Pancreatic ductal adenocarcinoma (PDAC) is the most aggressive malignancy with a five year survival rate of <5%. The aberrant expression of extracellular matrix (ECM) in the tumor stroma forms a compact physical barrier, which that leads to insufficient extravasation and penetration of nanosized therapies. To overcome the severe resistance of PDAC to conventional therapies, a sequentially triggered nanoparticle (aptamer/cell-penetrating peptide-camptothecin prodrug, i.e., Apt/CPP-CPTD NPs) with tumor penetration and intelligent drug release profile is designed. An ECM component (tenescin-C) targeting aptamer (GBI-10) is modified onto stroma-permeable cell-penetrating peptide (CPP) for the in vivo CPP camouflage and PDAC-homing. In PDAC stroma, tenascin-C can detach GBI-10 from CPP and exposed CPP can facilitate further PDAC penetration and tumor cell endocytosis. After being endocytosed into PDAC cells, intracellular high redox potential can further trigger controlled chemodrug release. Apt/CPP-CPTD NPs show both deep penetration in vitro 3D PDAC spheroids and in vivo tumor sections. The relatively mild in vitro cytotoxicity and excellent in vivo antitumor efficacy proves the improved PDAC targeting drug delivery and decreased systemic toxicity. The design of ECM-redox sequentially triggered stroma permeable NPs may provide a practical approach for deep penetration of PDAC and enhanced drug delivery efficacy.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/advs.201701070

Sequentially Triggered Nanoparticles with Tumor Penetration and Intelligent Drug Release for Pancreatic Cancer Therapy

Breast cancer is among most common form of cancer worldwide. It is also the major cause of death in female cancer patient around the world. Despite various therapeutic measures, it remains associated with high mortality rate. Aegle marmelos (L.) Correa has been extensively used in Indian medicine system Ayurveda, due to its various medicinal properties. However, there are very limited reports regarding its anticancer activity. Thus, the present research work has been aimed to study the anticancer activity of Aegle marmelos fruit extract on 7,12-dimethylbenz(a)anthracene (DMBA) induced breast cancer in rats. Female Charles Foster rats, 55-60 days old weighing around (150 ± 10 g) were used for the study and were induced DMBA (20 mg/mL dissolved in Olive oil) orally. After the development of breast tumors (about 0.5 cm), the rats were treated with Aegle marmelos ethanolic fruit pulp extract (200 mg/kg b.w./day) orally for 5 weeks and then volume of tumor was measured. Aegle marmelos treatment showed significantly reduced mammary tumor volume (P < 0.05), along with significant reduction (P < 0.0001) in the different serum biomarkers such as TNF-α level, serum malondialdehyde (MDA) level and glucose levels. Significant (P < 0.0001) improvement in both, the kidney and liver serum biomarker parameters were also observed after the treatment with Aegle marmelos ethanolic fruit pulp extract. From the entire study, taking everything into account it can be interpreted that Aegle marmelos ethanolic fruit pulp extract possesses anti-proliferative activity by suppressing the progression of breast tumors in rat model. The plant extract also possesses hepato-renal protective effect. Hence, it can be targeted as novel and safe anti-cancer drug against breast cancer.

/pdf/therapeutic-effect-of-aegle-marmelos-fruit-extract-against-2876lz9gg3.pdf

Therapeutic effect of Aegle marmelos fruit extract against DMBA induced breast cancer in rats.

// Yuling Yan 1,2 , Xilin Sun 1,2,3 and Baozhong Shen 1,2 1 Molecular Imaging Research Center (MIRC), Harbin Medical University, Harbin, Heilongjiang, China 2 TOF-PET/CT/MR Center, The Fourth Hospital of Harbin Medical University, Harbin, Heilongjiang, China 3 Molecular Imaging Program at Stanford (MIPS), Department of Radiology, Stanford University School of Medicine, Stanford, California, USA Correspondence to: Baozhong Shen, email: // Xilin Sun, email: // Keywords : DCE-MRI, contrast agent, macromolecular contrast agent, nanoparticle, low molecular contrast agent Received : January 07, 2017 Accepted : March 15, 2017 Published : March 22, 2017 Abstract Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is a noninvasive method to assess angiogenesis, which is widely used in clinical applications including diagnosis, monitoring therapy response and prognosis estimation in cancer patients. Contrast agents play a crucial role in DCE-MRI and should be carefully selected in order to improve accuracy in DCE-MRI examination. Over the past decades, there was much progress in the development of optimal contrast agents in DCE-MRI. In this review, we describe the recent research advances in this field and discuss properties of contrast agents, as well as their advantages and disadvantages. Finally, we discuss the research perspectives for improving this promising imaging method.

