ABSTRACT
Improved understanding of microRNA expression and function in cancer has revealed a range of microRNAs that negatively regulate many oncogenic pathways, thus representing potent tumor suppressors. Therapeutic targeting of the expression of these microRNAs to the site of tumors and metastases provides a promising avenue for cancer therapy. To overcome challenges associated with microRNA degradation, transient expression and poor targeting, novel nanoparticles are being developed and employed to shield microRNAs for tumor-targeted delivery. This review focuses on studies describing a variety of both natural and synthetic nanoparticle delivery vehicles that have been engineered for tumor-targeted delivery of tumor suppressor microRNAs in vivo.
Subject(s)
Antineoplastic Agents/administration & dosage , Dendrimers/administration & dosage , Liposomes/administration & dosage , MicroRNAs/administration & dosage , Nanoparticles/administration & dosage , Neoplasms/drug therapy , Animals , Dendrimers/chemistry , Extracellular Vesicles , Gene Expression Regulation, Neoplastic , Humans , Mice , MicroRNAs/genetics , MicroRNAs/metabolism , Molecular Targeted Therapy/methods , Neoplasms/genetics , Neoplasms/metabolism , Polyamines , Xenograft Model Antitumor AssaysABSTRACT
Extracellular vesicles (EVs) shuttle microRNA (miRNA) throughout the circulation and are believed to represent a fingerprint of the releasing cell. We isolated and characterized serum EVs of breast tumour-bearing animals, breast cancer (BC) patients, and healthy controls. EVs were characterized using transmission electron microscopy (TEM), protein quantification, western blotting, and nanoparticle tracking analysis (NTA). Absolute quantitative (AQ)-PCR was employed to analyse EV-miR-451a expression. Isolated EVs had the appropriate morphology and size. Patient sera contained significantly more EVs than did healthy controls. In tumour-bearing animals, a correlation between serum EV number and tumour burden was observed. There was no significant relationship between EV protein yield and EV quantity determined by NTA, highlighting the requirement for direct quantification. Using AQ-PCR to relate miRNA copy number to EV yield, a significant increase in miRNA-451a copies/EV was detected in BC patient sera, suggesting potential as a novel biomarker of breast cancer.
Subject(s)
Biomarkers, Tumor/blood , Breast Neoplasms/blood , Breast Neoplasms/genetics , Extracellular Vesicles/metabolism , MicroRNAs/blood , Animals , Case-Control Studies , Cell Line, Tumor , Disease Models, Animal , Extracellular Vesicles/ultrastructure , Female , Humans , Mice, Inbred BALB C , Mice, Nude , MicroRNAs/geneticsABSTRACT
Extracellular vesicles (EVs) are nanosized particles released by all cells that have been heralded as novel regulators of cell-to-cell communication. It is becoming increasingly clear that in response to a variety of stress conditions, cells employ EV-mediated intercellular communication to transmit a pro-survival message in the tumor microenvironment and beyond, supporting evasion of cell death and transmitting resistance to therapy. Understanding changes in EV cargo and secretion pattern during cell stress may uncover novel, targetable mechanisms underlying disease progression, metastasis and resistance to therapy. Further, the profile of EVs released into the circulation may provide a circulating biomarker predictive of response to therapy and indicative of microenvironmental conditions linked to disease progression, such as hypoxia. Continued progress in this exciting and rapidly expanding field of research will be dependent upon widespread adoption of transparent reporting standards and implementation of guidelines to establish a consensus on methods of EV isolation, characterisation and nomenclature employed.
