Development of elastin-like polypeptide for thermally targeted delivery of doxorubicin

Gene L. Bidwell; Izabela Fokt; Waldemar Priebe; Drazen Raucher

doi:10.1016/j.bcp.2006.10.028

Development of elastin-like polypeptide for thermally targeted delivery of doxorubicin

Gene L. Bidwell, Izabela Fokt, Waldemar Priebe, Drazen Raucher

Experimental Therapeutics

Research output: Contribution to journal › Article › peer-review

110 Scopus citations

Abstract

The chemotherapeutic drug doxorubicin (Dox) is widely used as an antitumor agent in hematological malignancies and solid tumors. However, one of the limitations of its clinical use is that systemic administration of an effective dose of Dox results in nonselective cardiac toxicity and myelosuppression. In order to minimize this nonspecific toxicity, Elastin-like polypeptide (ELP) was examined for its ability to serve as a macromolecular carrier for thermally targeted delivery of Dox. The ELP-based doxorubicin delivery vehicle (Tat-ELP-GFLG-Dox) consists of: (1) a peptide derived from the HIV-1 Tat protein to facilitate its cellular uptake, (2) ELP to allow thermal targeting, and (3) the lysosomally degradable glycylphenylalanylleucylglycine (GFLG) spacer and a cysteine residue conjugated to a thiol reactive doxorubicin derivative. Cytotoxicity of Tat-ELP-GFLG-Dox in MES-SA uterine sarcoma cells was enhanced 20-fold when aggregation of ELP was induced with hyperthermia. The ELP delivered doxorubicin displayed a cytoplasmic distribution and induced temperature dependent caspase activation.

Original language	English (US)
Pages (from-to)	620-631
Number of pages	12
Journal	Biochemical Pharmacology
Volume	73
Issue number	5
DOIs	https://doi.org/10.1016/j.bcp.2006.10.028
State	Published - Mar 1 2007

Keywords

Doxorubicin
Drug delivery
Elastin-like polypeptide
Macromolecule
Thermal targeting

ASJC Scopus subject areas

Biochemistry
Pharmacology

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10.1016/j.bcp.2006.10.028

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title = "Development of elastin-like polypeptide for thermally targeted delivery of doxorubicin",

abstract = "The chemotherapeutic drug doxorubicin (Dox) is widely used as an antitumor agent in hematological malignancies and solid tumors. However, one of the limitations of its clinical use is that systemic administration of an effective dose of Dox results in nonselective cardiac toxicity and myelosuppression. In order to minimize this nonspecific toxicity, Elastin-like polypeptide (ELP) was examined for its ability to serve as a macromolecular carrier for thermally targeted delivery of Dox. The ELP-based doxorubicin delivery vehicle (Tat-ELP-GFLG-Dox) consists of: (1) a peptide derived from the HIV-1 Tat protein to facilitate its cellular uptake, (2) ELP to allow thermal targeting, and (3) the lysosomally degradable glycylphenylalanylleucylglycine (GFLG) spacer and a cysteine residue conjugated to a thiol reactive doxorubicin derivative. Cytotoxicity of Tat-ELP-GFLG-Dox in MES-SA uterine sarcoma cells was enhanced 20-fold when aggregation of ELP was induced with hyperthermia. The ELP delivered doxorubicin displayed a cytoplasmic distribution and induced temperature dependent caspase activation.",

keywords = "Doxorubicin, Drug delivery, Elastin-like polypeptide, Macromolecule, Thermal targeting",

author = "Bidwell, {Gene L.} and Izabela Fokt and Waldemar Priebe and Drazen Raucher",

note = "Funding Information: This work was partially supported by the American Cancer Society Institutional Research Grant to the University of Mississippi Medical Center, the Wendy Will Case Cancer Fund, and The Welch Foundation (Houston, TX).",

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AU - Bidwell, Gene L.

AU - Fokt, Izabela

AU - Priebe, Waldemar

AU - Raucher, Drazen

N1 - Funding Information: This work was partially supported by the American Cancer Society Institutional Research Grant to the University of Mississippi Medical Center, the Wendy Will Case Cancer Fund, and The Welch Foundation (Houston, TX).

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N2 - The chemotherapeutic drug doxorubicin (Dox) is widely used as an antitumor agent in hematological malignancies and solid tumors. However, one of the limitations of its clinical use is that systemic administration of an effective dose of Dox results in nonselective cardiac toxicity and myelosuppression. In order to minimize this nonspecific toxicity, Elastin-like polypeptide (ELP) was examined for its ability to serve as a macromolecular carrier for thermally targeted delivery of Dox. The ELP-based doxorubicin delivery vehicle (Tat-ELP-GFLG-Dox) consists of: (1) a peptide derived from the HIV-1 Tat protein to facilitate its cellular uptake, (2) ELP to allow thermal targeting, and (3) the lysosomally degradable glycylphenylalanylleucylglycine (GFLG) spacer and a cysteine residue conjugated to a thiol reactive doxorubicin derivative. Cytotoxicity of Tat-ELP-GFLG-Dox in MES-SA uterine sarcoma cells was enhanced 20-fold when aggregation of ELP was induced with hyperthermia. The ELP delivered doxorubicin displayed a cytoplasmic distribution and induced temperature dependent caspase activation.

AB - The chemotherapeutic drug doxorubicin (Dox) is widely used as an antitumor agent in hematological malignancies and solid tumors. However, one of the limitations of its clinical use is that systemic administration of an effective dose of Dox results in nonselective cardiac toxicity and myelosuppression. In order to minimize this nonspecific toxicity, Elastin-like polypeptide (ELP) was examined for its ability to serve as a macromolecular carrier for thermally targeted delivery of Dox. The ELP-based doxorubicin delivery vehicle (Tat-ELP-GFLG-Dox) consists of: (1) a peptide derived from the HIV-1 Tat protein to facilitate its cellular uptake, (2) ELP to allow thermal targeting, and (3) the lysosomally degradable glycylphenylalanylleucylglycine (GFLG) spacer and a cysteine residue conjugated to a thiol reactive doxorubicin derivative. Cytotoxicity of Tat-ELP-GFLG-Dox in MES-SA uterine sarcoma cells was enhanced 20-fold when aggregation of ELP was induced with hyperthermia. The ELP delivered doxorubicin displayed a cytoplasmic distribution and induced temperature dependent caspase activation.

KW - Doxorubicin

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KW - Elastin-like polypeptide

KW - Macromolecule

KW - Thermal targeting

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Development of elastin-like polypeptide for thermally targeted delivery of doxorubicin

Abstract

Keywords

ASJC Scopus subject areas

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