title: Thermal targeting of an acid-sensitive doxorubicin conjugate of elastin-like polypeptide enhances the therapeutic efficacy compared with the parent compound in vivo.
abstract: Elastin-like polypeptides (ELP) aggregate in response to mild hyperthermia, but remain soluble under normal physiologic conditions. ELP macromolecules can accumulate in solid tumors because of the enhanced permeability and retention effect. Tumor retention of ELPs can be further enhanced through hyperthermia-induced aggregation of ELPs by local heating of the tumor. We evaluated the therapeutic potential of ELPs in delivering doxorubicin in the E0771 syngeneic mouse breast cancer model. The ELP-Dox conjugate consisted of a cell-penetrating peptide at the N-terminus and the 6-maleimidocaproyl hydrazone derivative of doxorubicin at the C-terminus of ELP. The acid-sensitive hydrazone linker ensured release of doxorubicin in the lysosomes/endosomes after cellular uptake of the drug conjugate. ELP-Dox dosed at 5 mg doxorubicin equivalent/kg, extended the plasma half-life of doxorubicin to 5.5 hours. In addition, tumor uptake of ELP-Dox increased 2-fold when hyperthermia was applied, and was also enhanced compared to free doxorubicin. Although high levels of doxorubicin were found in the heart of animals treated with free doxorubicin, no detectable levels of doxorubicin were found in ELP-Dox-treated animals, indicating a correlation between tumor targeting and reduction of potential cardiac toxicity by ELP-Dox. At an optimal dose of 12 mg doxorubicin equivalent/kg, ELP-Dox in combination with hyperthermia induced a complete tumor growth inhibition, which was distinctly superior to free drug that only moderately inhibited tumor growth. In summary, our findings show that thermal targeting of ELP increases the potency of doxorubicin underlying the potential of exploiting ELPs to enhance the therapeutic efficacy of conventional anticancer drugs.
authors.affiliation: Department of Biochemistry, University of Mississippi Medical Center, Jackson, Mississippi 39216, USA.
authors.forename: Shama
authors.initials: S
authors.lastname: Moktan
authors.forename: Eddie
authors.initials: E
authors.lastname: Perkins
authors.forename: Felix
authors.initials: F
authors.lastname: Kratz
authors.forename: Drazen
authors.initials: D
authors.lastname: Raucher
mesh_terms: D000818:Animals; D001692:Biological Transport; D045744:Cell Line, Tumor; D057846:Cell-Penetrating Peptides / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology*; D004549:Elastin / Q000737:chemistry*; D005260:Female; D006801:Humans; D006979:Hyperthermia, Induced; D020714:Maximum Tolerated Dose; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000628:therapy
chemical_list: D057846:Cell-Penetrating Peptides; D004317:Doxorubicin; D004549:Elastin