Kattesh V. Katti, M.Sc.Ed, PhD, DSC, FRSC, Curators’ Professor of Radiology and Physics, Margaret Proctor Mulligan Distinguished Professor of Cancer Research; Director, Institute of Green Nanotechnology, University of Missouri Cancer Nanotechnology Platform University of Missouri; Columbia, Missouri 65212, USA http://web.missouri.edu/~kattik/katti/katti
Kattesh V. Katti
Institute of Green Nanotechnolgy, University of Missouri - USA.
Cancer alone continues to kill more people than AIDS, malaria, and tuberculosis combined. According to the International Agency for Research on Cancer, there were 12.7 million new cancer cases in 2008. The World Health Organization projects that without major breakthroughs in cancer prevention, discovery of new and accurate diagnostic modalities and development of highly effective therapeutic approaches, the global number of deaths from cancer will increase by nearly 80% by 2030, with most occurring in low- and middle-income countries. There are over 100 pharmaceutical formulations approved by the US Food and Drug Administration (FDA) in order to combat this deadly pandemic. Although surgery and radiation treatments are the initial treatments for most cancers, a large number of oncological approaches are being used to control or cure cancer. Today cancer patients have more choices in which treatment or combination of treatments may be used encompassing three areas of emphasis: (a) Chemotherapy, (b)Hormone therapy; (c) Biological treatment. Despite the currently available choice of established anticancer agents for first-line of activity against cancer, effective delivery of chemotherapeutic, hormonal and biological pharmaceuticals to the tumor tissue and cancer cells selectively continues to be the most vexing problems in cancer oncology. Problems associated with effective delivery of cancer drugs pose severe oncological challenges especially when treating solid tumors (sarcomas, carcinomas, and lymphomas) which account for over 85% of all human cancers. Circumventing these problems is not easy because molecular and cellular biology of neoplastic cells alone has failed to explain the nonuniform uptake of these agents in solid tumors. Repeated delivery of cancer drugs leads to systemic toxicity creating major collateral adverse effects where cancer cells mutate making them resistant to chemotherapeutic treatments. Therefore, the discovery of new drug delivery approaches that effectively penetrate extracellular compartments consisting of vascular and interstitial valves within solid tumors is of profound importance. Radioactive nanoparticles with diagnostic and therapeutic capabilities provide intelligent drug delivery systems to maximize therapeutic activity and to minimize undesirable side-effects. For example the radioisotope of gold metal, Au-198, provides a desirable beta energy emission and half-life that destroys tumor cells/tumor tissue (βmax = 0.96 MeV; half-life of 2.7 days). Its penetration range (up to 4 mm in tissue or up to 1100 cell diameters) is sufficiently long to provide cross-fire effects to destroy tumor cells/tissue, but short enough to minimize radiation exposure to adjacent tissues. One particularly attractive feature of radioactive gold nanoparticles is that it does not have to be incorporated into every tumor cell to have a therapeutic effect. The path length of the emitted radiation is sufficient to allow effective therapy following uptake into a subpopulation of tumor cells. It is this feature that has attracted recent attention to apply nanotechnology for the effective delivery of therapeutic doses of beta emitting nanoparticles selectively to tumor tissue and tumor cells. We have reported the synthesis of novel radioactive gold nanoparticles using the trimeric phosphine (referred to as ‘Katti Peptide’: http://issuu.com/academyofinventors/docs/final_fellows_program_for_web/1 http://academyofinventors.org/conference/docs/fellows-program-2014.pdf discovered in our laboratory (1).We have recently carried out extensive in vitro and in vivo investigations to validate the hypothesis that glyco protein (gum Arabic) functionalized radioactive Au-198 nanoparticles are stable and biocompatible under in vivo conditions. Our research efforts have demonstrated that the complex polysaccharides and protein structures within the GA backbone can effectively lock gold nanoparticles on the protein matrix to produce non-toxic gold nanoparticulate constructs (GA-AuNP) which are stable under in vivo conditions for potential applications in tumor therapy (1). Our detailed in vivo studies, through intratumoral administration of GA-198AuNP (1.5Ci/tumor), in SCID mice bearing human prostate cancer xenografts, have demonstrated retention of over 154.05 ±40.7 %ID/gm within the tumor at 30 min that declined to 87.0±16.9 %ID/gm by 24 h. The overall reduction in tumor volume was 80% three weeks after a single dose intratumoral administration of GA-198AuNP (408µCi). The therapeutic efficacy data for GA-198AuNP corroborate their ability to induce tumor staticity because tumors harvested from the treatment group consisted largely of necrotic tissue, indicating extensive tumor cell kill. In our continued efforts to apply Green Nanotechnology for the development of therapeutic radioactive gold nanoparticles, recently we have discovered that the high antioxidant capacity of Epigallocatechin gallate (EGCG), which is the most abundant catechin polyphenol in tea, can be used to convert radioactive Gold-198 precursor to the corresponding biocompatible radioactive gold nanoparticles functionalized with Laminin receptor specific EGCG. Laminin receptors are overexpressed in a large number of human tumors and the high in vivo affinity of EGCG toward Laminin receptors has allowed to develop Laminin receptor specific radioactive gold nanoparticles to achieve tumor specificity (1-4). This lecture will provide: (a) scope and prospects of beta emitting radioisotopes in nanomedicine; (b) details on the intervention of nuclear activation analysis and various radioanalytical approaches for the production of tumor specific radioactive gold-198 nanoparticles; and (c) full in vivo investigations on therapeutic properties of EGCG-198-AuNP agent in treating prostate tumors and (d) the overall implications of Green Nanotechnology of therapeutic beta emitting nanoparticles in oncology.