Targeting a genetically engineered elastin-like polypeptide to solid tumors by local hyperthermia.
Elastin-like polypeptides (ELPs) are biopolymers of the pentapeptide repeat Val-Pro-Gly-Xaa-Gly that undergo an inverse temperature phase transition. They are soluble in aqueous solutions below their transition temperature (T1) but hydrophobically collapse and aggregate at temperatures greater than T1. We hypothesized that ELPs conjugated to drugs would enable thermally targeted drug delivery to solid tumors if their T1 were between body temperature and the temperature in a locally heated region. To test this hypothesis, we synthesized a thermally responsive ELP with a T1 of 41 degrees C and a thermally unresponsive control ELP in Escherichia coli using recombinant DNA techniques. In vivo fluorescence videomicroscopy and radiolabel distribution studies of ELP delivery to human tumors (SKOV-3 ovarian carcinoma and D-54MG glioma) implanted in nude mice demonstrated that hyperthermic targeting of the thermally responsive ELP for 1 h provides a approximately 2-fold increase in tumor localization compared to the same polypeptide without hyperthermia. We observed aggregates of the thermally responsive ELP by fluorescence videomicroscopy within the heated tumor microvasculature but not in control experiments, which demonstrates that the phase transition of the thermally responsive ELP carrier can be engineered to occur in vivo at a specified temperature. By exploiting the phase transition-induced aggregation of these polypeptides, this method provides a new way to thermally target polymer-drug conjugates to solid tumors.
Department of Biomedical Engineering, Duke University, Durham, NC 27708-0281, USA.
D E
DE
Meyer
G A
GA
Kong
M W
MW
Dewhirst
M R
MR
Zalutsky
A
A
Chilkoti
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D004355:Drug Stability; D004549:Elastin / Q000737:chemistry / Q000235:genetics / Q000493:pharmacokinetics*; D005260:Female; D005910:Glioma / Q000378:metabolism*; D006801:Humans; D006979:Hyperthermia, Induced; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D018715:Microscopy, Video; D008969:Molecular Sequence Data; D010051:Ovarian Neoplasms / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry / Q000235:genetics / Q000493:pharmacokinetics*; D015202:Protein Engineering; D013696:Temperature; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D010455:Peptides; D004549:Elastin