Abstract Nanomedicine has emerged as a promising therapeutic approach, but its translation to the clinic has been hindered by the lack of cellular models to anticipate how tumor cells will respond to therapy. Three-dimensional (3D) cell culture models are thought to more accurately recapitulate key features of primary tumors than two-dimensional (2D) cultures. Heterotypic 3D tumor spheroids, composed of multiple cell types, have become more popular than homotypic spheroids, which consist of a single cell type, as a superior model for mimicking in vivo tumor heterogeneity and physiology. The stromal interactions demonstrated in heterotypic 3D tumor spheroids can affect various aspects, including response to therapy, cancer progression, nanomedicine penetration, and drug resistance. Accordingly, to design more effective anticancer nanomedicinal therapeutics, not only tumor cells but also stromal cells (e.g., fibroblasts and immune cells) should be considered to create a more physiologically relevant in vivo microenvironment. This review aims to demonstrate current knowledge of heterotypic 3D tumor spheroids in cancer research, to illustrate current advances in utilizing these tumor models as a novel and versatile platform for in vitro evaluation of nanomedicine-based therapeutics in cancer research, and to discuss challenges, guidelines, and future directions in this field. Graphical Abstract 

Heterotypic tumor spheroids: a platform for nanomedicine evaluation

Quantitative PET tracking of intra-articularly administered 89Zr-peptide-decorated nanoemulsions.

Nanomedicines have been investigated for delivering drugs to tumors due to their ability to accumulate in the tumor tissues. 2D in vitro cell culture has been used to investigate the antitumoral potential of nanomedicines. However, a 2D model cannot adequately mimic the in vivo tissue conditions because of the lack of cell-cell interaction, a gradient of nutrients and the expression of genes. To overcome this limitation, 3D cell culture models have emerged as promising platforms that better replicate the complexity of native tumors. For this purpose, different techniques can be used to produce 3D models, including scaffold-free, scaffold-based and microfluidic-based models. This review addresses the principles, advantages and limitations of these culture methods for evaluating the antitumoral efficacy of nanomedicines.

Three-dimensional culture models: emerging platforms for screening the antitumoral efficacy of nanomedicines.

Sphingomyelin (SM) and its metabolites are crucial regulators of tumor cell growth, differentiation, senescence, and programmed cell death. With the rise in lipid-based nanomaterials, engineered lipidic nanomaterials inspired by SM metabolism, corresponding lipid targeting, and signaling activation have made fascinating advances in cancer therapeutic processes. In this review, we first described the specific pathways of SM metabolism and the roles of their associated bioactive molecules in mediating cell survival or death. We next summarized the advantages and specific applications of SM metabolism-based lipidic nanomaterials in specific cancer therapies. Finally, we discussed the challenges and perspectives of this emerging and promising SM metabolism-based nanomaterials research area.

Engineered Lipidic Nanomaterials Inspired by Sphingomyelin Metabolism for Cancer Therapy

Gene therapy is a promising therapeutic approach that has experienced significant groth in recent decades, with gene nanomedicines reaching the clinics. However, it is still necessary to continue developing novel vectors able to carry, protect, and release the nucleic acids into the target cells, to respond to the widespread demand for new gene therapies to address current unmet clinical needs. We propose here the use of zebrafish embryos as an in vivo platform to evaluate the potential of newly developed nanosystems for gene therapy applications in cancer treatment. Zebrafish embryos have several advantages such as low maintenance costs, transparency, robustness, and a high homology with the human genome. In this work, a new type of putrescine-sphingomyelin nanosystems (PSN), specifically designed for cancer gene therapy applications, was successfully characterized and demonstrated its potential for delivery of plasmid DNA (pDNA) and miRNA (miR). On one hand, we were able to validate a regulatory effect of the PSN/miR on gene expression after injection in embryos of 0 hpf. Additionally, experiments proved the potential of the model to study the transport of the associated nucleic acids (pDNA and miR) upon incubation in zebrafish water. The biodistribution of PSN/pDNA and PSN/miR in vivo was also assessed after microinjection into the zebrafish vasculature, demonstrating that the nucleic acids remained associated with the PSN in an in vivo environment, and could successfully reach disseminated cancer cells in zebrafish xenografts. Altogether, these results demonstrate the potential of zebrafish as an in vivo model to evaluate nanotechnology-based gene therapies for cancer treatment, as well as the capacity of the developed versatile PSN formulation for gene therapy applications.

/pdf/zebrafish-as-a-platform-to-evaluate-the-potential-of-lipidic-txy0fdpx.pdf

Zebrafish as a platform to evaluate the potential of lipidic nanoemulsions for gene therapy in cancer

Before in vivo studies: In vitro screening of sphingomyelin nanosystems using a relevant 3D multicellular pancreatic tumor spheroid model.

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Before in vivo studies: In vitro screening of sphingomyelin nanosystems using a relevant 3D multicellular pancreatic tumor spheroid model.