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Innovation in (gold) Nanoparticle-Enhanced Therapy

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S Krishnan
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B Chithrani

R Berbeco

S Krishnan1*, B Chithrani2*, R Berbeco3*, (1) (2) (3) Brigham and Women's Hospital, Boston, MA


TH-E-BRD-1 Thursday 1:00PM - 2:50PM Room: Ballroom D

Radiation therapy relies on the concept of delivering high dose to tumor volumes whilst simultaneously aiming to minimize irradiation of healthy tissue. Gold and other metallic nanoparticles (GNPs) have the potential to greatly enhance dose depositions in their close proximity. While it was originally thought that this effect would only be significant for kV photon beams, it has been shown that GNPs also enhance dose and increase cell killing and survival fraction for MV photons as well as protons. GNPs have been shown to be preferentially taken up in tumors, depending on the GNP properties either internalized in the tumor cells or clustering in the tumor vasculature. Therefore GNPs offer an intriguing additional option to target the tumor while sparing healthy tissue.

While a growing amount of research shows GNP induced enhancement factors in the order of 1.5 and higher, GNPs have not yet entered into clinical routine. In this symposium we will have three presentations discussing the current status of GNP based research, the potential to include GNPs in radiation therapy and the limitations and problems to use GNPs in the clinic.

Physical and biological underpinnings of radiosensitization with gold nano particles
An evolving body of recent literature alludes to the potential to sensitize tumors to radiation therapy using metallic nanoparticles. In preclinical studies, the techniques that hold promise for eventual clinical deployment are nanoparticle-assisted radiation dose enhancement and hyperthermic radiosensitization. To understand the underlying nanoparticle-radiation interactions, computational techniques offer an explanation for and predict the biophysical consequences at a nano-/meso-scopic scale. Nonetheless, there are persisting gaps in knowledge relating to the molecular mechanism of action of these radiosensitization approaches – some of these issues will be addressed. Since the literature relating to the diverse disciplines involved in these efforts spans across multiple specialties (clinical radiation oncology, radiation physics, radiation biology, nanotechnology, material science, biomedical engineering, pharmacology, chemistry, and tumor biology) and numerous specialty journals, there is no single compilation of extant research in this arena or forum for merging analogous concepts and paradigms. This symposium will provide such a venue – my presentation will start with familiarizing the audience with the potential applications of metallic nanoparticles in radiation therapy using specific illustrative examples and begin to explore ways to understand the underlying mechanisms of the effects observed.

Biological effects of Gold nanoparticles in radiation therapy
Gold nanoparticles (GNP) have been investigated as platforms to carry drugs or radio-sensitizing agents to tumors due to the biocompatibility of gold and relative ease of conjugation with therapeutic and targeting moieties. Recently, there has been interest in exploiting the physical properties of gold, specifically the high atomic number, to enhance radiation therapy. When irradiated, gold atoms will produce low energy electrons, depositing energy within a short distance. The ratio of dose deposited in the presence of the GNP to the dose deposited in the absence of GNP is referred to as the dose enhancement factor (DEF). This factor has been shown to depend on the concentration of GNP and the energy of the incident photons. The physics of this process, preliminary in vitro and in vivo experiments and future directions for this nascent field are described in this presentation.

Gold Nanoparticles for improved therapeutic outcome in radiation therapy
The application of nanoparticles (NPs) for improved therapeutics is at the forefront of cancer nanotechnology. Among other NP systems, gold nanoparticles (GNPs) are extensively used due to its impressive ability to act as both an anticancer drug carrier in chemotherapy and as a dose enhancer in radiotherapy. Cellular uptake of GNPs was dependent on their size. Among GNPs of diameter between 14-74 nm, GNPs of size 50 nm has the highest uptake. Radiosensitization was dependent on the size of the GNPs as well. GNPs of size 50-nm showed the highest radiosensitization enhancement factor compared to GNPs of 14 and 74 nm for lower- (105 kVp) and higher- (6 MVp) energy photons. GNPs used in those studies were predominantly localized in the cell cytoplasm. However, the therapeutic response can be further enhanced if NPs can be effectively targeted into the nucleus. Here, we present an effective strategy for designing a GNP-peptide complex for nuclear targeting. Two peptides were conjugated onto a GNP: One peptide enhanced the uptake while the other peptide enhanced the nuclear delivery. The nuclear-targeted cells displayed a fourfold increase in the therapeutic response when treated with radiation as compared to untargeted ones. DNA double-strand breaks were quantified using radiation-induced foci of γ-H2AX and 53BP1, and a modest increase in the number of foci per nucleus was observed in irradiated cell populations with internalized GNPs. This research will establish a more aggressive NP-based treatment approach for improved outcome in cancer therapy.

Learning Objectives:
1. Introduce radiosensitization concepts of metallic nanoparticle and provide the theoretical basis
2. Provide an overview over the size and coating dependence for GNP uptake in cells
3. Provide a compilation of the extant, multi-discipline research on metallic nanoparticles
4. Understand the prospects for future studies and innovations and the potential for applications of metallic nanoparticles in radiation therapy


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