Abstract |
The therapeutic index of current anti- cancer chemotherapeutics can be improved by two major mechanisms: 1) developing drugs which are specifically toxic to the cancer cells and 2) developing methods to deliver drugs to the tumor site. In an attempt to combine these approaches, we developed a thermally responsive polypeptide inhibitor of c-Myc. This polypeptide is based on the thermally responsive Elastin-like polypeptide (ELP). When injected systemically, ELP-fused drugs will aggregate and accumulate at the tumor site where local hyperthermia is applied. ELP was fused to a peptide which blocks c-Myc/Max dimerization (H1), thereby inhibiting transcription activation by c-Myc (ELP-H1). In this study, the cellular uptake, intracellular distribution, and potency of the Pen, Tat and Bac cell penetrating peptides fused to ELP-H1 were evaluated. While Pen-ELP-H1 and Tat-ELP-H1 were localized in the cytoplasm, Bac-ELP-H1 localized to the nucleus in a subset of the cells and was the most potent inhibitor of MCF-7 cell proliferation. This data demonstrates that ELP can be targeted to the desired cellular compartment simply by choice of the CPP used, resulting in a more potent nuclear targeted c-Myc inhibitory polypeptide which may be beneficial in cancer therapy.
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Authors | Gene L Bidwell 3rd, Aisha N Davis, Drazen Raucher |
Journal | Journal of controlled release : official journal of the Controlled Release Society
(J Control Release)
Vol. 135
Issue 1
Pg. 2-10
(Apr 02 2009)
ISSN: 1873-4995 [Electronic] Netherlands |
PMID | 19095020
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Antineoplastic Agents
- Drug Carriers
- MYC protein, human
- Peptide Fragments
- Peptides
- Proto-Oncogene Proteins c-myc
- Recombinant Fusion Proteins
- elastin polypentapeptide
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Topics |
- Antineoplastic Agents
(administration & dosage, pharmacokinetics, pharmacology)
- Cell Line, Tumor
- Cell Nucleus
(drug effects, metabolism)
- Cell Proliferation
(drug effects)
- Cytoplasm
(drug effects, metabolism)
- Dose-Response Relationship, Drug
- Drug Carriers
(chemical synthesis, chemistry, pharmacokinetics)
- Female
- Humans
- Hyperthermia, Induced
- Microscopy, Fluorescence
- Neoplasms
(drug therapy, metabolism)
- Peptide Fragments
(chemical synthesis, chemistry, pharmacokinetics)
- Peptides
(chemical synthesis, chemistry, pharmacokinetics)
- Phase Transition
- Proto-Oncogene Proteins c-myc
(antagonists & inhibitors)
- Recombinant Fusion Proteins
(chemical synthesis, chemistry, pharmacokinetics)
- Temperature
- Time Factors
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