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Targeted gold nanoparticles enhance sensitization of prostate tumors to megavoltage radiation therapy in vivo.

ABSTRACT: We report potent radiosensitization of prostate cancers in vitro and in vivo using goserelin-conjugated gold nanorods. Progressive receptor-mediated internalization of conjugated nanorods over time increases the radiation interaction cross-section of cells and contributes to the effects observed in vitro. The low concentrations of gold required, the long interval between injection of nanoparticles and radiation, and the use of megavoltage radiation to generate radiosensitization in vivo foretell the possibility of eventual clinical translation of this approach.The ability of gold nanoparticles (AuNPs) to enhance the effect of physical radiation dose on tumor cells is known. This radiosensitization effect is thought to result from an increased number of photoelectric absorption events and the increased number of electrons present in gold. The authors here sought to further increase the amount and specificity of gold accumulation in prostatic cancer cells by conjugating gold nanorods to goserelin, a synthetic luteinizing hormone releasing hormone (LHRH) analogue that would bind to the LHRH receptor overexpressed in prostate cancers. It was shown that tumour cells were more sensitive to megavoltage radiation therapy. It is hoped that there would be eventual clinical translation of this approach.

SUBMITTER: Wolfe T

PROVIDER: S-EPMC4476911 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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Targeted gold nanoparticles enhance sensitization of prostate tumors to megavoltage radiation therapy in vivo.

Wolfe Tatiana T Chatterjee Dev D Lee Jihyoun J Grant Jonathan D JD Bhattarai Shanta S Tailor Ramesh R Goodrich Glenn G Nicolucci Patricia P Krishnan Sunil S

Nanomedicine : nanotechnology, biology, and medicine 20150131 5

We report potent radiosensitization of prostate cancers in vitro and in vivo using goserelin-conjugated gold nanorods. Progressive receptor-mediated internalization of conjugated nanorods over time increases the radiation interaction cross-section of cells and contributes to the effects observed in vitro. The low concentrations of gold required, the long interval between injection of nanoparticles and radiation, and the use of megavoltage radiation to generate radiosensitization in vivo foretell ...[more]

PMID: 25652893

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Project description:BackgroundThis study investigated the effectiveness and underpinning mechanisms of radiosensitization using octaarginine (R8)-modified gold nanoparticle-poly(ethylene glycol) (GNP-PEG-R8) in colorectal cancer cell line LS180 to megavoltage radiotherapy in vitro.MethodIn-house synthesized GNP-PEG was characterized by transmission electron microscopy, dynamic light scattering, ultraviolet-visible spectrophotometry, and X-ray photoelectron spectroscopy. Inductively coupled plasma mass spectroscopy was used to quantify internalization. Direct cytotoxicity was established using the Cell Counting Kit-8, while radiosensitivity was determined using the gold standard in vitro clonogenic assay. Cell-cycle distribution, apoptosis, reactive oxygen species (ROS), and mitochondrial membrane potential (MMP) were analyzed by flow cytometry, further exploring the key mechanisms driving GNP-PEG-R8 radiosensitization.ResultsThe core GNP diameter was 6.3±1.1 nm (mean±SD). Following functionalization, the hydrodynamic diameter increased to 19.7±2.8 nm and 27.8±1.8 nm for GNP-PEG and GNP-PEG-R8, with respective surface plasmon resonance peaks of 515 nm and 525 nm. Furthermore, incorporation of the R8 significantly increased nanoparticle internalization compared to GNP-PEG (p<0.001) over a 1 h treatment period. Functionalized GNPs confer little cytotoxicity below 400 nM. In clonogenic assays, radiation combined with GNP-PEG-R8 induced a significant reduction in colony formation compared with radiation alone, generating a sensitizer enhancement ratio of 1.59. Furthermore, GNP-PEG-R8 plus radiation predominantly induced cell-cycle arrest in the G2/M phase, increasing G2/M stalling by an additional 10% over GNP-PEG, markedly promoting apoptosis (p<0.001). Finally, ROS levels and alterations in MMP were investigated, indicating a highly significant (p<0.001) change in both parameters following the combined treatment of GNP-PEG-R8 and radiation over radiation alone.ConclusionR8-modified GNPs were efficiently internalized by LS180 cells, exhibiting minimal cytotoxicity. This yielded significant radiosensitization in response to megavoltage radiation. GNP-PEG-R8 may enhance radiosensitivity by arresting cell cycle and inducing apoptosis, with elevated ROS identified as the likely initiator.

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Targeted gold nanoparticles enhance sensitization of prostate tumors to megavoltage radiation therapy in vivo.

Publications

Targeted gold nanoparticles enhance sensitization of prostate tumors to megavoltage radiation therapy in vivo.

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