Single cell model for simultaneous drug delivery and efflux.
Multidrug resistance (MDR) of some cancer cells is a major challenge for chemotherapy of systemic cancers to overcome. To experimentally uncover the cellular mechanisms leading to MDR, it is necessary to quantitatively assess both drug influx into, and efflux from, the cells exposed to drug treatment. By using a novel molecular microdelivery system to enforce continuous and adjustable drug influx into single cells by controlled diffusion through a gel plug in a micropipet tip, drug resistance studies can now be performed on the single cell level. Our dynamic model of this scheme incorporates drug delivery, diffusive mixing, and accumulation inside the cytoplasm, and efflux by both passive and active membrane transport. Model simulations using available experimental information on these processes can assist in the design of MDR related experiments on single cancer cells which are expected to lead to a quantitative evaluation of mechanisms. Simulations indicate that drug resistance of a cancer cell can be quantified better by its dynamic response than by steady-state analysis.
Yi
C
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Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH 44106, USA.
Saidel
G M
GM
Gratzl
M
M
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001693:Biological Transport, Active; D002462:Cell Membrane / Q000378:metabolism; D003630:Daunorubicin / Q000008:administration & dosage / Q000493:pharmacokinetics; D004058:Diffusion; D018432:Drug Resistance, Multiple / Q000502:physiology*; D019008:Drug Resistance, Neoplasm; D008954:Models, Biological; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism*; D017711:Nonlinear Dynamics
D000970:Antineoplastic Agents; D003630:Daunorubicin