Targeted Radiotherapy Of Cancer Research Articles

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

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.

Preparation and validation of cyclodextrin-based excipients for radioiodinated hypericin applied in a targeted cancer radiotherapy

BackgroundIodine-131 labeled hypericin (131I-Hyp) has been utilized as a necrosis-avid theragnostic tracer in a dual targeting pan-anticancer strategy called OncoCiDia. Widespread use of previously-tested solvent dimethyl sulfoxide (DMSO) is limited by safety concerns. To tackle this, the present study was designed to explore a clinically feasible excipient for the formulation of the hydrophobic 131I-Hyp for intravenous administration. MethodSolubility of Hyp in serial solutions of already-approved hydroxypropyl-β-cyclodextrin (HP-β-CD) was evaluated by UVspectrophotometry and 50% HP-β-CD was chosen for further experiments. Two novel HP-β-CD-based formulations of 131I-Hyp were compared with previous DMSO-based formulation, with regards to necrosis-targetability and biodistribution, by magnetic resonance imaging, single-photon emission computed tomography (SPECT), gamma counting, autoradiography, fluorescence microscopy and histopathology. ResultsHyp solubility was enhanced with increasing HP-β-CD concentrations. The radiochemical purity of 131I-Hyp was higher than 90% in all formulations. The necrosis-targetability of 131I-Hyp in the novel formulations was confirmed in vivo by SPECT and in vitro by autoradiography, fluorescence microscopy and histopathology. The plasma clearance of radioactivity was faster in the novel formulations. ConclusionThe novel 131I-Hyp formulations with HP-β-CD could be a suitable pharmaceutical excipient for 131I-Hyp for intravenous administration.

Nanoparticles for targeted cancer radiotherapy

Radiotherapy, where ionizing radiation is locally delivered either through an external beam or by surgically implanting radionuclide-based seeds in the tumor, is one of the gold standard treatments for cancer. Due to the non-selective nature of radiation, healthy tissue surrounding the cancerous region is usually affected by the treatment. Hence, new strategies, including targeted alpha therapy, are being studied to improve the selectivity of the treatment and minimize side effects. Several challenges, however, limit the current development of targeted radiotherapy, such as the functionalization of the therapeutic agent with targeting vectors and controlling the release of recoiling daughters. Nanoparticles offer unique opportunities as drug delivery vehicles, since they are biocompatible, enhance the cellular uptake of drugs, and are easily functionalized with targeting molecules. In this review, we examine how nanoparticles can be used for targeted radiotherapy, either as sensitizers of external beams or as delivery vehicles for therapeutic radionuclides. We describe the clinical relevance of different types of nanoparticles, followed by an analysis of how these nanoconstructs can solve some of the main limitations of conventional radiotherapy. Finally, we critically discuss the current situation of nanoparticle-based radiotherapy in clinical settings and challenges that need to be overcome in the future for further development of the field.

Neutron-irradiated antibody-functionalised carbon nanocapsules for targeted cancer radiotherapy

Radiotherapy is a cancer treatment utilising high doses of ionizing radiation to destroy cancer cells. Our team has pioneered neutron activation of 152Sm, filled and sealed into single-walled (SWCNTs) and multi-walled carbon nanotubes (MWCNTs), to create stable and high-dose radioactive carbon nanocapsules for cancer radiotherapy. In this work, MWCNTs filled with enriched 152SmCl3 (Sm@MWCNTs) were sealed and irradiated, followed by surface functionalisation with an epidermal growth factor receptor (EGFR)-targeting antibody. Characterisation of functionalised Sm@MWCNTs was carried out using thermogravimetric analysis, gel electrophoresis and transmission electron microscopy. The organ biodistribution of the radioactive functionalised 153Sm@MWCNTs and therapeutic efficacy were studied in an experimental melanoma lung metastatic tumour model in mice after intravenous injection. Quantitative biodistribution analyses showed high accumulation of 153Sm@MWCNT-Ab in lung. Significant tumour growth reduction was induced by both treatments of 153Sm@MWCNTs functionalised with or without the antibody after a single intravenous injection. Although EGFR targeting showed no improvement in therapeutic efficacy, reduced spleen toxicity and normal haematological profiles were obtained for both functionalised derivatives. The current study demonstrated the possibility of performing chemical functionalisation and antibody conjugation on radioactive nanocapsules post-irradiation for the preparation of targeted radiopharmaceuticals.

