Targeted Drug Delivery: How to Exploit Cavitation to Promote Permeability of Blood Vessels and Focus on Diseased Tissues
The administration of drugs through nanotechnological release systems has various advantages over conventional pharmacological therapies and, in this field, targeted drug delivery is one of the most significant opportunities for alternative drug administration methods, especially for patients in chronic conditions that require continuous massive doses of drugs and suffer from the collateral effects produced from prolonged use. Thus, studying the mechanisms that favour the focused passage of molecules through the endothelium barrier that coats blood vessels is fundamental in order to reduce the toxic effects produced by the diffusion of drugs throughout the circulatory system and in healthy tissues.
The group of researchers coordinated by Prof. Carlo Massimo Casciola from the Sapienza Department of Mechanical and Aerospace Engineering, in collaboration with the Centre for Life Nano Science at the Italian Institute of Technology (CLNS-IIT) and the Department of Mechanical Engineering at Temple University, has developed a new methodology to induce the in vitro aperture of inter-cellular junctions through cavitation and measurement of the permeability levels of the endothelium to improve drug efficiency and circumscribe their effect throughout the organism. The study, which has been recently published on Small, aims to validate protocols for in vivo applications of ultrasound cavitation.
Thanks to recent progress made in the field of micro and nanotechnology, the team was able to recreate a blood vessel in vitro: a membrane of endothelial cells capable of acting as a biological barrier thanks to the correct formation of inter-cellular junctions. Thanks to a blood vessel-on-a-chip microfluidic device, the researchers were able to reproduce the physiological parameters of blood flow that produced an artificial endothelium capable of correctly operating as a barrier.
In order to induce the mechanical effects of cavitation on the endothelium, micro-bubbles that are typical used as contrast agents in ultrasound scans were injected into the blood vessels and exposed to ultrasounds. The effects of cavitation on the vitality of the cells and the integrity of the inter-cellular joints were evaluate via immunofluorescence thanks to confocal microscopy and imaging analyses.
“The results,” explains Carlo Massimo Casciola, “reveal how the micro-bubbles amplify the effect of the ultrasounds and induce a temporary aperture of the inter-cellular junctions that are repsonsible for the permeabilization of the endothelial barrier. Moreover, the junction opening proved to be completely reversible and therefore potentially safe for the integrity of the endothelium.”
The breakthrough is the possibility of measuring the aperture of the barrier in reproducible conditions, which opens up new possibilities for the study of endothelium permeabilization in ill tissues to refine the targeted release of drugs.
The research, characterised by the convergence of engineering and biological competences, was carried out by a group of researchers coordinated by Prof. Carlo Massimo Casciola for Sapienza, a research group led by Dr. Giovanna Peruzzi for CLNS-IIT and Prof. Mohammad Kiani at Temple University. The platform for experimental investigation was developed as part of European Project Horizon 2020 - ERC Proof of Concept. Experiments were carried out at the CLNS-IIT Labs.
Reversible Cavitation-Induced Junctional Opening in an Artificial Endothelial Layer - Giulia Silvani, Chiara Scognamiglio, Davide Caprini, Luca Marino, Mauro Chinappi, Giorgia Sinibaldi, Giovanna Peruzzi, Mohammad F. Kiani, Carlo M. Casciola - Small (2019) DOI https://doi.org/10.1002/smll.201905375
Carlo Massimo Casciola
Department of Mechanical and Aerospace Engineering