Microfluidic assay for selection and optimization of drug delivery vehicles to tumors
Inventors
Prabhakarpandian, Balabhaskar • Pant, Kapil • Sundaram, Shivshankar
Assignees
Publication Number
US-8355876-B2
Publication Date
2013-01-15
Expiration Date
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Abstract
An apparatus and method for assaying a tumor drug delivery vehicle comprises a synthetic microvascular network of interconnected flow channels in fluid communication through a porous wall with a tissue space containing animal cells and means for quantifying drug delivery from the microvascular network to the animal cells.
Core Innovation
An apparatus and method for assaying a tumor drug delivery vehicle comprises a synthetic microvascular network of interconnected flow channels in fluid communication through a porous wall with a tissue space containing animal cells and means for quantifying drug delivery from the microvascular network to the animal cells. The apparatus includes an optically clear microfluidic chip containing a microvascular network of interconnected flow channels having dimensions from 10-500 μm in cross-section, luminal surfaces of the flow channels coated with a confluent layer of cultured endothelial cells, and tumor cells cultured in extravascular tissue spaces surrounded by the flow channels.
The invention addresses shortcomings of existing in-vitro tumor drug delivery models that are often poor predictors of drug delivery to tumors because simple in-vitro models cannot accurately capture complex phenomenon involved in tumor drug delivery, which are affected by the physico-chemical properties of drugs and delivery vehicles and complex tumor microvasculature. The patent states that tumor microvasculature is substantially different from that found in normal tissue, including higher interstitial pressures and often higher vascular permeability.
The microchannels are separated from the tissue space by pores or gaps in the walls of the channels having dimensions in the range of 0.2-5 μm to represent leaky vessels that allow transport of delivery vehicles across vascular walls and into the tissue spaces. The device embodiments include synthetic microvascular networks (SMNs) derived from digitized physiological microvascular networks and idealized microvascular networks (IMNs), tissue spaces with ports and optional posts or scaffolds to form monolayers, bilayers, and three-dimensional solid tumors, and means for introducing candidate drug delivery vehicles into and flowing them through the flow channels to assess their ability to reach, permeate, or transfect cultured tumor cells.
Claims Coverage
The claims include three independent claims, covering a microfluidic chip with specific structural features, an apparatus incorporating the chip with fluid handling and detection means, and a method for assaying drug delivery vehicles. Main inventive features are extracted below.
Network of nonlinear interconnected flow channels
A network of nonlinear, interconnected flow channels in fluid communication with a network inlet and a network outlet, with luminal cross-sectional dimensions of between 10 and 500 μm and having a geometric characteristic selected from a variable cross-sectional shape, variable cross-sectional area, turn, bend, bifurcation, junction, convolution, anastomosis, and combinations thereof.
Tissue space separated by porous wall
A tissue space in fluid communication with a tissue space inlet and outlet having cross-sectional luminal dimensions between 100 μm and 1 cm, the tissue space separated from a lumen of at least one flow channel by a porous wall containing pores or gaps having cross-sections of between 0.2 and 5 microns and in liquid communication with said flow channel, and the tissue space contains cultured cells.
Integration of pumping means
An apparatus comprising the microfluidic chip and pumping means configured to move fluid from the network inlet to the network outlet.
Optical detection means
Optical detection means configured to visualize and quantitate cells, drug delivery vehicles and drugs.
Microfluidic assay method for drug delivery vehicles
A method comprising providing the optically transparent microfluidic chip, introducing a liquid containing a drug delivery vehicle and drug into the network inlet, causing the liquid to move through the network of interconnected flow channels, and quantifying the amount of the drug reaching the tissue space, the cells, or both.
The independent claims principally cover (1) a structurally defined optically transparent microfluidic chip with nonlinear interconnected flow channels and a tissue space separated by porous walls containing cultured cells, (2) an apparatus that adds pumping and optical detection to the chip, and (3) a method of introducing, flowing, and quantifying drug delivery vehicles and drugs within the microfluidic network.
Stated Advantages
Accounts for the geometric and flow properties, increased permeability, and higher interstitial pressures of tumor microvasculature.
Mimics physiological microvascular environments by coating luminal surfaces with a confluent layer of cultured endothelial cells and using porous channel walls to represent leaky vessels.
Enables selection and optimization of candidate drug delivery vehicles based on their ability to reach, permeate, or transfect cultured tumor cells.
Can be altered to assay for drug delivery to other tissues and to mimic diffusion across other physiological barriers including the blood-brain barrier and linings of the small intestine.
Documented Applications
Screening tumor drug delivery vehicles and selecting or optimizing performance based on ability to reach, permeate, or transfect cultured tumor cells.
Transport and stability studies of delivery vehicles, including assessment of circulation, stability, aggregation, and degradation [procedural detail omitted for safety].
Analyzing gene delivery by delivery vehicles by detecting expression of a fluorescent protein reporter in tumor cells (e.g., GFP) as an indicator of delivery success [procedural detail omitted for safety].
Analyzing drug delivery by delivery vehicles by assessing effects on tumor growth and by electrical impedance measurements across tissue spaces to detect cell death in response to drug delivery [procedural detail omitted for safety].
Testing a variety of drug delivery vehicles such as nanopolymers, Qdots, biological or synthetic vehicles, and other listed carriers for tumor drug delivery.
Assaying drug delivery to other tissues and mimicking other physiological barriers by modifying pore size and tissue space contents.
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