Magnetization transfer MRI in pancreatic cancer xenograft models

Li, Weiguo; Zhang, Zhuoli; Nicolai, J.; Yang, Guang; Omary, Reed A.; Larson, Andrew C.

doi:10.1002/mrm.24127

Cited by 33 publications

(51 citation statements)

References 36 publications

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“…Tumor perfusion can be characterized noninvasively by MRI, via application of DCE-MRI (34)(35)(36)(37). The DCE data indicating higher permeability supports the histologic analysis of perfusion and the IFP data: 3 days following Cellax treatment, the tumor vessel permeability in the core of tumors (K trans ) was significantly increased compared with other therapies (Fig.…”

Section: Discussionsupporting

confidence: 66%

Docetaxel Conjugate Nanoparticles That Target α-Smooth Muscle Actin–Expressing Stromal Cells Suppress Breast Cancer Metastasis

et al. 2013

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Docetaxel-conjugate nanoparticles, known as Cellax, were synthesized by covalently conjugating docetaxel and polyethylene glycol to acetylated carboxymethylcellulose via ester linkages, yielding a polymeric conjugate that self-assembled into 120 nm particles suitable for intravenous administration. In 4T1 and MDA-MB-231 orthotopic breast tumor models, Cellax therapy reduced a-smooth muscle actin (a-SMA) content by 82% and 70%, respectively, whereas native docetaxel and nab-paclitaxel (albumin-paclitaxel nanoparticle, Abraxane) exerted no significant antistromal activity. In Cellax-treated mice, tumor perfusion was increased by approximately 70-fold (FITC-lectin binding), tumor vascular permeability was enhanced by more than 30% (dynamic contrast-enhanced magnetic resonance imaging), tumor matrix was decreased by 2.5-fold (immunohistochemistry), and tumor interstitial fluid pressure was suppressed by approximately 3-fold after Cellax therapy compared with the control, native docetaxel, and nab-paclitaxel groups. The antistromal effect of Cellax treatment corresponded to a significantly enhanced antimetastatic effect: lung nodules were reduced by 7-to 24-fold by Cellax treatment, whereas native docetaxel and nab-paclitaxel treatments were ineffective. Studies of the 4T1 tumor showed that more than 85% of the Cellax nanoparticles were delivered to the a-SMAþ stroma. Significant tumor stromal depletion occurred within 16 hours ($50% depletion) postinjection, and the a-SMAþ stroma population was almost undetectable ($3%) by 1 week. The 4T1 tumor epithelial cell population was not significantly reduced in the week after Cellax injection. These data suggest that Cellax targets tumor stroma and performs more efficaciously than docetaxel and nabpaclitaxel. Cancer Res; 73(15); 4862-71. Ó2013 AACR.

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Section: Discussionsupporting

confidence: 66%

Docetaxel Conjugate Nanoparticles That Target α-Smooth Muscle Actin–Expressing Stromal Cells Suppress Breast Cancer Metastasis

et al. 2013

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“…The initially higher MT values at day 1 are probably due to the high collagen content used for injection of the hMPCs. This is supported by previous work on monitoring of intestinal fibrosis of Crohn disease (27), as well as a study on pancreatic cancer xenografts (28), which demonstrated a correlation of collagen content and high MTR values. The decrease of MT values from day 1 to day 3 is likely due to initial remodeling and degradation of the injected collagen, and only after day 3 do changes in MT values reflect the process of muscle fiber formation from injected hMPCs.…”

Section: Injected Hmpcs Form Functional Muscle Tissuesupporting

confidence: 78%

Magnetization Transfer MR Imaging to Monitor Muscle Tissue Formation during Myogenic in Vivo Differentiation of Muscle Precursor Cells