Synthesis and biological evaluation of 2.4 nm thiolate-protected gold nanoparticles conjugated to Cetuximab for targeting glioblastoma cancer cells via the EGFR

Therapeutic monoclonal antibodies benefit to patients and the conjugation to gold nanoparticles (AuNPs) might bring additional activities to these macromolecules. However, the behavior of the conjugate will largely depend on the bulkiness of the AuNP and small sizes are moreover preferable for diffusion. Water-soluble thiolate-protected AuNPs having diameters of 2–3 nm can be synthesized with narrow polydispersity and can selectively react with incoming organic thiols via a SN2-like mechanism. We therefore synthesized a mixed thionitrobenzoic acid- , thioaminobenzoic acid-monolayered AuNP of 2.4 nm in diameter and developed a site-selective conjugation strategy to link the AuNP to Cetuximab, an anti-epidermal growth factor receptor (EGFR) antibody used in clinic. The water-soluble 80 kDa AuNP was fully characterized and then reacted to the hinge area of Cetuximab, which was selectively reduced using mild concentration of TCEP. The conjugation proceeded smoothly and could be analyzed by polyacrylamide gel electrophoresis, indicating the formation of a 1:1 AuNP-IgG conjugate as the main product. When added to EGFR expressing glioblastoma cells, the AuNP-Cetuximab conjugate selectively bound to the cell surface receptor, inhibited EGFR autophosphorylation and entered into endosomes like Cetuximab. Altogether, we describe a simple and robust protocol for a site-directed conjugation of a thiolate-protected AuNP to Cetuximab, which could be easily monitored, thereby allowing to assess the quality of the product formation. The conjugated 2.4 nm AuNP did not majorly affect the biological behavior of Cetuximab, but provided it with the electronic properties of the AuNP. This offers the ability to detect the tagged antibody and opens application for targeted cancer radiotherapy.

Electrochemical Separation and Purification of Astatine for Radiopharmaceutical Application

The second longest lived isotope Astatine (211At: T1/2=7.5 h), is one the most promising α-emitters for targeted cancer radiotherapy. The liquid/liquid extraction method has been shown to provide good separation of 211At from bismuth metal. However, of the liquid/liquid (L/L) extraction (separation) steps [1] used in the current manual isolation procedure presents a significant challenge due to the nature of the diisopropyl ether / hydrochloric acid (DIPE/HCl) and diisopropyl ether / sodium hydroxide (DIPE/NaOH) mixtures. The present work is focused on to evaluate the feasibility of electrochemical methods in the purification of 211At. This approach will be an alternative to hydrogen astatide (H211At) wet distillation. At the present time, Bi (III) is considered the primary contaminant from which 211At must be electrochemically purified. The initial electrochemical studies were conducted with iodine as an astatine segregate in bismuth solution. As the concentration of astatine in the original solution is much lower than micro molar levels, there are two different approaches have been adopted; (i) separation of bismuth from the original solution [Ref 1; step 4] through electrodeposition and (ii) direct extraction of iodine from the original solution [Ref 1; step 3 or 4]. Figure 1(a) shows the cyclic voltammograms (CV) for bismuth on various substrate electrodes; namely Pt, Au and glassy carbon (GC). In these, the GC substrate found to be the suitable martial than others, which could be due to surface nature of carbon. In the case second approach, initially, iodide separation was carried out without bismuth in an acidic electrolyte with various concentrations of iodide to identify the suitable substrate material and minimum separation levels. Figure 1(b) shows the model CV for iodide on Pt electrode, surprisingly iodine deposit was also observed at the working electrode. Conversely, there are no characteristic electrochemical peaks and deposits were observed for GC and Au. This study indicates iodide can be extracted with Pt electrodes and Pt catalyzes the reactions. Acknowledgements Financial support from the Department of Energy (DOE) is greatly acknowledged. Selvarani Ganesan is thankful for subcontract from the Pacific Northwest National Laboratory (Contract No. 244236; PI: Matthew J O'Hara). Reference E.R. Balkin, D.K. Hamlin, K. Gagnon, M.-K Chyan, S. Pal, S. Watanabe, and D.S. Wilbur, Appl. Sci., 3 (2013) 636-655. Figure 1

