Microfluidic co-culture devices to assess penetration of nanoparticles into cancer cell mass.

Maria Jarvis,Kapil Pant,Jenna Ott,Samir Mitragotri,Michael Arnold,Balabhaskar Prabhakarpandian

doi:10.1002/btm2.10079

Abstract

In vitro and in vivo assessment of safety and efficacy are the essential first steps in developing nanoparticle‐based therapeutic systems. However, it is often challenging to use the knowledge gained from in vitro studies to predict the outcome of in vivo studies since the complexity of the in vivo environment, including the existence of flow and a multicellular environment, is often lacking in traditional in vitro models. Here, we describe a microfluidic co‐culture model comprising 4T1 breast cancer cells and EA.hy926 endothelial cells under physiological flow conditions and its utilization to assess the penetration of therapeutic nanoparticles from the vascular compartment into a cancerous cell mass. Camptothecin nanocrystals (∼310 nm in length), surface‐functionalized with PEG or folic acid, were used as a test nanocarrier. Camptothecin nanocrystals exhibited only superficial penetration into the cancerous cell mass under fluidic conditions, but exhibited cytotoxicity throughout the cancerous cell mass. This likely suggests that superficially penetrated nanocrystals dissolve at the periphery and lead to diffusion of molecular camptothecin deep into the cancerous cell mass. The results indicate the potential of microfluidic co‐culture devices to assess nanoparticle‐cancerous cell interactions, which are otherwise difficult to study using standard in vitro cultures.

Highlights

Canonical drug delivery research usually commences with the validation of a carrier or a drug using in vitro static cell cultures in which cells are grown in 2D monolayers and are subjected to the drug and subsequently tested through a variety of established methods for cellular uptake and cytotoxicity effects
FI G URE 8 A co-culture idealized microfluidic device coated with a fibronectin basement membrane was imaged immediately after flow (t 5 0 hr) with CPT-UM crystals under the Near UV Channel at 4x and 10x as depicted from left to right to track the progress of the CPT-UM UV fluorescent nanocrystals through the outer channel into the inner tissue culture chamber
FI G URE 9 A co-culture idealized microfluidic device coated with a fibronectin basement membrane was imaged immediately after flow (t 5 0 hr) with CPT-UM crystals under the Near UV Channel at 20x as depicted from left to right to track the progress of the CPT-UM UV fluorescent nanocrystals through the outer channel into the inner tissue culture chamber

Summary

Introduction

Canonical drug delivery research usually commences with the validation of a carrier or a drug using in vitro static cell cultures in which cells are grown in 2D monolayers and are subjected to the drug and subsequently tested through a variety of established methods for cellular uptake and cytotoxicity effects. On average, five compounds from the initial pool of 5,000–10,000 enter clinical trials, and only one becomes a successful FDA approved drug.[1] Since carriers often alter the drug’s efficacy and toxicity, drug-carrier combinations must go through the same rigorous validation and approval process. This approach limits the likelihood and speed of translation of in vitro foundational research to in vivo outcomes.[2]. The knowledge gap between the performance of the carriers in vitro and in vivo is often difficult to bridge due to the disparate nature of the two methods of studies. By definition, involve a dynamic environment where a multitude of contributing factors could collectively dictate the outcome and it is often difficult to isolate confounding elements and elucidate the mechanistic differences between in vivo and in vitro observations

Objectives

Findings

Discussion

Conclusion