Ablation of experimental colon cancer by intratumoral<sup>224</sup>Radium-loaded wires is mediated by alpha particles released from atoms which spread in the tumor and can be augmented by chemotherapy

Reitkopf-Brodutch, Shira; Confino, Hila; Schmidt, Michael; Cooks, Tomer; Efrati, Margalit; Arazi, L.; Rath‐Wolfson, Lea; Marshak, Gideon; Kelson, I.; Keisari, Yona

doi:10.3109/09553002.2015.959666

Cited by 22 publications

(25 citation statements)

References 44 publications

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“…In this study we evaluated the therapeutic potential of α-particle emitters on solid tumors using an engineered approach that alleviates the key factor of diffusion-limited transport. For the delivery of α-particle Reported therapeutic approaches using charged heavy particles include external beam (for example 12 C ions [35,36]) and brachytherapy implants (for example 224 Ra-loaded wires emitting α-particles [37,38]). The current study describes a therapeutic approach that is administered systemically, it is expected to reach solid tumors following the EPR effect, and is designed to interstitially release highly diffusing forms of the α-particle emitters as a response to the intrinsic -if it is the case [15,39,40] -mild acidity of tumors.…”

Section: Discussionmentioning

confidence: 99%

Alpha-particle radiotherapy: For large solid tumors diffusion trumps targeting

Zhu¹,

Sempkowski²,

Holleran³

et al. 2017

Biomaterials

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Diffusion limitations on the penetration of nanocarriers in solid tumors hamper their therapeutic use when labeled with α-particle emitters. This is mostly due to the α-particles' relatively short range (≤100 μm) resulting in partial tumor irradiation and limited killing. To utilize the high therapeutic potential of α-particles against solid tumors, we designed non-targeted, non-internalizing nanometer-sized tunable carriers (pH-tunable liposomes) that are triggered to release, within the slightly acidic tumor interstitium, highly-diffusive forms of the encapsulated α-particle generator Actinium-225 (Ac) resulting in more homogeneous distributions of the α-particle emitters, improving uniformity in tumor irradiation and increasing killing efficacies. On large multicellular spheroids (400 μm-in-diameter), used as surrogates of the avascular areas of solid tumors, interstitially-releasing liposomes resulted in best growth control independent of HER2 expression followed in performance by (a) the HER2-targeting radiolabeled antibody or (b) the non-responsive liposomes. In an orthotopic human HER2-negative mouse model, interstitially-releasing Ac-loaded liposomes resulted in the longest overall and median survival. This study demonstrates the therapeutic potential of a general strategy to bypass the diffusion-limited transport of radionuclide carriers in solid tumors enabling interstitial release from non-internalizing nanocarriers of highly-diffusing and deeper tumor-penetrating molecular forms of α-particle emitters, independent of cell-targeting.

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Section: Discussionmentioning

confidence: 99%

Alpha-particle radiotherapy: For large solid tumors diffusion trumps targeting

Zhu¹,

Sempkowski²,

Holleran³

et al. 2017

Biomaterials

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“…The current study represents an excellent example of successful recapitulation and validation of preclinical studies that demonstrated impressive tumor responses. [1][2][3][4][8][9][10][11][12] The innovative development of a brachytherapy dose delivery that takes advantage of short-range diffusion of alpha particles is unique and could potentially be paradigm changing. Brachytherapy has relied on radioactive beta and gamma sources for many years, and new, radio-biologically more potent sources could provide great benefit for patients with other solid tumors whose prognosis is poor.…”

Section: Months After Dart Insertionmentioning

confidence: 99%

Initial Safety and Tumor Control Results From a “First-in-Human” Multicenter Prospective Trial Evaluating a Novel Alpha-Emitting Radionuclide for the Treatment of Locally Advanced Recurrent Squamous Cell Carcinomas of the Skin and Head and Neck

