Reaching the tumor: mobility of polymeric micelles inside anin vitrotumor-on-a-chip model with dual ECM

Abstract

Degradable polymeric micelles are promising drug delivery systems due to their hydrophobic core and responsive design. When applying micellar nanocarriers for tumor delivery, one of the bottlenecks encountered in vivo is the tumor tissue barrier: crossing the dense mesh of cells and extracellular matrix (ECM). Sometimes overlooked, the extracellular matrix can trap nanoformulations based on charge, size and hydrophobicity. Here we used a simple design of a microfluidic chip with two types of ECM and MCF7 spheroids to allow high throughput screening of the interactions between biological interfaces and polymeric micelles. To demostrarte the applicapility of the chip, a small library of fluorescently labelled polymeric micelles varying in their hydrophilic shell and hydrophobic core forming blocks was studied. Three widely used hydrophilic shells were tested and compared, poly(ethylene glycol), poly(2-ethyl-2-oxazoline), and poly(acrylic acid), along with two enzyamticaly degradable dendritic hydrophobic cores (based on Hexyl or Nonyl end-gorups). Using ratiometric imaging of unimer:micelle fluorescence and FRAP inside the chip model, we obtained the local assembly state and dynamics inside the chip. Notably, we observed different micelle behaviors in the basal lamina ECM, from avoidance of ECM structure to binding of the poly(acrylic acid) formulations. Binding to basal lamina correlated with higher uptake into MCF7 spheroids. Overall, we proposed a simple microfluidic chip containing dual ECM and spheroids for the assessment of the interactions of polymeric nanocarrires with biological interfaces and evaluating nanoformulations capacity to cross the tumor tissue barrier.