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Enhancing the abscopal effect of radiation and immune checkpoint inhibitor therapies with magnetic nanoparticle hyperthermia in a model of metastatic breast cancer.

ABSTRACT: Purpose: Enhancing immune responses in triple negative breast cancers (TNBCs) remains a challenge. Our study aimed to determine whether magnetic iron oxide nanoparticle (MION) hyperthermia (HT) can enhance abscopal effects with radiotherapy (RT) and immune checkpoint inhibitors (IT) in a metastatic TNBC model.Methods: One week after implanting 4T1-luc cells into the mammary glands of BALB/c mice, tumors were treated with RT (3?×?8?Gy)±local HT, mild (HTM, 43?°C/20?min) or partially ablative (HTAbl, 45?°C/5?min plus 43?°C/15?min),±IT with anti-PD-1 and anti-CTLA-4 antibodies (both 4?×?10?mg/kg, i.p.). Tumor growth was measured daily. Two weeks after treatment, lungs and livers were harvested for histopathology evaluation of metastases.Results: Compared to untreated controls, all treatment groups demonstrated a decreased tumor volume; however, when compared against surgical resection, only RT?+?HTM+IT, RT?+?HTAbl+IT and RT?+?HTAbl had similar or smaller tumors. These cohorts showed more infiltration of CD3+ T-lymphocytes into the primary tumor. Tumor growth effects were partially reversed with T-cell depletion. Combinations that proved most effective for primary tumors generated modest reductions in numbers of lung metastases. Conversely, numbers of lung metastases showed potential to increase following HT?+?IT treatment, particularly when compared to RT. Compared to untreated controls, there was no improvement in survival with any treatment.Conclusions: Single-fraction MION HT added to RT?+?IT improved local tumor control and recruitment of CD3+ T-lymphocytes, with only a modest effect to reduce lung metastases and no improvement in overall survival. HT?+?IT showed potential to increase metastatic dissemination to lungs.

SUBMITTER: Oei AL

PROVIDER: S-EPMC7017719 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Enhancing the abscopal effect of radiation and immune checkpoint inhibitor therapies with magnetic nanoparticle hyperthermia in a model of metastatic breast cancer.

Oei Arlene L AL Korangath Preethi P Mulka Kathleen K Helenius Mikko M Coulter Jonathan B JB Stewart Jacqueline J Velarde Esteban E Crezee Johannes J Simons Brian B Stalpers Lukas J A LJA Kok H Petra HP Gabrielson Kathleen K Franken Nicolaas A P NAP Ivkov Robert R

International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group 20191101 sup1

Purpose: Enhancing immune responses in triple negative breast cancers (TNBCs) remains a challenge. Our study aimed to determine whether magnetic iron oxide nanoparticle (MION) hyperthermia (HT) can enhance abscopal effects with radiotherapy (RT) and immune checkpoint inhibitors (IT) in a metastatic TNBC model.Methods: One week after implanting 4T1-luc cells into the mammary glands of BALB/c mice, tumors were treated with RT (3 × 8 Gy)±local HT, mild (HTM, 43 °C/20 min) o ...[more]

PMID: 31795835

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Project description:Magnetic resonance (MR) nano-theranostic hyperthermia uses magnetic nanoparticles to target and accumulate at the lesions and generate heat to kill lesion cells directly through hyperthermia or indirectly through thermal activation and control releasing of drugs. Preclinical and translational applications of MR nano-theranostic hyperthermia are currently limited by a few major theoretical difficulties and experimental challenges in in vivo conditions. For example, conventional models for estimating the heat generated and the optimal magnetic nanoparticle sizes for hyperthermia do not accurately reproduce reported in vivo experimental results. In this work, a revised cluster-based model was proposed to predict the specific loss power (SLP) by explicitly considering magnetic nanoparticle aggregation in in vivo conditions. By comparing with the reported experimental results of magnetite Fe3O4 and cobalt ferrite CoFe2O4 magnetic nanoparticles, it is shown that the revised cluster-based model provides a more accurate prediction of the experimental values than the conventional models that assume magnetic nanoparticles act as single units. It also provides a clear physical picture: the aggregation of magnetic nanoparticles increases the cluster magnetic anisotropy while reducing both the cluster domain magnetization and the average magnetic moment, which, in turn, shift the predicted SLP toward a smaller magnetic nanoparticle diameter with lower peak values. As a result, the heating efficiency and the SLP values are decreased. The improvement in the prediction accuracy in in vivo conditions is particularly pronounced when the magnetic nanoparticle diameter is in the range of ~10-20 nm. This happens to be an important size range for MR cancer nano-theranostics, as it exhibits the highest efficacy against both primary and metastatic tumors in vivo. Our studies show that a relatively 20%-25% smaller magnetic nanoparticle diameter should be chosen to reach the maximal heating efficiency in comparison with the optimal size predicted by previous models.

Project description:Superparamagnetic nanoparticles (SPIONs) could enable cancer theranostics if magnetic resonance imaging (MRI) and magnetic hyperthermia treatment (MHT) were combined. However, the particle size of SPIONs is smaller than the pores of fenestrated capillaries in normal tissues because superparamagnetism is expressed only at a particle size <10 nm. Therefore, SPIONs leak from the capillaries of normal tissues, resulting in low accumulation in tumors. Furthermore, MHT studies have been conducted in an impractical way: direct injection of magnetic materials into tumor and application of hazardous alternating current (AC) magnetic fields. To accomplish effective enhancement of MRI contrast agents in tumors and inhibition of tumor growth by MHT with intravenous injection and a safe AC magnetic field, we clustered SPIONs not only to prevent their leakage from fenestrated capillaries in normal tissues, but also for increasing their relaxivity and the specific absorption rate. We modified the clusters with folic acid (FA) and polyethylene glycol (PEG) to promote their accumulation in tumors. SPION clustering and cluster modification with FA and PEG were achieved simultaneously via the thiol-ene click reaction. Twenty-four hours after intravenous injection of FA- and PEG-modified SPION nanoclusters (FA-PEG-SPION NCs), they accumulated locally in cancer (not necrotic) tissues within the tumor and enhanced the MRI contrast. Furthermore, 24 h after intravenous injection of the NCs, the mice were placed in an AC magnetic field with H = 8 kA/m and f = 230 kHz (Hf = 1.8×10(9) A/m?s) for 20 min. The tumors of the mice underwent local heating by application of an AC magnetic field. The temperature of the tumor was higher than the surrounding tissues by ?6°C at 20 min after treatment. Thirty-five days after treatment, the tumor volume of treated mice was one-tenth that of the control mice. Furthermore, the treated mice were alive after 12 weeks; control mice died up to 8 weeks after treatment.

Dataset Information

Enhancing the abscopal effect of radiation and immune checkpoint inhibitor therapies with magnetic nanoparticle hyperthermia in a model of metastatic breast cancer.

Publications

Enhancing the abscopal effect of radiation and immune checkpoint inhibitor therapies with magnetic nanoparticle hyperthermia in a model of metastatic breast cancer.

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