This study reports a three-dimensional compaction printing (3DCP) technique for a continuous carbon fiber reinforced thermoplastic (CFRTP). A hot-compaction roller was equipped with a fused filament ...fabrication (FFF)-based 3D printer to press the filament against the printer bed immediately after the printing to reduce voids and improve adhesion between the filaments. Unidirectional CFRTP coupon specimens were fabricated and the tensile and bending properties of the specimens were investigated. The test results showed that the tensile and bending properties of the printed CFRTP were improved by the hot compaction during 3D printing. Voids in the specimen were visualized using scanning electron microscopy and X-ray computed tomography, and it was confirmed that the hot compaction reduced the void content. The experimental results showed that 3DCP was superior to conventional FFF in the fabrication of CFRTP parts for structural applications.
Abstract
Metabolic reprogramming is one of the defining features of cancer and abnormal metabolism is associated with many other pathologies. Molecular imaging techniques capable of detecting such ...changes have become essential for cancer diagnosis, treatment planning, and surveillance. In particular,
18
F-FDG (fluorodeoxyglucose) PET has emerged as an essential imaging modality for cancer because of its unique ability to detect a disturbed molecular pathway through measurements of glucose uptake. However, FDG-PET has limitations that restrict its usefulness in certain situations and the information gained is limited to glucose uptake only.
13
C magnetic resonance spectroscopy theoretically has certain advantages over FDG-PET, but its inherent low sensitivity has restricted its use mostly to single voxel measurements unless dissolution dynamic nuclear polarization (dDNP) is used to increase the signal, which brings additional complications for clinical use. We show here a new method of imaging glucose metabolism
in vivo
by MRI chemical shift imaging (CSI) experiments that relies on a simple, but robust and efficient, post-processing procedure by the higher dimensional analog of singular value decomposition, tensor decomposition. Using this procedure, we achieve an order of magnitude increase in signal to noise in both dDNP and non-hyperpolarized non-localized experiments without sacrificing accuracy. In CSI experiments an approximately 30-fold increase was observed, enough that the glucose to lactate conversion indicative of the Warburg effect can be imaged without hyper-polarization with a time resolution of 12s and an overall spatial resolution that compares favorably to
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F-FDG PET.
Immune checkpoint blockade (ICB) has become a standard therapy for several cancers, however, the response to ICB is inconsistent and a method for noninvasive assessment has not been established to ...date. To investigate the capability of multimodal imaging to evaluate treatment response to ICB therapy, hyperpolarized
C MRI using 1-
C pyruvate and 1,4-
C2 fumarate and dynamic contrast enhanced (DCE) MRI was evaluated to detect early changes in tumor glycolysis, necrosis, and intratumor perfusion/permeability, respectively. Mouse tumor models served as platforms for high (MC38 colon adenocarcinoma) and low (B16-F10 melanoma) sensitivity to dual ICB of PD-L1 and CTLA4. Glycolytic flux significantly decreased following treatment only in the less sensitive B16-F10 tumors. Imaging 1,4-
C2 fumarate conversion to 1,4-
C2 malate showed a significant increase in necrotic cell death following treatment in the ICB-sensitive MC38 tumors, with essentially no change in B16-F10 tumors. DCE-MRI showed significantly increased perfusion/permeability in MC38-treated tumors, whereas a similar, but statistically nonsignificant, trend was observed in B16-F10 tumors. When tumor volume was also taken into consideration, each imaging biomarker was linearly correlated with future survival in both models. These results suggest that hyperpolarized
C MRI and DCE MRI may serve as useful noninvasive imaging markers to detect early response to ICB therapy. SIGNIFICANCE: Hyperpolarized
C MRI and dynamic contrast enhanced MRI in murine tumor models provide useful insight into evaluating early response to immune checkpoint blockade therapy.
.
In hypoxic tumor microenvironments, the strongly reducing redox environment reduces evofosfamide (TH-302) to release a cytotoxic bromo-isophosphoramide (Br-IPM) moiety. This drug therefore ...preferentially attacks hypoxic regions in tumors where other standard anticancer treatments such as chemotherapy and radiation therapy are often ineffective. Various combination therapies with evofosfamide have been proposed and tested in preclinical and clinical settings. However, the treatment effect of evofosfamide monotherapy on tumor hypoxia has not been fully understood, partly due to the lack of quantitative methods to assess tumor pO
. Here, we use quantitative pO
imaging by electron paramagnetic resonance (EPR) to evaluate the change in tumor hypoxia in response to evofosfamide treatment using two pancreatic ductal adenocarcinoma xenograft models: MIA Paca-2 tumors responding to evofosfamide and Su.86.86 tumors that do not respond.
EPR imaging showed that oxygenation improved globally after evofosfamide treatment in hypoxic MIA Paca-2 tumors, in agreement with the
results obtained from hypoxia staining by pimonidazole and in apparent contrast to the decrease in K
observed in dynamic contrast-enhanced magnetic resonance imaging (DCE MRI).
