Application of High-Z Gold Nanoparticles in Targeted Cancer Radiotherapy-Pharmacokinetic Modeling, Monte Carlo Simulation and Radiobiological Effect Modeling.

Wei Bo Li,Junli Li,Gabriele Multhoff,Maxim Shevtsov,Yibao Zhang,Rui Qiu,Stefan Stangl,Bernhard Michalke,Melanie A Kimm,Alexander Klapproth,Jan Schuemann,Kerstin Hürkamp,Alicia Hernandez,Mario A Bernal

doi:10.3390/cancers13215370

Abstract

Simple SummaryHigh-Z gold nanoparticles show potential as radiosensitizers in the radiotherapy of cancer. In this paper, we introduce the benefits and procedures for the application of gold nanoparticles in targeted cancer radiotherapy. Based on microscopic images of the distribution of antibody-conjugated nanoparticles, we established pharmacokinetic models simulating the biodistribution of nanoparticle conjugates in the tumor and tumor environment in preclinical models. This information has been implemented in radiation transport Monte Carlo simulation codes for further investigating physical and chemical enhancement and radiobiological effects, such as DNA strand breaks and cell survival. Future perspectives and challenges of translating this promising gold nanoparticle-aided radiotherapy into clinical practice are also discussed.High-Z gold nanoparticles (AuNPs) conjugated to a targeting antibody can help to improve tumor control in radiotherapy while simultaneously minimizing radiotoxicity to adjacent healthy tissue. This paper summarizes the main findings of a joint research program which applied AuNP-conjugates in preclinical modeling of radiotherapy at the Klinikum rechts der Isar, Technical University of Munich and Helmholtz Zentrum München. A pharmacokinetic model of superparamagnetic iron oxide nanoparticles was developed in preparation for a model simulating the uptake and distribution of AuNPs in mice. Multi-scale Monte Carlo simulations were performed on a single AuNP and multiple AuNPs in tumor cells at cellular and molecular levels to determine enhancements in the radiation dose and generation of chemical radicals in close proximity to AuNPs. A biologically based mathematical model was developed to predict the biological response of AuNPs in radiation enhancement. Although simulations of a single AuNP demonstrated a clear dose enhancement, simulations relating to the generation of chemical radicals and the induction of DNA strand breaks induced by multiple AuNPs showed only a minor dose enhancement. The differences in the simulated enhancements at molecular and cellular levels indicate that further investigations are necessary to better understand the impact of the physical, chemical, and biological parameters in preclinical experimental settings prior to a translation of these AuNPs models into targeted cancer radiotherapy.

Highlights

The exceptionally rapid development of the innovative techniques in radiology and radiotherapy which have followed Wilhelm Conrad Röntgen’s discovery of X-rays at the end of 19th century has enabled a considerably deeper understanding of human diseases and improved the treatment and management of patients with cancer [1]
The results of (1) cmHsp70.1 mAbAuNP conjugation in vitro and in vivo are initially summarized, followed by our results of (2) the pharmacokinetic model for superparamagnetic iron oxide nanoparticles (SPIONs) in mice and cellular compartmental model for AuNP conjugation; (3) the dose enhancement around a single AuNP and for multiple AuNPs distributed within a cell; (4) the enhanced cell survival fraction for multiple AuNPs in cells
Three different types of AuNP-conjugates, cmHsp70.1 monoclonal antibody (mAb)-AuNPs, and IgG1-AuNPs, and unconjugated AuNPs were incubated with tumor cell lines 4T1 and CT26 for 24 h at 37 ◦C to simulate the AuNP-uptake [57]

Summary

Introduction

The exceptionally rapid development of the innovative techniques in radiology and radiotherapy which have followed Wilhelm Conrad Röntgen’s discovery of X-rays at the end of 19th century has enabled a considerably deeper understanding of human diseases and improved the treatment and management of patients with cancer [1]. AuNPs have become very popular for studying radiation sensitization due to the strongly enhanced physical dose and beneficial biological effects, and due to the presumed biocompatibility and the production of chemical radicals induced by secondary electrons [14]. This concept is termed as “gold nanoparticle-assisted radiation therapy” or “gold nanoparticle-aided radiotherapy” [15,16,17]

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