Rottmar¹,

Haralampieva²,

Salemi³

et al. 2016

Radiology

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Purpose To determine whether magnetization transfer (MT) magnetic resonance (MR) imaging may serve as a quantitative measure of the degree of fiber formation during differentiation of muscle precursor cells into engineered muscle tissue as a potential noninvasive monitoring tool in mice. Materials and Methods The study was approved by the local ethics committee (no. StV 01/2008) and the local Veterinary Office (license no. 99/2013). Human muscle progenitor cells (hMPCs) derived from rectus abdominis muscles were subcutaneously injected into CD-1 nude mice (CD-1 nude mice, Crl:CD1-Foxn1(nu); Charles River Laboratories, Wilmington, Mass) for development of muscle tissue. The mice underwent MR imaging examinations at 4.7 T at days 1, 3, 7, 14, 21, and 28 after cell transplantation by using a gradient-echo sequence with an MT prepulse and systematic variation of the off-resonance frequency (50-37 500 Hz) at an amplitude of 800°. Direct saturation was estimated from a Bloch equation simulation. The MT ratio (MTR) was correlated to immunohistochemistry findings, Western blot results, and results of myography. Data were analyzed by using one-way or two-way analysis of variance with the Sidak or Tukey multiple comparisons test. Results In the reference skeletal muscle, highest MT was found for 2500 Hz off-resonance frequency with an MTR ± standard deviation of 57.5% ± 3.5. The developing muscle tissue exhibited increasing MT values during the 28 days of myogenic in vivo differentiation and did not reach the values of native skeletal muscle. Mean values of MTR (2500 Hz) for hMPCs were 27.6% ± 6.3 (day 1), 24.7% ± 8.7 (day 3), 28.2% ± 5.7 (day 7), 35.9% ± 5.0 (day 14), 37.0% ± 7.9 (day 21), and 39.9% ± 8.1 (day 28). The results from MT MR imaging correlated qualitatively well with muscle tissue expression of specific skeletal markers, as well as muscle contractility. Conclusion MT MR imaging may be used to noninvasively monitor the process of myogenic in vivo differentiation of hMPCs as a biomarker of the quantity and quality of muscle fiber formation.

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“…23 No significant difference in the longitudinal assessment of magnetization transfer ratio (MTR) signal between vehicle versus monotherapy or the combination treatment in PKT mice was seen despite a slower rate of tumor growth (Figure 5 D , E and F ). Contrary to our expectations, treatment with AZD1480 and gemcitabine did not deplete collagen or hyaluronan content despite the decrease in tumor size, decreased expression of the stromal effector SPARC and enhanced drug delivery to the tumor.…”

Section: Resultsmentioning

confidence: 97%

Signal Transducer and Activator of Transcription 3, Mediated Remodeling of the Tumor Microenvironment Results in Enhanced Tumor Drug Delivery in a Mouse Model of Pancreatic Cancer

et al. 2015

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BACKGROUND & AIMS A hallmark of pancreatic ductal adenocarcinoma (PDAC) is the presence of a dense desmoplastic reaction (stroma) that impedes drug delivery to the tumor. Attempts to deplete the tumor stroma have resulted in formation of more aggressive tumors. We have identified STAT3 as a biomarker of resistance to cytotoxic and molecularly targeted therapy in PDAC. The purpose of this study is to investigate the effects of targeting STAT3 on the PDAC stroma and on therapeutic resistance. METHODS Activated STAT3 protein expression was determined in human pancreatic tissues and tumor cell lines. In vivo effects of AZD1480, a JAK/STAT3 inhibitor, gemcitabine or the combination were determined in Ptf1acre/+;LSL-KrasG12D/+;Tgfbr2flox/flox (PKT) mice and in orthotopic tumor xenografts. Drug delivery was analyzed by MALDI-imaging mass spectrometry. Collagen second harmonic generation (SHG) imaging quantified tumor collagen alignment and density. RESULTS STAT3 activation correlates with decreased survival and advanced tumor stage in patients with PDAC. STAT3 inhibition combined with gemcitabine significantly inhibits tumor growth in both an orthotopic and the PKT mouse model of PDAC. This combined therapy attenuates in vivo expression of SPARC, increases microvessel density and enhances drug delivery to the tumor without depletion of stromal collagen or hyaluronan. Instead, the PDAC tumors demonstrate vascular normalization, remodeling of the tumor stroma and downregulation of cytidine deaminase (Cda). CONCLUSIONS Targeted inhibition of STAT3 combined with gemcitabine enhances in vivo drug delivery and therapeutic response in PDAC. These effects occur through tumor stromal remodeling and downregulation of Cda without depletion of tumor stromal content.

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Magnetization transfer MRI in pancreatic cancer xenograft models

Cited by 33 publications

References 36 publications

Docetaxel Conjugate Nanoparticles That Target α-Smooth Muscle Actin–Expressing Stromal Cells Suppress Breast Cancer Metastasis

Docetaxel Conjugate Nanoparticles That Target α-Smooth Muscle Actin–Expressing Stromal Cells Suppress Breast Cancer Metastasis

Magnetization Transfer MR Imaging to Monitor Muscle Tissue Formation during Myogenic in Vivo Differentiation of Muscle Precursor Cells

Signal Transducer and Activator of Transcription 3, Mediated Remodeling of the Tumor Microenvironment Results in Enhanced Tumor Drug Delivery in a Mouse Model of Pancreatic Cancer

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