Popovtzer

Rosenfeld

Mizrachi

et al. 2020

International Journal of Radiation Oncology*Biology*Physics

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Purpose: Our purpose was to report the feasibility and safety of diffusing alpha-emitter radiation therapy (DaRT), which entails the interstitial implantation of a novel alpha-emitting brachytherapy source, for the treatment of locally advanced and recurrent squamous cancers of the skin and head and neck. Methods and Materials: This prospective first-inhuman , multicenter clinical study evaluated 31 lesions in 28 patients. The primary objective was to determine the feasibility and safety of this approach, and the secondary objectives were to evaluate the initial tumor response and local progression-free survival. Eligibility criteria included all patients with biopsy-proven squamous cancers of the skin and head and neck with either primary tumors or recurrent/previously treated disease by either surgery or prior external beam radiation therapy; 13 of 31 lesions (42%) had received prior radiation therapy. Toxicity was evaluated according to the Common Terminology Criteria for Adverse Events version 4.03. Tumor response was assessed at 30 to 45 days at a follow-up visit using the Response Evaluation Criteria in Solid Tumors, version 1.1. Median follow-up time was 6.7 months. Results: Acute toxicity included mostly local pain and erythema at the implantation site followed by swelling and mild skin ulceration. For pain and grade 2 skin ulcerations, 90% of patients had resolution within 3 to 5 weeks. Complete response to the Ra-224 DaRT treatment was observed in 22 lesions (22/28; 78.6%); 6 lesions (6/28, 21.4%) manifested a partial response (>30% tumor reduction). Among the 22 lesions with a complete response, 5 (22%) developed a subsequent local relapse at the site of DaRT implantation at a median time of 4.9 months (range, 2.43-5.52 months). The 1-year local progression-free survival probability at the implanted site was 44% overall (confidence interval [CI], 20.3%-64.3%) and 60% (95% CI,

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“…Additionally, a significant increase in the survival rate was noted for DaRT treated mice (63% for treated vs. 29% untreated). Additional studies have shown the prospect of this therapy for treating squamous cell carcinomas [81], glioblastomas [81], melanoma [81], breast [80], colon [80,81,85], pancreatic [84], prostate [81], and lung cancers [83]. This method does have its drawbacks though.…”

Section: Radium and Targeted Alpha Therapymentioning

confidence: 99%

The Radiochemical and Radiopharmaceutical Applications of Radium

2016

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This review focuses on the chemistry and application of radium isotopes to environmental monitoring, analytical, and medicinal uses. In recent years, radium has been used primarily as a tracer to study the migration of radioactive substances in environmental systems. Tracing the naturally occurring radium isotopes in mineral and water sources allows for the determination of source location, residence time, and concentrations. An understanding of the concentration of radionuclides in our food and water sources is essential to everyone's health as alpha particle decay is highly damaging in vivo. Due to this high radiobiological effectiveness, there is increased interest in using alpha-emitting radionuclides to prepare new, therapeutic radiopharmaceutical drugs. Selected studies from the recent literature are provided as examples of these modern applications of radium isotopes.

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Ablation of experimental colon cancer by intratumoral²²⁴Radium-loaded wires is mediated by alpha particles released from atoms which spread in the tumor and can be augmented by chemotherapy

Abstract: (224)Ra-loaded wires ablate solid tumors by the release of alpha-particle emitting atoms inside the tissue, an effect that can be enhanced by combining this method with chemotherapy.

Cited by 22 publications

References 44 publications

Alpha-particle radiotherapy: For large solid tumors diffusion trumps targeting

Alpha-particle radiotherapy: For large solid tumors diffusion trumps targeting

Initial Safety and Tumor Control Results From a “First-in-Human” Multicenter Prospective Trial Evaluating a Novel Alpha-Emitting Radionuclide for the Treatment of Locally Advanced Recurrent Squamous Cell Carcinomas of the Skin and Head and Neck

The Radiochemical and Radiopharmaceutical Applications of Radium

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Ablation of experimental colon cancer by intratumoral224Radium-loaded wires is mediated by alpha particles released from atoms which spread in the tumor and can be augmented by chemotherapy

Abstract: (224)Ra-loaded wires ablate solid tumors by the release of alpha-particle emitting atoms inside the tissue, an effect that can be enhanced by combining this method with chemotherapy.

Cited by 22 publications

References 44 publications

Alpha-particle radiotherapy: For large solid tumors diffusion trumps targeting

Alpha-particle radiotherapy: For large solid tumors diffusion trumps targeting

Initial Safety and Tumor Control Results From a “First-in-Human” Multicenter Prospective Trial Evaluating a Novel Alpha-Emitting Radionuclide for the Treatment of Locally Advanced Recurrent Squamous Cell Carcinomas of the Skin and Head and Neck

The Radiochemical and Radiopharmaceutical Applications of Radium

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Ablation of experimental colon cancer by intratumoral²²⁴Radium-loaded wires is mediated by alpha particles released from atoms which spread in the tumor and can be augmented by chemotherapy