title: Thermal cycling enhances the accumulation of a temperature-sensitive biopolymer in solid tumors.
abstract: The delivery of anticancer therapeutics to solid tumors remains a critical problem in the treatment of cancer. This study reports a new methodology to target a temperature-responsive macromolecular drug carrier, an elastin-like polypeptide (ELP) to solid tumors. Using a dorsal skin fold window chamber model and intravital laser scanning confocal microscopy, we show that the ELP forms micron-sized aggregates that adhere to the tumor vasculature only when tumors are heated to 41.5 degrees C. Upon return to normothermia, the vascular particles dissolve into the plasma, increasing the vascular concentration, which drives more ELPs across the tumor blood vessel and significantly increases its extravascular accumulation. These observations suggested that thermal cycling of tumors would increase the exposure of tumor cells to ELP drug carriers. We investigated this hypothesis in this study by thermally cycling an implanted tumor in nude mice from body temperature to 41.5 degrees C thrice within 1.5 h, and showed the repeated formation of adherent microparticles of ELP in the heated tumor vasculature in each thermal cycle. These results suggest that thermal cycling of tumors can be repeated multiple times to further increase the accumulation of a thermally responsive polymeric drug carrier in solid tumors over a single heat-cool cycle. More broadly, this study shows a new approach--tumor thermal cycling--to exploit stimuli-responsive polymers in vivo to target the tumor vasculature or extravascular compartment with high specificity.
authors.affiliation: Department of Biomedical Engineering, Duke University, Durham, NC 27708, USA.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Dreher
authors.forename: Wenge
authors.initials: W
authors.lastname: Liu
authors.forename: Charles R
authors.initials: CR
authors.lastname: Michelich
authors.forename: Mark W
authors.initials: MW
authors.lastname: Dewhirst
authors.forename: Ashutosh
authors.initials: A
authors.lastname: Chilkoti
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism*; D003131:Combined Modality Therapy; D016503:Drug Delivery Systems; D004549:Elastin / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D006801:Humans; D006834:Hydrazines / Q000008:administration & dosage / Q000493:pharmacokinetics; D006979:Hyperthermia, Induced / Q000379:methods*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010455:Peptides / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D011806:Quinolinium Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics
chemical_list: C417561:Alexa 488 hydrazide; C481052:Alexa fluor 546; D006834:Hydrazines; D010455:Peptides; D011806:Quinolinium Compounds; C033943:elastin polypentapeptide; D004549:Elastin