The observation that evofosfamide not only kills the hypoxic region of the tumor but also improves oxygenation in the residual tumor regions provides a rationale for combination therapies using radiation and antiproliferatives post evofosfamide for improved outcomes.
This study suggests that reoxygenation after evofosfamide treatment is due to decreased oxygen demand rather than improved perfusion. Following the change in pO
after treatment may therefore yield a way of monitoring treatment response.
. 35, 904-915.
Pancreatic ductal adenocarcinoma (PDAC) is characterized by hypoxic niches that lead to treatment resistance. Therefore, studies of tumor oxygenation and metabolic profiling should contribute to ...improved treatment strategies. Here, we define two imaging biomarkers that predict differences in tumor response to therapy: (i) partial oxygen pressure (pO
), measured by EPR imaging; and (ii) 1-
C pyruvate metabolism rate, measured by hyperpolarized
C MRI. Three human PDAC xenografts with varying treatment sensitivity (Hs766t, MiaPaCa2, and Su.86.86) were grown in mice. The median pO
of the mature Hs766t, MiaPaCa2, and Su.86.86 tumors was 9.1 ± 1.7, 11.1 ± 2.2, and 17.6 ± 2.6 mm Hg, and the rate of pyruvate-to-lactate conversion was 2.72 ± 0.48, 2.28 ± 0.26, and 1.98 ± 0.51 per minute, respectively (
= 6, each). These results are in agreement with steady-state data of matabolites quantified by mass spectroscopy and histologic analysis, indicating glycolytic and hypoxia profile in Hs766t, MiaPaca2, and Su.86.86 tumors. Fractionated radiotherapy (5 Gy × 5) resulted in a tumor growth delay of 16.7 ± 1.6 and 18.0 ± 2.7 days in MiaPaca2 and Su.86.86 tumors, respectively, compared with 6.3 ± 2.7 days in hypoxic Hs766t tumors. Treatment with gemcitabine, a first-line chemotherapeutic agent, or the hypoxia-activated prodrug TH-302 was more effective against Hs766t tumors (20.0 ± 3.5 and 25.0 ± 7.7 days increase in survival time, respectively) than MiaPaCa2 (2.7 ± 0.4 and 6.7 ± 0.7 days) and Su.86.86 (4.7 ± 0.6 and 0.7 ± 0.6 days) tumors. Collectively, these results demonstrate the ability of molecular imaging biomarkers to predict the response of PDAC to treatment with radiotherapy and TH-302.
pO2 imaging data and clinically available metabolic imaging data provide useful insight into predicting the treatment efficacy of chemotherapy, radiation, and a hypoxia-activated prodrug as monotherapies and combination therapies in PDAC tumor xenograft models.
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Proton-electron double-resonance imaging (PEDRI) employs electron paramagnetic resonance irradiation with low-field magnetic resonance imaging so that the electron spin polarization is transferred to ...nearby protons, resulting in higher signals. PEDRI provides information about free radical distribution and, indirectly, about the local microenvironment such as partial pressure of oxygen (pO
), tissue permeability, redox status, and acid-base balance. Recent Advances: Local acid-base balance can be imaged by exploiting the different resonance frequency of radical probes between R and RH
forms. Redox status can also be imaged by using the loss of radical-related signal after reduction. These methods require optimized radical probes and pulse sequences.
High-power radio frequency irradiation is needed for optimum signal enhancement, which may be harmful to living tissue by unwanted heat deposition. Free radical probes differ depending on the purpose of PEDRI. Some probes are less effective for enhancing signal than others, which can reduce image quality. It is so far not possible to image endogenous radicals by PEDRI because low concentrations and broad line widths of the radicals lead to negligible signal enhancement.
PEDRI has similarities with electron paramagnetic resonance imaging (EPRI) because both techniques observe the EPR signal, directly in the case of EPRI and indirectly with PEDRI. PEDRI provides information that is vital to research on homeostasis, development of diseases, or treatment responses in vivo. It is expected that the development of new EPR techniques will give insights into novel PEDRI applications and vice versa. Antioxid. Redox Signal. 28, 1345-1364.
Molecular imaging approaches for metabolic and physiologic imaging of tumors have become important for treatment planning and response monitoring. However, the relationship between the physiologic ...and metabolic aspects of tumors is not fully understood. Here, we developed new hyperpolarized MRI and electron paramagnetic resonance imaging procedures that allow more direct assessment of tumor glycolysis and oxygenation status quantitatively. We investigated the spatial relationship between hypoxia, glucose uptake, and glycolysis in three human pancreatic ductal adenocarcinoma tumor xenografts with differing physiologic and metabolic characteristics. At the bulk tumor level, there was a strong positive correlation between
F-FDG-PET and lactate production, while pO
was inversely related to lactate production and
F-2-fluoro-2-deoxy-D-glucose (
F-FDG) uptake. However, metabolism was not uniform throughout the tumors, and the whole tumor results masked different localizations that became apparent while imaging.