Biologic Evaluation of a Novel 188Re-Labeled Porphyrin in Mice Tumor Model

The aim of this study was to develop a (188)Re-labeled porphyrin-based tumor-specific agent and to evaluate its biologic behavior, including tumor-regressing effectiveness, in mouse tumor models for possible use in achieving targeted cancer radiotherapy. (188)Re was obtained from an alumina-column-based (188)W-(188)Re generator constructed in-house. The compound, 5,10,15,20-tetrakis[3,4-bis(carboxymethyleneoxy)phenyl]porphyrin, was synthesized and labeled with (188)ReO(4)(-). (188)Re-labeled porphyrin complex was produced with a radiochemical purity of approximately 98% with reasonably good in vitro stability (>24 hours at 4 degrees C). Swiss mice bearing thymic lymphoma and fibrosarcoma were used as tumor models. The biodistribution studies revealed satisfactory tumor retention (2.07% +/- 0.80% injected activity per g) with insignificant activities in blood (0.53%), liver (0.26%) and kidney (0.04%) at 24 hours. The radiolabeled conjugate treatment increased the average tumor-doubling time and decreased the average specific growth rate substantially in thymic lymphoma, compared to fibrosarcoma tumor. (188)Re-labeled 5,10,15,20-tetrakis[3,4 bis(carboxymethyleneoxy)phenyl] porphyrin has specific affinity toward the fibrosarcoma and thymic lymphoma tumors in mice. Thymic lymphoma was found to be more sensitive to the radionuclide complex, compared to fibrosarcoma. The (188)Re-labeled porphyrin complex showed promising results and warrants further investigations.

Molecular Surgery with Auger Electron-Emitting Radiopharmaceuticals

The intense focus of radiochemical damage and cytotoxicity induced by Auger electron emitters is well known and provides a basis for their potential use in cancer therapy. Auger electron-emitting radionuclides decay by electron capture and/or internal conversion. The key feature of these modes of decay is the simultaneous release of low energy electrons, collectively known as Auger electrons. The unique characteristic of the majority of these electrons is their ultra short-range – they traverse only molecular dimensions – in biological tissue, resulting in a highly localized energy deposition in the immediate site of the decaying radionuclide. Therefore, Auger emitters have the potential to provide exquisite cell specificity in targeted cancer radiotherapy applications. However, their very limited effective range implies that there is a requirement to deliver these radionuclides to the DNA of target cells, to realize their maximum potential in cancer therapy. The radiobiological properties and therapeutic potential of Auger emitters has been the subject of intense exploration by a small but dedicated group of researchers for the past four decades. In this article we focus on recent advances relating to targeted cancer therapy with Auger electron-emitting radionuclides. State-of-the-art technologies for potential DNA-targeted cancer radiotherapy with Auger emitters are also presented. Keywords: Auger electrons, auger electron emitters, DNA targeting, radiopharmaceuticals, radioimmunotherapy

Targeted Nanomaterials for Radiotherapy

Nanomaterials have garnered increasing interest recently as potential therapeutic drug-delivery vehicles. Among the existing nanomaterials are the pure carbon-based particles, such as fullerenes and nanotubes, various organic dendrimers, liposomes and other polymeric compounds. These vehicles have been decorated with a wide spectrum of target-reactive ligands, such as antibodies and peptides, which interact with cell-surface tumor antigens or vascular epitopes. Once targeted, these new nanomaterials can then deliver radioisotopes or isotope generators to the cancer cells. Here, we will review some of the more common nanomaterials under investigation and their current and future applications as drug-delivery scaffolds with particular emphasis on targeted cancer radiotherapy.

Wet harvesting of no-carrier-added 211At from an irradiated 209Bi target for radiopharmaceutical applications

Astatine-211 is one of the most promising a-emitters for targeted cancer radiotherapy. However, research and clinical trials involving 211At-labeled radiopharmaceuticals have often been impeded due to the irregular and sometimes inconveniently low recovery yields obtained by the currently used dry distillation procedure. Therefore, a wet harvesting procedure isolating 211At from an irradiated 209Bi target was explored. The procedure involves target dissolution in concentrated HNO3 and extraction of the high oxidation state 211At activity with butyl or isopropyl ether. This method resulted in consistent and nearly quantitative yields. The activity was re-extracted in aqueous phase and applied to NIS6 UVW human glioma cells transfected with cDNA encoding the human sodium/iodide symporter (NIS). The significant and specific uptake of 211At activity by these cells suggests that in the ether phase, high oxidation state 211At is reduced to [211At]astatide anion. The synthesis of the first astatinated organic compound derived from wet harvested 211At, 3-astatobenzoic acid (ABA), was achieved.