Targeted drug delivery by thermally responsive polymers.
This review article summarizes recent results on the development of macromolecular carriers for thermal targeting of therapeutics to solid tumors. This approach employs thermally responsive polymers in conjunction with targeted heating of the tumor. The two thermally responsive polymers that are discussed in this article, poly(N-isopropylacrylamide-co-acrylamide) (poly(NIPAAm)) and an artificial elastin-like polypeptide (ELP), were designed to exhibit a soluble-insoluble lower critical solution transition in response to increased temperature slightly above 37 degrees C. In vivo fluorescent videomicroscopy and radiolabel distribution studies of ELP delivery to human tumors implanted in nude mice demonstrated that hyperthermic targeting of the thermally responsive ELP for 1 h provides a approximately two-fold increase in tumor localization compared to the same polypeptide without hyperthermia. Similar results were also obtained for poly(NIPAAm) though the extent of accumulation was somewhat lesser than observed for the ELP. The endocytotic uptake of a thermally responsive ELP was also observed to be significantly enhanced by the thermally triggered phase transition of the polypeptide in cell culture for three different tumor cell lines. Preliminary cytotoxicity studies of an ELP-doxorubicin conjugate indicate that the ELP-doxorubicin conjugate has near equivalent cytotoxicity as free doxorubicin in a cell culture assay.
Department of Biomedical Engineering, Box 90281, Duke University, Durham, NC 27708-0281, USA. chilkoti@duke.edu
Ashutosh
A
Chilkoti
Matthew R
MR
Dreher
Dan E
DE
Meyer
Drazen
D
Raucher
D000180:Acrylic Resins / Q000138:chemical synthesis*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D004317:Doxorubicin / Q000008:administration & dosage; D004337:Drug Carriers; D016503:Drug Delivery Systems; D004549:Elastin / Q000031:analogs & derivatives* / Q000138:chemical synthesis*; D005453:Fluorescence; D006361:Heating; D006801:Humans; D010455:Peptides / Q000138:chemical synthesis*; D011108:Polymers; D014407:Tumor Cells, Cultured
D000180:Acrylic Resins; D000970:Antineoplastic Agents; D004337:Drug Carriers; D010455:Peptides; D011108:Polymers; C469412:poly(N-isopropylacrylamide-co-acrylamide); D004317:Doxorubicin; D004549:Elastin