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Microfluidic technique to measure intratumoral transport and calculate drug efficacy shows that binding is essential for doxorubicin and release hampers Doxil

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Integrative Biology Vol - 5 Issue - 8

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Microfluidic technique to measure intratumoral transport and calculate drug efficacy shows that binding is essential for doxorubicin and release hampers Doxil

Content Provider	Royal Society of Chemistry (RSC)
Author	Toley, Bhushan J. Forbes, Neil S. Harrington, Josephine L. Lovatt, Zachary G. Tropeano
Copyright Year	2013
Abstract	Intratumoral transport and binding are important mechanisms that determine the efficacy of cancer drugs. Current drug screening methods rely heavily on monolayers of cancer cells, which overlook the contribution of tissue-level transport and binding. To quantify these factors, we developed a method that couples an in vitro, drug-delivery device containing a three-dimensional cell mass and a mathematical model of drug diffusion, binding to DNA, release from carriers, and clearance. Spheroids derived from LS174T human colon carcinoma cells were inserted into rectangular chambers to form rectangular cell masses (tissue) and subjected to continuous medium perfusion. To simulate drug delivery and clearance, the tissues were treated with doxorubicin followed by drug-free medium. To evaluate the effect of liposome encapsulation, tissues were treated with liposome-encapsulated doxorubicin (Doxil). Spatiotemporal dynamics of drug distribution and apoptosis was measured by fluorescence microscopy. The diffusivity and DNA binding constant of doxorubicin were determined by fitting experimental data to the mathematical model. Results show that an ideal combination of diffusivity, binding constant, clearance rate, and cytotoxicity contribute to the high therapeutic efficacy of doxorubicin. There was no detectable release of doxorubicin from Doxil in the tissues. The rate of doxorubicin release, evaluated by fitting experimental data to the mathematical model, was below therapeutically effective levels. These results show that despite enhanced systemic circulation obtained by liposome encapsulation, the therapeutic effect of Doxil is limited by slow intratumoral drug release. The experimental and computational methods developed here to calculate drug efficacy provide mechanisms to explain poor performance of drug candidates, and enable design of more successful cancer drugs.
Starting Page	1184
Ending Page	1196
Page Count	13
File Format	HTM / HTML PDF
ISSN	17579694
Volume Number	5
Issue Number	9
Journal	Integrative Biology
DOI	10.1039/c3ib40021b
Language	English
Publisher	Royal Society of Chemistry
Access Restriction	Open
Subject Keyword	Cancer Mathematical model Diffusion DNA Colorectal cancer Carcinoma Perfusion Drug delivery Doxorubicin Liposome Apoptosis Fluorescence microscope Binding constant Cytotoxicity Circulatory system
Content Type	Text
Resource Type	Article
Subject	Medicine Biochemistry Biophysics

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Microfluidic Technique to Measure Intratumoral Transport and Calculate Drug Efficacy Shows that Binding is Essential for Doxorubicin and Release Hampers Doxil

Mild hyperthermia triggered doxorubicin release from optimized stealth thermosensitive liposomes improves intratumoral drug delivery and efficacy.

Doxorubicin-Loaded Multivesicular Liposomes (DepoFoam) as a Sustained Release Carrier Intended for Locoregional Delivery in Cancer Treatment: Development, Characterization, and Cytotoxicity Evaluation.

Local delivery of doxorubicin through supramolecular peptide amphiphile nanofiber gels

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Amphiphilic block copolymer micelles with fluorescence as nano-carriers for doxorubicin delivery

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Synchronized release of Doxil and Nutlin-3 by remote degradation of polysaccharide matrices and its possible use in the local treatment of colorectal cancer

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Microfluidic technique to measure intratumoral transport and calculate drug efficacy shows that binding is essential for doxorubicin and release hampers Doxil

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Microfluidic Technique to Measure Intratumoral Transport and Calculate Drug Efficacy Shows that Binding is Essential for Doxorubicin and Release Hampers Doxil

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Microfluidic technique to measure intratumoral transport and calculate drug efficacy shows that binding is essential for doxorubicin and release hampers Doxil