x-ray-visualization-intraductal-ethanol-based-ablative-treatment-for

X-Ray Visualization of Intraductal Ethanol-Based Ablative Treatment for Prevention of Breast Cancer in Rat Models

There are still a limited number of primary interventions for prevention of breast cancer. For women at a high risk of developing breast cancer, the most ...

intraductal-delivery-x-ray-visualization-ethanol-based-ablative

Intraductal Delivery and X-ray Visualization of Ethanol-Based Ablative Solution for Prevention and Local Treatment of Breast Cancer in Mouse Models

Breast cancer is the most prevalent cancer and the second-leading cause of cancer-related death for women in the USA. For high-risk women, prophylactic ...

Michigan State University

Histiocytic sarcoma in humans is an aggressive orphan disease with a poor prognosis as treatment options are limited. Dogs are the only species that spontaneously develops histiocytic sarcoma with an appreciable frequency, and may have value as a translational model system. In the current study, high-throughput drug screening utilizing histiocytic sarcoma cells isolated from canine neoplasms identified these cells as particularly sensitive to a MEK inhibitor, trametinib. One of the canine cell lines carries a mutation in PTPN11 (E76K), and another one in KRAS (Q61H), which are associated with the activation of oncogenic MAPK signaling. Both mutations were previously reported in human histiocytic sarcoma. Trametinib inhibited sensitive cell lines by promoting cell apoptosis, indicated by a significant increase in caspase 3/7. Furthermore,  findings were successfully recapitulated in an intrasplenic orthotopic xenograft mouse model, which represents a disseminated aggressive form of histiocytic sarcoma. Mice with histiocytic sarcoma xenograft neoplasms that were treated with trametinib had significantly longer survival times. Target engagement was validated as activity of ERK, downstream of MEK, was significantly downregulated in neoplasms of treated mice. Additionally, trametinib was found in plasma and neoplastic tissues within projected therapeutic levels. These findings demonstrate that in dogs, histiocytic sarcoma may be associated with a dysfunctional MAPK pathway, at least in some cases, and may be effectively targeted through MEK inhibition. Clinical trials to test safety and efficacy of trametinib in dogs with histiocytic sarcoma are warranted, and may provide valuable translational information to similar diseases in humans. .

Targeting MEK in a Translational Model of Histiocytic Sarcoma.

Peripheral nerve injury remains a large clinical problem, with challenges to the successful translation of nerve repair devices. One promising technology is the multichannel scaffold, a conduit incorporating arrays of linear microchannels, which has high open lumen volume to guide regenerating nerves toward distal targets. To maximize open lumen volume, and scale-up scaffolds for translation, this study explored how mechanical properties were affected by 1) material choice (poly(lactide co-glycolide) (PLGA) and poly(caprolactone) (PCL)), 2) microstructure (porous and non-porous), and 3) channel architecture (200 µm and 300 µm diameter). After testing in transverse compression and bending, it was noted that introduction of porosity and increasing microchannel diameter increased scaffold compliance from 0.05 ± 0.1-2.75 ± 0.8 mm/N. Porosity also increased flexibility and eliminated kinking, which could potentially damage regenerating nerves. Material choice determined both scaffold deformation and mechanics. Porous PLGA scaffolds were stiffer than porous PCL, with greater deformation. Having demonstrated stability and flexibility, porous PCL multichannel scaffolds were scaled from 1.5 mm to 10 mm in diameter, a range applicable to the clinic. Even at 10 mm in diameter, the linear structure, high open lumen volume and compliance were retained. This demonstrates significant progress towards translation and brings multichannel technology closer to the clinic.

The mechanics of scaling-up multichannel scaffold technology for clinical nerve repair.

