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Enzyme-activated nanoconjugates for tunable release of doxorubicin in hepatic cancer cells

Paper ID Volume ID Publish Year Pages File Format Full-Text
6633 508 2013 12 PDF Available
Title
Enzyme-activated nanoconjugates for tunable release of doxorubicin in hepatic cancer cells
Abstract

We report the synthesis of a series of aromatic azo-linkers (L1–L4), which are selectively recognized and cleaved by azoreductase enzymes present in the cytoplasm of hepatic cancer cells via a NADPH-dependent mechanism. We utilized L1–L4 azo-linkers to conjugate doxorubicin to generation 5 (G5) of poly(amidoamine) dendrimers to prepare G5–L(x)–DOX nanoconjugates. We incorporated electron-donating oxygen (O) or nitrogen (N) groups in the para and ortho positions of L1–L4 azo-linkers to control the electronegativity of G5–L(x)–DOX conjugates and investigated their cleavage by azoreductase enzymes and the associated release of loaded DOX molecules. Hammett σ values of G5–L(x)–DOX conjugates ranged from −0.44 to −1.27, which is below the reported σ threshold (−0.37) required for binding to azoreductase enzymes. Results show that incubation of G5–L1–DOX (σ = −0.44), G5–L2–DOX (σ = −0.71), G5–L3–DOX (σ = −1.00), and G5–L4–DOX (σ = −1.27) conjugates with human liver microsomal (HLM) enzymes and the S9 fraction isolated from HepG2 hepatic cancer cells results in release of 4%–8%, 17%, 60%, and 100% of the conjugated DOX molecules, respectively. These results show that increasing the electronegativity (i.e. lower σ value) of L1–L4 azo-linkers increases their susceptibility to cleavage by azoreductase enzymes. Intracellular cleavage of G5–L(x)–DOX nanoconjugates, release of conjugated DOX molecules, and cytotoxicity correlated with conjugate's electronegativity (σ value) was investigated, with G5–L4–DOX conjugate exhibiting the highest toxicity towards hepatic cancer cells with an IC50 of 13 nm ± 5 nm in HepG2 cells. Cleavage of G5–L(x)–DOX conjugates was specific to hepatic cancer cells as shown by low non-specific DOX release upon incubation with non-enzymatic insect proteins and the S9 fraction isolated from rat cardiomyocytes. These enzyme-activated G5–L(x)–DOX conjugates represent a drug delivery platform that can achieve tunable and cell-specific release of the loaded cargo in hepatic cancer cells.

Keywords
PAMAM dendrimers; Polymer-anticancer drug conjugates; Azo-linkers; Azoreductase enzymes; Enzyme-sensitive linkers; Hepatic cancer
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Enzyme-activated nanoconjugates for tunable release of doxorubicin in hepatic cancer cells
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Publisher
Database: Elsevier - ScienceDirect
Journal: Biomaterials - Volume 34, Issue 19, June 2013, Pages 4655–4666
Authors
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Subjects
Physical Sciences and Engineering Chemical Engineering Bioengineering
Get Full-Text Now
Don't Miss Today's Special Offer
Price was $35.95
You save - $31
Price after discount Only $4.95
100% Money Back Guarantee
Full-text PDF Download
Online Support
Any Questions? feel free to contact us