The passage of nano-drug delivery systems（nanoDDS） through the tumor tissue, after extravasation via the enhanced permeability and retention（EPR） effect, is often hindered by the presence of various stromal barriers. These barriers are formed by the complex interaction of tumor cells and various “normal” stromal cells within the tumor microenvironment. In particular, fibrotic elements within the tumor microenvironment, mainly comprising fibroblasts that have acquired abnormal phenotypes and the abundant extracellular matrix components that these cells secrete, constitute a formidable barrier to nanoDDS delivery. While targeting fibrosis is considered a promising strategy, the heterogeneity of fibroblasts and the complex functional consequences of fibrosis on tumor progression and therapeutic response have rendered the establishment of anti-fibrotic treatment strategies especially difficult. In this review, we provide a general overview of our current understanding of the fibrotic elements within the tumor microenvironment and discuss implications toward establishing a more efficacious nanoDDS treatment strategy.

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RNA signaling pathways are transduced via microvesicles or exosomes in cellular population. Wide varieties of RNA such as mRNA, microRNA, circular RNA, and long non-coding RNA play different roles in the signaling pathways. Treatment-resistant cancer has properties such as epithelial-mesenchymal transition（EMT） or cancer stem cells（CSCs）, and signaling pathways mediated by microRNAs in exosomes alter corresponding to the surrounding environment in cancer metastasis. In this review, RNA signaling pathway in cellular population via exosome is focused.

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Spheroids have attracted much attention in medical research as a tool to understand both disease mechanisms and drug actions in culture. Cell-cell and/or cell-extracellular matrices interactions seen in spheroids allow cells to mimic in vivo cellular microenvironments, resulting in recapitulating in vivo-like cell functions in culture. However, the microenvironments could also function as a barrier to deliver drugs to cells in spheroids. To tackle this drawback, a sulfobetaine polymer was developed as a spheroid-permeable polymer. In this article, the enhanced anticancer activity of anticancer drugs by conjugation with the spheroid-permeable polymer was introduced.

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In preclinical studies for cancer drug discovery, cancer models including 2D-cell culture models and animal models have been used. However, 2D-cell culture models lack the structural and functional properties derived from 3D-structure of cancer tissues, and animal models have issues such as species differences between humans and animals, immune function, high-throughput, producibility, and real-time pharmacokinetic evaluation. In fact, the probability that drug candidate administered to a cancer patient is approved is about 5%, which is lower than that of other drugs, and there is a large gap between non-clinical and clinical trials. In order to clarify the nature of cancer and to create new therapeutic intervention, it is necessary to develop a cancer model that reproduces such heterogeneity of cancer and to analyze the response to drugs. In vitro 3D-cancer models composed of human cells have great potential as a new cancer model. The paradigm shift from 2D to 3D culture models has led to significant progress in the study of 3D in vitro cancer models. To construct such 3D in vitro cancer models, it is important to develop biomaterials that can serve as scaffolds for cancer. Here, we will introduce the role of biomaterials for the construction of in vitro models of cancer microenvironment. By utilizing biomaterials, we will obtain in vitro models of the cancer microenvironment with stromal cells which can reproduce in vivo-like cell functions and drug responses, instead of the conventional in vitro cancer model that focuses only on cancer cells. The in vitro model of cancer microenvironment can be used as a drug evaluation model for drug screening, and also contribute to biomarker discovery and the realization of personalized medicine. By using a co-culture model that incorporates not only patient-derived cancer cells but also patient-derived immune cells, it is expected to be possible to construct a personalized in vitro model for cancer immunity.

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For the development of DDS for cancer therapy and diagnosis, it is important to visualize and evaluate the characterization and alteration of the cancer microenvironment in vivo. MRI has been widely used in clinical applications, providing high spatial resolution, excellent soft tissue contrast, and many kinds of functional imaging. MRI can provide important information for DDS development and its clinical application. In this paper, I will outline （1）in vivo imaging methods for the evaluation of the cancer microenvironment. I will also summarize trends in （2）what DDS can bring to MRI diagnosis and research, （3）MRI contrast agents and imaging methods for evaluating the tumor microenvironment, and （4）the role of MRI in addressing the challenges of DDS.

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Advances in imaging technology have enabled observation of various biological phenomena at the nanoscale resolution, which was previously not possible. However, extracting useful information from such images to understand various phenomena is becoming increasingly difficult because of the complexity and large amount of data involved. Numerous computational techniques, such as classic signal processing filters using image processing software, and segmentation of region of interest using machine learning, have been proposed for image analysis. Thus, selecting an appropriate method according to research goals is critical. In this paper, we briefly review our image analysis methods and their related techniques applied for analysis of cell population and intracellular images acquired by the latest imaging technology. Our image analysis methods include noise reduction, dynamic analysis of cell population and microtubules, segmentation of cytoplasmic membrane, and cell division event detection.

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