Canine histiocytic sarcoma is a highly aggressive and metastatic hematopoietic neoplasm that responds poorly to currently available treatment regimens. Our goal was to establish a clinically relevant xenograft mouse model to assess the preclinical efficacy of novel cancer treatment protocols for histiocytic sarcoma. We developed an intrasplenic xenograft mouse model characterized by consistent tumor growth and development of metastasis to the liver and other abdominal organs. This model represents the metastatic or disseminated form of canine histiocytic sarcoma, which is considered the most clinically challenging form of the disease. Transfection of tumor cells with a luciferase vector supported the use of in vivo bioluminescence imaging to track tumor progression over time and to assess the response of this murine model to novel chemotherapeutic agents. Dasatinib treatment of the mice with intrasplenic xenografts decreased tumor growth and increased survival times, compared with mice treated with vehicle only. Our findings indicate the potential of dasatinib for the treatment of histiocytic sarcoma in dogs and for similar diseases in humans. These results warrant additional studies to clinically test the efficacy of dasatinib in dogs with histiocytic sarcoma.

Development of an Orthotopic Intrasplenic Xenograft Mouse Model of Canine Histiocytic Sarcoma and Its Use in Evaluating the Efficacy of Treatment with Dasatinib.

While rodents are the primary animal models for contrast agent evaluation, rodents can potentially misrepresent human organ clearance of newly developed contrast agents. For example, gadolinium (Gd)-BOPTA has ~50% hepatic clearance in rodents, but ~5% in humans. This study demonstrates the benefit of chimeric mice expressing human hepatic OATPs (organic anion-transporting polypeptides) to improve evaluation of novel contrast agents for clinical use.

Chimeric mouse model for MRI contrast agent evaluation.

MRI-based cell tracking identifies the location of magnetically labeled cells with hypointense voxels. Here we demonstrate a strain-dependent effect of liver MRI background on the feasibility of MRI-based cell tracking of transplanted cells in the mouse liver.

Effect of mouse strain and diet on feasibility of MRI-based cell tracking in the liver.

Prophylactic mastectomy is the most effective intervention to prevent breast cancer. However, this major surgery has life-changing consequences at the physical, emotional, psychological, and social levels. Therefore, only high-risk individuals consider this aggressive procedure, which completely removes the mammary epithelial cells from which breast cancer arises along with surrounding tissue. Here, we seek to develop a minimally invasive procedure as an alternative to prophylactic mastectomy by intraductal (ID) delivery of a cell-killing solution that locally ablates the mammary epithelial cells before they become malignant.

Ductal tree ablation by local delivery of ethanol prevents tumor formation in an aggressive mouse model of breast cancer.

Here, we describe the synthesis, characterization and in vitro and in vivo performance of a series of tantalum oxide (TaO) based nanoparticles (NPs) for computed tomography (CT). Five distinct versions of 9-12 nm diameter silane coated TaO nanocrystals (NCs) were fabricated by a sol-gel method with varying degrees of hydrophilicity and with or without fluorescence, with the highest reported Ta content to date (78%). Highly hydrophilic NCs were left bare and were evaluated in vivo in mice for micro-CT of full body vasculature, where following intravenous injection, TaO NCs demonstrate high vascular CT contrast, circulation in blood for ∼3 h, and eventual accumulation in RES organs; and following injection locally in the mammary gland, where the full ductal tree structure can be clearly delineated. Partially hydrophilic NCs were encapsulated within mesoporous silica nanoparticles (MSNPs; TaO@MSNPs) and hydrophobic NCs were encapsulated within poly(lactic-co-glycolic acid) (PLGA; TaO@PLGA) NPs, serving as potential CT-imagable drug delivery vehicles. Bolus intramuscular injections of TaO@PLGA NPs and TaO@MSNPs to mimic the accumulation of NPs at a tumor site produce high signal enhancement in mice. In vitro studies on bare NCs and formulated NPs demonstrate high cytocompatibility and low dissolution of TaO. This work solidifies that TaO-based NPs are versatile contrast agents for CT.

Tantalum oxide nanoparticles as versatile contrast agents for X-ray computed tomography.

Magnetic particle imaging (MPI), using superparamagnetic nanoparticles as an imaging tracer, is touted as a quantitative biomedical imaging technology, but MPI signal properties have never been characterized for magnetic nanoparticles undergoing biodegradation. We show that MPI signal properties can increase or decrease as iron oxide nanoparticles degrade, depending on the nanoparticle formulation and nanocrystal size, and degradation rate and mechanism. Further, we show that long-term in vitro MPI experiments only roughly approximate long-term in vivo MPI signal properties. Further, we demonstrate for the first time, an environmentally sensitive MPI contrast mechanism opening the door to smart contrast paradigms in MPI.