F-FDG uptake negatively correlated with pO
in the center of the tumor and positively correlated with pO
on the periphery. In contrast to pO
and
F-FDG uptake, lactate dehydrogenase activity was distributed relatively evenly throughout the tumor. The heterogeneity revealed by each measure suggests a multimodal molecular imaging approach can improve tumor characterization, potentially leading to better prognostics in cancer treatment. SIGNIFICANCE: Novel multimodal molecular imaging techniques reveal the potential of three interrelated imaging biomarkers to profile the tumor microenvironment and interrelationships of hypoxia, glucose uptake, and glycolysis.
PEGylated human hyaluronidase (PEGPH20) enzymatically depletes hyaluronan, an important component of the extracellular matrix, increasing the delivery of therapeutic molecules. Combinations of ...chemotherapy and PEGPH20, however, have been unsuccessful in Phase III clinical trials. We hypothesize that by increasing tumor oxygenation by improving vascular patency and perfusion, PEGPH20 will also act as a radiosensitization agent.
The effect of PEGPH20 on radiation treatment was analyzed with respect to tumor growth, survival time, p02, local blood volume, and the perfusion/permeability of blood vessels in a human pancreatic adenocarcinoma BxPC3 mouse model overexpressing hyaluronan synthase 3 (HAS3).
Mice overexpressing HAS3 developed fast growing, radiation resistant tumors that became rapidly more hypoxic as time progressed. Treatment with PEGPH20 increased survival times when used in combination with radiation therapy, significantly more than either radiation therapy or PEGPH20 alone. In mice that overexpressed HAS3, EPR imaging showed an increase in local pO2 that could be linked to increases in perfusion/permeability and local blood volume immediately after PEGPH20 treatment. Hyperpolarized 1-13C pyruvate suggested PEGPH20 caused a metabolic shift towards decreased glycolytic flux. These effects were confined to the mice overexpressing HAS3 - no effect of PEGPH20 on survival, radiation treatment, or pO2 was seen in wild type BxPC3 tumors.
PEGPH20 may be useful for radiosensitization of pancreatic cancer but only in the subset of tumors with substantial hyaluronan accumulation. The response of the treatment may potentially be monitored by non-invasive imaging of the hemodynamic and metabolic changes in the tumor microenvironment.
Magnetic resonance‐based approaches to obtain metabolic information on cancer have been explored for decades. Electron paramagnetic resonance (EPR) has been developed to pursue metabolic profiling ...and successfully used to monitor several physiologic parameters such as pO2, pH, and redox status. All these parameters are associated with pathophysiology of various diseases. Especially in oncology, cancer hypoxia has been intensively studied because of its relationship with metabolic alterations, acquiring treatment resistance, or a malignant phenotype. Thus, pO2 imaging leads to an indirect metabolic assessment in this regard. Proton electron double‐resonance imaging (PEDRI) is an imaging technique to visualize EPR by using the Overhauser effect. Most biological parameters assessed in EPR can be visualized using PEDRI. However, EPR and PEDRI have not been evaluated sufficiently for clinical application due to limitations such as toxicity of the probes or high specific absorption rate. Hyperpolarized (HP) 13C MRI is a novel imaging technique that can directly visualize the metabolic profile. Production of metabolites of the HP 13C probe delivered to target tissue are evaluated in this modality. Unlike EPR or PEDRI, which require the injection of radical probes, 13C MRI requires a probe that can be physiologically metabolized and efficiently hyperpolarized. Among several methods for hyperpolarizing probes, dissolution dynamic nuclear hyperpolarization is a widely used technique for in vivo imaging. Pyruvate is the most suitable probe for HP 13C MRI because it is part of the glycolytic pathway and the high efficiency of pyruvate‐to‐lactate conversion is a distinguishing feature of cancer. Its clinical applicability also makes it a promising metabolic imaging modality. Here, we summarize the applications of these indirect and direct MR‐based metabolic assessments focusing on pO2 and pyruvate‐to‐lactate conversion. The two parameters are strongly associated with each other, hence the acquired information is potentially interchangeable when evaluating treatment response to oxygen‐dependent cancer therapies.
Electron paramagnetic resonance and proton electron double‐resonance imaging have been developed to pursue metabolic profiling and successfully used to monitor pO2 in cancerous tissue in animal models. On the other hand, hyperpolarized 13C MRI has been developed to visualize the activity of the glycolytic pathway and has been brought into the clinic. In this review, we summarize the applications of these MR‐based metabolic imaging methods, focusing on pO2 and pyruvate‐to‐lactate conversion, which are strongly associated with each other.
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