/pdf/contrast-agents-in-dynamic-contrast-enhanced-magnetic-1qh4l2i7hp.pdf

Contrast agents in dynamic contrast-enhanced magnetic resonance imaging

In animal models of cancer, oncologic imaging has evolved from a simple assessment of tumor location and size to sophisticated multimodality exploration of molecular, physiologic, genetic, immunologic, and biochemical events at microscopic to macroscopic levels, performed noninvasively and sometimes in real time. Here, we briefly review animal imaging technology and molecular imaging probes together with selected applications from recent literature. Fast and sensitive optical imaging is primarily used to track luciferase-expressing tumor cells, image molecular targets with fluorescence probes, and to report on metabolic and physiologic phenotypes using smart switchable luminescent probes. MicroPET/single-photon emission CT have proven to be two of the most translational modalities for molecular and metabolic imaging of cancers: immuno-PET is a promising and rapidly evolving area of imaging research. Sophisticated MRI techniques provide high-resolution images of small metastases, tumor inflammation, perfusion, oxygenation, and acidity. Disseminated tumors to the bone and lung are easily detected by microCT, while ultrasound provides real-time visualization of tumor vasculature and perfusion. Recently available photoacoustic imaging provides real-time evaluation of vascular patency, oxygenation, and nanoparticle distributions. New hybrid instruments, such as PET-MRI, promise more convenient combination of the capabilities of each modality, enabling enhanced research efficacy and throughput.

Preclinical Applications of Multi-Platform Imaging in Animal Models of Cancer

The purpose of this work was to determine the relationship between the apparent diffusion coefficient (ADC, from diffusion-weighted (DW) MRI), the extravascular, extracellular volume fraction (ve , from dynamic contrast-enhanced (DCE) MRI), and histological measurement of the extracellular space fraction. Athymic nude mice were injected with either human epidermal growth factor receptor 2 positive (HER2+) BT474 (n = 15) or triple negative MDA-MB-231 (n = 20) breast cancer cells, treated with either Herceptin (n = 8), Abraxane (low dose n = 7, high dose n = 6), or saline (n = 7 for each cell line), and imaged using DW- and DCE-MRI before, during, and after treatment. After the final imaging acquisition, the tissue was resected and evaluated by histological analysis. H&E-stained central slices were scanned using a digital brightfield microscope and evaluated with thresholding techniques to calculate the extracellular space. For both BT474 and MDA-MB-231, the median ADC of the central slice exhibited a significantly positive correlation with the corresponding central slice extracellular space as measured by H&E (p = 0.03, p 0.05). While ADC correlates well with the histologically determined fraction of extracellular space, these data add to the growing body of literature that suggests that ve derived from DCE-MRI is not a reliable biomarker of extracellular space for a range of physiological conditions.

/pdf/correlation-of-tumor-characteristics-derived-from-dce-mri-3o5twxfdcs.pdf

Correlation of tumor characteristics derived from DCE-MRI and DW-MRI with histology in murine models of breast cancer.

Dynamic contrast-enhanced (DCE) MRI assessment of microvascular characteristics in the murine orthotopic pancreatic cancer model

The aim of this study was to successfully establish an orthotopic murine model using two different human pancreatic adenocarcinoma cell lines and to propose a 3.0 tesla MRI protocol for noninvasive characterization of this model. SW1990 and MIAPaca-2 tumor cells were injected into the pancreas of BALB/C nu/nu mice. Tumor growth rate and morphological information were assessed by 3.0 tesla MRI (T1WI, T2WI and DCE-MRI) and immunohistology. Proliferation of SW1990 was significantly faster than that of MIAPaca-2 (P=0.000), but MIAPaca-2 mice had a significantly shorter survival than SW1990 mice (41 days and 44 days respectively, P=0.027). MRI could reliably monitor tumor growth in both cell lines: the tumors exhibiting a spherical growth pattern showed a high-intensity signal, and the SW1990 group developed significantly larger tumors compared with the MIAPaCa-2 group. There were no statistical differences between the two groups in which tumor size was assessed using electronic calipers and an MRI scan (P=0.680). Both tumors showed a slow gradual enhancement pattern. Immunohistochemistry demonstrated tumor tissues showing high expression of Ki-67. This model closely mimics human pancreatic cancer and permits monitoring of tumor growth and morphological information by noninvasive 3.0 tesla MRI studies reducing the number of mice required.

