The chorioallantoic membrane as a bio-barrier model for the evaluation of nanoscale drug delivery systems for tumour therapy.
Preis Eduard,Schulze Jan,Gutberlet Bernd,Pinnapireddy Shashank Reddy,Jedelská Jarmila,Bakowsky Udo
Advanced drug delivery reviews
In 2010, the European Parliament and the European Union adopted a directive on the protection of animals used for scientific purposes. The directive aims to protect animals in scientific research, with the final goal of complete replacement of procedures on live animals for scientific and educational purposes as soon as it is scientifically viable. Furthermore, the directive announces the implementation of the 3Rs principle: "When choosing methods, the principles of replacement, reduction and refinement should be implemented through a strict hierarchy of the requirement to use alternative methods." The visibility, accessibility, and the rapid growth of the chorioallantoic membrane (CAM) offers a clear advantage for various manipulations and for the simulation of different Bio-Barriers according to the 3R principle. The extensive vascularisation on the CAM provides an excellent substrate for the cultivation of tumour cells or tumour xenografts which could be used for the therapeutic evaluation of nanoscale drug delivery systems. The tumour can be targeted either by topical application, intratumoural injection or i.v. injection. Different application sites and biological barriers can be examined within a single model.
Nanomedicine promotes ferroptosis to inhibit tumour proliferation in vivo.
Luo Yifeng,Niu Gang,Yi Hui,Li Qingling,Wu Zhiqiang,Wang Jing,Yang Juan,Li Bo,Peng Yuan,Liang Ying,Wang Weiwei,Peng Zhenwei,Shuai Xintao,Guo Yu
miR-101-3p may play a therapeutic role in various tumours. However, its anti-tumour mechanism remains unclear, and a definitive strategy to treat tumour cells in vivo is lacking. The objective of this study was to investigate the inhibitory mechanism of miR-101-3p on tumour cells and to develop relevant nanomedicines for in vivo therapy. The expression levels of miR-101-3p and its target protein TBLR1 in tumour tissues and cells were detected, and their relationship with ferroptosis was clarified. Furthermore, the efficacy of nanocarriers in achieving in vivo therapeutic gene delivery was evaluated. Nanomedicine was further developed, with the anti-proliferative in vivo therapeutic effect validated using a subcutaneous xenograft cancer model. The expression level of miR-101-3p negatively correlated with clinical tumour size and TNM stage. miR-101-3p restores ferroptosis in tumour cells by directly targeting TBLR1, which in turn promotes apoptosis and inhibits proliferation. We developed nanomedicine that can deliver miR-101-3p to tumour cells in vivo to achieve ferroptosis recovery, as well as to inhibit in vivo tumour proliferation. The miR-101-3p/TBLR1 axis plays an important role in tumour ferroptosis. Nanopharmaceuticals that increase miR-101-3p levels may be effective therapies to inhibit tumour proliferation.
Quantitative imaging of intracellular nanoparticle exposure enables prediction of nanotherapeutic efficacy.
Yin Qingqing,Pan Anni,Chen Binlong,Wang Zenghui,Tang Mingmei,Yan Yue,Wang Yaoqi,Xia Heming,Chen Wei,Du Hongliang,Chen Meifang,Fu Chuanxun,Wang Yanni,Yuan Xia,Lu Zhihao,Zhang Qiang,Wang Yiguang
Nanoparticle internalisation is crucial for the precise delivery of drug/genes to its intracellular targets. Conventional quantification strategies can provide the overall profiling of nanoparticle biodistribution, but fail to unambiguously differentiate the intracellularly bioavailable particles from those in tumour intravascular and extracellular microenvironment. Herein, we develop a binary ratiometric nanoreporter (BiRN) that can specifically convert subtle pH variations involved in the endocytic events into digitised signal output, enabling the accurately quantifying of cellular internalisation without introducing extracellular contributions. Using BiRN technology, we find only 10.7-28.2% of accumulated nanoparticles are internalised into intracellular compartments with high heterogeneity within and between different tumour types. We demonstrate the therapeutic responses of nanomedicines are successfully predicted based on intracellular nanoparticle exposure rather than the overall accumulation in tumour mass. This nonlinear optical nanotechnology offers a valuable imaging tool to evaluate the tumour targeting of new nanomedicines and stratify patients for personalised cancer therapy.
Inhibition of post-surgery tumour recurrence via a hydrogel releasing CAR-T cells and anti-PDL1-conjugated platelets.
Hu Quanyin,Li Hongjun,Archibong Edikan,Chen Qian,Ruan Huitong,Ahn Sarah,Dukhovlinova Elena,Kang Yang,Wen Di,Dotti Gianpietro,Gu Zhen
Nature biomedical engineering
The immunosuppressive microenvironment of solid tumours reduces the antitumour activity of chimeric antigen receptor T cells (CAR-T cells). Here, we show that the release-through the implantation of a hyaluronic acid hydrogel-of CAR-T cells targeting the human chondroitin sulfate proteoglycan 4, polymer nanoparticles encapsulating the cytokine interleukin-15 and platelets conjugated with the checkpoint inhibitor programmed death-ligand 1 into the tumour cavity of mice with a resected subcutaneous melanoma tumour inhibits the local recurrence of the tumour as well as the growth of distant tumours, through the abscopal effect. The hydrogel, which functions as a reservoir, facilitates the enhanced distribution of the CAR-T cells within the surgical bed, and the inflammatory microenvironment triggers platelet activation and the subsequent release of platelet-derived microparticles. The post-surgery local delivery of combination immunotherapy through a biocompatible hydrogel reservoir could represent a translational route for preventing the recurrence of cancers with resectable tumours.
Developing liver organoids from induced pluripotent stem cells (iPSCs): An alternative source of organoid generation for liver cancer research.
Nguyen Romario,Da Won Bae Sarah,Qiao Liang,George Jacob
Primary liver cancer (PLC) represents a significant proportion of all human cancers and constitutes a substantial health and economic burden to society. Traditional therapeutic approaches such as surgical resection and chemotherapy often fail due to tumour relapse or innate tumour chemoresistance. There is a dearth of efficient treatments for PLC in part due to the poor capacity of current laboratory models to reflect critical features of the native tumour in vivo. The increasing incorporation of organoid systems has led to a resurgence of interest in liver cancer research. Organoid systems show promise as the gold standard for recapitulating tumours in vitro. Further, developments in culturing techniques will improve the various shortcomings of the current systems. Induced pluripotent stem cell (iPSC)-derived liver organoids are a promising alternative to the conventional liver organoid model as it circumvents the need to rely on primary resections which are often scarce. In this concise review, we will discuss novel techniques for organoid culture with a focus on organoid co-cultures and their advantages over traditional organoid systems. A detailed technical protocol for the generation of iPSC-derived liver organoids is provided as an appendix.