Complex Relationship Between Iron Oxide Nanoparticle Degradation and Signal Intensity in Magnetic Particle Imaging.

Clinical effectiveness of implantable medical devices would be improved with in situ monitoring to ensure device positioning, determine subsequent damage, measure biodegradation, and follow healing. While standard clinical imaging protocols are appropriate for diagnosing disease and injury, these protocols have not been vetted for imaging devices. This study investigated how radiologists use clinical imaging to detect the location and integrity of implanted devices and whether embedding nanoparticle contrast agents into devices can improve assessment. To mimic the variety of devices available, phantoms from hydrophobic polymer films and hydrophilic gels were constructed, with and without computed tomography (CT)-visible TaO and magnetic resonance imaging (MRI)-visible FeO nanoparticles. Some phantoms were purposely damaged by nick or transection. Phantoms were implanted in vitro into tissue and imaged with clinical CT, MRI, and ultrasound. In a blinded study, radiologists independently evaluated whether phantoms were present, assessed the type, and diagnosed whether phantoms were damaged or intact. Radiologists identified the location of phantoms 80% of the time. However, without incorporated nanoparticles, radiologists correctly assessed damage in only 54% of cases. With an incorporated imaging agent, the percentage jumped to 86%. The imaging technique which was most useful to radiologists varied with the properties of phantoms. With benefits and drawbacks to all three imaging modalities, future implanted devices should be engineered for visibility in the modality which best fits the treated tissue, the implanted device's physical location, and the type of required information. Imaging protocols should also be tailored to best exploit the properties of the imaging agents.

Design Considerations to Facilitate Clinical Radiological Evaluation of Implantable Biomedical Structures.

Individual imaging modalities have certain advantages, but each suffers from drawbacks that other modalities may overcome. The goal of this study was to create a novel contrast agent suitable for various imaging modalities that after a single administration can bridge and strengthen the collaboration between the research fields as well as enrich the information obtained from any one modality.

ArticleTotal : 2	Year
Publication title Cited by 2	2022
Publication title Cited by 5	2022

Article	Year
Targeting MEK in a Translational Model of Histiocytic Sarcoma. Molecular cancer therapeutics\| PubMed ID: 30135215	2018
The mechanics of scaling-up multichannel scaffold technology for clinical nerve repair. Journal of the mechanical behavior of biomedical materials\| PubMed ID: 30597378	2019
Development of an Orthotopic Intrasplenic Xenograft Mouse Model of Canine Histiocytic Sarcoma and Its Use in Evaluating the Efficacy of Treatment with Dasatinib. Comparative medicine\| PubMed ID: 30717820	2019
Chimeric mouse model for MRI contrast agent evaluation. Magnetic resonance in medicine\| PubMed ID: 30874333	2019
Effect of mouse strain and diet on feasibility of MRI-based cell tracking in the liver. Magnetic resonance in medicine\| PubMed ID: 31765493	2020
Ductal tree ablation by local delivery of ethanol prevents tumor formation in an aggressive mouse model of breast cancer. Breast cancer research : BCR\| PubMed ID: 31779648	2019
Tantalum oxide nanoparticles as versatile contrast agents for X-ray computed tomography. Nanoscale\| PubMed ID: 32211669	2020
Complex Relationship Between Iron Oxide Nanoparticle Degradation and Signal Intensity in Magnetic Particle Imaging. ACS applied nano materials\| PubMed ID: 33163909	2020
Design Considerations to Facilitate Clinical Radiological Evaluation of Implantable Biomedical Structures. ACS biomaterials science & engineering\| PubMed ID: 33449622	2021
Omniparticle Contrast Agent for Multimodal Imaging: Synthesis and Characterization in an Animal Model. Molecular imaging and biology\| PubMed ID: 36071300	2022

Jeremy Hix

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