Application of 3.0 tesla magnetic resonance imaging for diagnosis in the orthotopic nude mouse model of pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human malignancies, with a poor long-term prognosis, and effective therapeutic options are lacking. Observing the dynamics of the pathogenesis of pancreatic intraepithelial neoplasia (PanIN) and PDAC in tumor models can facilitate understanding of the molecular mechanisms involved in early PDAC. Furthermore, it can compensate for the research limitations associated with analyzing clinical specimens of late-stage PDAC. In this study, we orthotopically treated the pancreas with dimethylbenzanthracene (DMBA) combined with caerulein in wild-type C57BL/6 J mice to induce inflammation-related pancreatic carcinogenesis. We observed that DMBA and caerulein treatment induced a chronic consumptive disease, which caused a decrease in the relative body and pancreas weights, diminishing the health status of the mice and enhancing the inflammation-related histological changes. Moreover, mid-dose and high-frequency treatment with caerulein caused prolonged inflammatory damage to the pancreas and contributed to a permissive environment for the development of PDAC. CXCL12/CXCR4, CCL2/CCR2, and several cytokines, such as interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α were upregulated in the tumor tissue of DMBA and caerulein-induced PDAC mice. This orthotopic mouse pancreatic carcinogenesis model mimic human disease because it reproduces a spectrum of pathological changes observed in human PDAC, ranging from inflammatory lesions to pancreatic intraepithelial neoplasia. Thus, this mouse model may improve the understanding of molecular mechanisms underlying the injury-inflammation-cancer pathway in the early stages of pancreatic carcinogenesis.

Orthotopic inflammation-related pancreatic carcinogenesis in a wild-type mouse induced by combined application of caerulein and dimethylbenzanthracene

To investigate the value of using diffusion-weighted imaging (DWI) and intravoxel incoherent motion DWI (IVIM-DWI) to assess the chemotherapy response of pancreatic cancer in an orthotopic mouse model. Twenty-four BALB/C nu/nu mice in two groups (n = 12/group) with human pancreatic adenocarcinoma xenografts were dosed intravenously with saline (group 1) and gemcitabine (group 2). DWI with 3 b values (b = 50, 400 and 800 s/mm2) and IVIM-DWI with multiple b values (b = 0, 25, 50, 80, 100, 300, 500, 800 s/mm2) were performed on the day before and 1 and 10 days after the treatment. Regions of interest (ROI) were drawn and tumor ADC, Dslow, Dfast and fp values derived from the DWI and IVIM-DWI were compared between the two groups. At the day 28 after the treatment, the tumors were harvested for histologic analyses. The values of ADC and Dslow in the entire tumor region were significantly increased in gemcitabine-treated group in contrast to saline-untreated group at day 1 (1.88 ± 0.34 × 10−3 s/mm2 vs 1.45 ± 0.16 × 10−3 s/mm2, P = 0.028, and 1.74 ± 0.29 × 10−3 s/mm2 vs 1.34 ± 0.26 × 10−3 s/mm2, P =0.030), but Dfast and fp values were not significantly different. Immunohistochemical results showed that cell proliferation was significantly reduced (P < 0.001) and cell apoptosis (P < 0.001) significantly increased in gemcitabine group compared to saline group. MVD was not significantly different. Both ADC value and Dslow value can be used as early imaging marker to assess the early chemotherapy response of pancreatic cancer.

Chemotherapy response of pancreatic cancer by diffusion-weighted imaging (DWI) and intravoxel incoherent motion DWI (IVIM-DWI) in an orthotopic mouse model.

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Dynamic contrast-enhanced (DCE) MRI assessment of microvascular characteristics in the murine orthotopic pancreatic cancer model

Application of 3.0 tesla magnetic resonance imaging for diagnosis in the orthotopic nude mouse model of pancreatic cancer.

Orthotopic inflammation-related pancreatic carcinogenesis in a wild-type mouse induced by combined application of caerulein and dimethylbenzanthracene

Chemotherapy response of pancreatic cancer by diffusion-weighted imaging (DWI) and intravoxel incoherent motion DWI (IVIM-DWI) in an orthotopic mouse model.