Real-time Ratiometric Imaging of Micelles Assembly State in a Microfluidic Cancer-on-a-chip

Abstract

The performance of supramolecular nanocarriers as drug delivery systems depends on their stability in the complex and dynamic biological media. After administration, nanocarriers are challenged by confronting different barriers such as shear stress and proteins present in blood, endothelial wall, extracellular matrix and eventually cancer cell membranes. While early disassembly will result in a premature drug release, extreme stability of the nanocarriers can lead to poor drug release and low efficiency. Therefore, comprehensive understanding of the stability and assembly state of supramolecular carriers in each stage of delivery is a key factor for the rational design of these systems. One of the key challenges is that current 2D in vitro models do not provide exhaustive information, as they do not fully recapitulate the 3D tumor microenvironment. This deficiency of the 2D models complexity is the main reason for the differences observed in vivo when testing the performance of supramolecular nanocarriers.Herein, we present a real-time monitoring study of self-assembled micelles stability and extravasation, combining spectral confocal microscopy and a microfluidic tumor-on-a-chip. The combination of advanced imaging and a reliable organ-on-a-chip model allow us to track micelle disassembly by following the spectral properties of the amphiphiles in space and time during the crucial steps of drug delivery. The spectrally active micelles were introduced under flow and their position and conformation followed during the crossing of barriers by spectral imaging, revealing the interplay between carrier structure, micellar stability and extravasation. Integrating

From 2D to 3D Cancer Cell Models—The Enigmas of Drug Delivery Research

“…In this procedure, the permeabilization was improved by increasing the concentration of the detergent used (Triton X-100) [146]. Next to the scaffold, the dense multilayered nature of the spheroids and some organoid To recreate vascularization, scaffold-embedded spheroids can be immobilized in close proximity to a layer of endothelial cells [132,133]. In nanomedicine, this system can be of particular interest to investigate how nanoparticles overcome (or not) the endothelial barrier.…”

“…These channels are independently pressurized to mimic the elevated interstitial fluid pressure and are configured in a 3D structure by stacking two polydimethylsiloxane (PDMS) layers of microchannels with a porous membrane sandwiched between the layers [123]. The side channels can be perfused with endothelial cells to simulate the endothelial wall [130,132]. (E) Microfluidic platform with three types of channels -capillary, interstitial and lymphatic channels (noted with red, yellow and red colors).…”

“…To recreate vascularization, scaffold-embedded spheroids can be immobilized in close proximity to a layer of endothelial cells [ 132 , 133 ]. In nanomedicine, this system can be of particular interest to investigate how nanoparticles overcome (or not) the endothelial barrier.…”

“…The combination of flow, an endothelial wall, ECM and embedded MTCSs, offers a good simulation of the barriers that nanocarriers have to overcome in vivo. Using this approach, Feiner Gracia et al monitored the stability and extravasation of self-assembled micelles using spectral confocal microscopy [ 132 ]. The formation of leaky vasculature could be detected in the regions where cancer cells were in close proximity to the endothelial layer.…”

“…The devices contain an array of trapezoidal posts that cage the matrix solution into well-defined regions with uniform surface interface. The side channels can be perfused with endothelial cells to simulate the endothelial wall [ 130 , 132 ]. ( E ) Microfluidic platform with three types of channels - capillary, interstitial and lymphatic channels (noted with red, yellow and red colors).…”