/diagnosis with Shawn E. Lupold, PhD, and Co-Director of the Prostate Cancer Program at the Sidney Kimmel Cancer Center at Hopkins.

Prostate Specific Membrane Antigen (PSMA) is an established target for cancer therapeutic and imaging agents due to its high expression on the surface of prostate cancer cells and within the neovasculature of other solid tumors. Drs. Mukherjee and Lupold have developed a humanized anti-PSMA antibody conjugated silica-coated iron oxide nanoparticles for PSMA-specific cell binding – a iron oxide nanoparticle that can hone specifically to prostate cancer cells. [2] Customized assays utilizing iron spectral absorbance and Enzyme-Linked Immunoassay (ELISA) were developed to screen nanoparticle formulations for immunoreactivity and PSMA-targeting. Antibody and PSMA-specific targeting of the optimized nanoparticle was evaluated using an isogenic PSMA-positive and PSMA-negative cell line pair. These nanoparticles and the methods used to validate their function support the promise of targeted theranostic agents for future treatment of prostate and other cancers.

Although nanoparticles offer significant promise for new mode of diagnosis and therapy, they come with new challenges. For example, Iron oxide nanoparticles capable of generating localized heat are reshaping the concept of targeted and focal hyperthermia as a cancer therapy. Traditional hyperthermia (or energy ablation) uses energy sources to destroy a target lesion, usually localized with imaging like CT, MRI or ultrasound. However, nanoparticle-mediated hyperthermia is different than traditional hyperthermia in a few senses. First, nanoparticle-mediated hyperthermia has the ability to target microscopic foci of cancer not seen on traditional imaging. In addition, traditional hyperthermia often destroys tissues, both malignant and benign, within a “killzone” created by the energy source. Drs. Mukherjee and Lupold have studied and compared (using temperature sensitive secreted luciferase-based reporter gene system) thermal stress response, at the cellular level, to macroscopic and NP hyperthermia. [3] The results indicate that cells can detect mild heat stress from nanoparticles at temperatures too low to measurably alter the macroscopic temperature of the system – indicating that the target cells can be “cooked” without damaging nearby normal cells. The results also suggest that cells which were closer to the nanoscopic heat source experienced greater thermal stress. Further characterization of the nature of nanoparticle heating and its relationship to macroscopic hyperthermia is needed prior to moving nanoparticle research into human experiments and the clinic.

[1] N. Ahmed, H. Fessi, A. Elaissari, Drug discovery today 2012, 17, 928-934.
[2] A. Mukherjee, T. Darlington, R. Baldwin, et al ChemMedChem 2014.
[3] A. Mukherjee, M. Castanares, M. Hedayati, et al Nanomedicine (Lond) 2014.



  1. Iron-Oxide Based Nanoparticles can beat Prostate Cancer? Researchers say the findings suggest formation of the hybrid genes (fusion transcripts that are formed from previously separate genes) may underlie the aggressive behavior of prostate cancer. Each man has more than 30,000 individual genes; only genes involved in iron metabolism disorders contribute to prostate cancer. Genes that maintain iron homeostasis may facilitate iron uptake, storage or egress, or the regulation of any of these processes. Around 5-9% of prostate cancers are linked to genes and family history. DNA is a complex molecule, and errors creep in all the time. Regulation of iron levels is a task of the whole body, as well as for individual cells. In most cases, the cell can correct its own defects, but when Cellular Iron Overload attacks DNA and chromosomes, molecular biologists observe poly-gene fusion transcripts and chromothripsis in the prostate cancer cell lines. All metastatic and advanced prostate cancers are characterized by extensive genomic instability, which can be detected among all histological subtypes and among different foci within prostate tumor. The genomic changes occur at different levels, from mutations in single or few nucleotides to gains or losses of entire chromosomes or large chromosome regions. Prostate cancer cells are riddled with genetic errors, and each prostate tumor has its own chaotic set of genetic mistakes. Based on autopsy material, in both men and women, primary tumors always develop at body sites of excessive iron deposits. Mechanisms of carcinogenesis are simple. On the one hand, genes involved in iron metabolism disorders create inherited prostate cancers and other cancers. On the other hand, any health problems (old age, obesity, prostatitis), lifestyle factors (sexually transmitted infections, lack of exercise) and environmental causes (ionizing radiation, chemical carcinogens) distort iron metabolism (the set of chemical reactions maintaining homeostasis of iron) and create spontaneous prostate cancers and other cancers. Cancer that spreads outside the prostate gland to the lymph nodes, bones, or other areas is called metastatic prostate cancer. Currently, no treatments can cure advanced prostate cancer. Surgery (ceramic blades), direct intratumoral injections of iron-deficiency agents (modern medical plastic syringes and ceramic needles) and clinical iron-deficiency methods (special diets; accurate blood donations) can successfully beat inherited and spontaneous; localized, inoperable and metastatic prostate cancers. ; ; ; Brady Urological Insitute at Johns Hopkins & MNT & Google & Vadim Shapoval

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