Conjugation of poly-L-lysine to bacterial cytosine deaminase improves the efficacy of enzyme/prodrug cancer therapy

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Abstract

We previously observed that bacterial cytosine deaminase (bCD) conjugated with multimodal imaging reporter labeled poly-L-lysine (PLL) demonstrated high therapeutic efficacy in an enzyme/prodrug cancer therapeutic strategy. To understand the role of polycationic PLL in the cellular uptake of bCD-PLL conjugate, two control molecules, bCD-BF, without the PLL moiety, and bCD-AcPLL, with all positive charges in PLL neutralized, were prepared. bCD-PLL demonstrated about 50 times higher cellular uptake than that of control molecules in human breast MDA-MB-231 cancer cells. Internalized bCD-PLL demonstrated high enzymatic stability in cell cultures as indicated by significant cytotoxicity after addition of prodrug, whereas no obvious cytotoxicity was detected by control molecules. These data indicate that conjugated PLL not only provides a multivalent modification platform to facilitate the delivery of a high payload of imaging reporters or targeting moieties without compromising enzymatic activity but also enhances therapeutic efficacy by accelerating the intracellular uptake of prodrug-activating enzyme.

Original languageEnglish (US)
Pages (from-to)3572-3582
Number of pages11
JournalJournal of Medicinal Chemistry
Volume51
Issue number12
DOIs
StatePublished - Jun 26 2008

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Cytosine Deaminase
Prodrugs
Lysine
Enzymes
Neoplasms
Therapeutics
Cytotoxicity
Molecules
Multimodal Imaging
Imaging techniques
Cell culture
Breast
Cell Culture Techniques
Cells

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

@article{5f2a0c6671f9431aaba049059c54eef9,
title = "Conjugation of poly-L-lysine to bacterial cytosine deaminase improves the efficacy of enzyme/prodrug cancer therapy",
abstract = "We previously observed that bacterial cytosine deaminase (bCD) conjugated with multimodal imaging reporter labeled poly-L-lysine (PLL) demonstrated high therapeutic efficacy in an enzyme/prodrug cancer therapeutic strategy. To understand the role of polycationic PLL in the cellular uptake of bCD-PLL conjugate, two control molecules, bCD-BF, without the PLL moiety, and bCD-AcPLL, with all positive charges in PLL neutralized, were prepared. bCD-PLL demonstrated about 50 times higher cellular uptake than that of control molecules in human breast MDA-MB-231 cancer cells. Internalized bCD-PLL demonstrated high enzymatic stability in cell cultures as indicated by significant cytotoxicity after addition of prodrug, whereas no obvious cytotoxicity was detected by control molecules. These data indicate that conjugated PLL not only provides a multivalent modification platform to facilitate the delivery of a high payload of imaging reporters or targeting moieties without compromising enzymatic activity but also enhances therapeutic efficacy by accelerating the intracellular uptake of prodrug-activating enzyme.",
author = "Cong Li and Flonne Wildes and Winnard, {Paul T} and Dmitri Artemov and Marie-France Penet and Bhujwalla, {Zaver M}",
year = "2008",
month = "6",
day = "26",
doi = "10.1021/jm800288h",
language = "English (US)",
volume = "51",
pages = "3572--3582",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "12",

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TY - JOUR

T1 - Conjugation of poly-L-lysine to bacterial cytosine deaminase improves the efficacy of enzyme/prodrug cancer therapy

AU - Li, Cong

AU - Wildes, Flonne

AU - Winnard, Paul T

AU - Artemov, Dmitri

AU - Penet, Marie-France

AU - Bhujwalla, Zaver M

PY - 2008/6/26

Y1 - 2008/6/26

N2 - We previously observed that bacterial cytosine deaminase (bCD) conjugated with multimodal imaging reporter labeled poly-L-lysine (PLL) demonstrated high therapeutic efficacy in an enzyme/prodrug cancer therapeutic strategy. To understand the role of polycationic PLL in the cellular uptake of bCD-PLL conjugate, two control molecules, bCD-BF, without the PLL moiety, and bCD-AcPLL, with all positive charges in PLL neutralized, were prepared. bCD-PLL demonstrated about 50 times higher cellular uptake than that of control molecules in human breast MDA-MB-231 cancer cells. Internalized bCD-PLL demonstrated high enzymatic stability in cell cultures as indicated by significant cytotoxicity after addition of prodrug, whereas no obvious cytotoxicity was detected by control molecules. These data indicate that conjugated PLL not only provides a multivalent modification platform to facilitate the delivery of a high payload of imaging reporters or targeting moieties without compromising enzymatic activity but also enhances therapeutic efficacy by accelerating the intracellular uptake of prodrug-activating enzyme.

AB - We previously observed that bacterial cytosine deaminase (bCD) conjugated with multimodal imaging reporter labeled poly-L-lysine (PLL) demonstrated high therapeutic efficacy in an enzyme/prodrug cancer therapeutic strategy. To understand the role of polycationic PLL in the cellular uptake of bCD-PLL conjugate, two control molecules, bCD-BF, without the PLL moiety, and bCD-AcPLL, with all positive charges in PLL neutralized, were prepared. bCD-PLL demonstrated about 50 times higher cellular uptake than that of control molecules in human breast MDA-MB-231 cancer cells. Internalized bCD-PLL demonstrated high enzymatic stability in cell cultures as indicated by significant cytotoxicity after addition of prodrug, whereas no obvious cytotoxicity was detected by control molecules. These data indicate that conjugated PLL not only provides a multivalent modification platform to facilitate the delivery of a high payload of imaging reporters or targeting moieties without compromising enzymatic activity but also enhances therapeutic efficacy by accelerating the intracellular uptake of prodrug-activating enzyme.

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