title: Injectable intratumoral depot of thermally responsive polypeptide-radionuclide conjugates delays tumor progression in a mouse model.
abstract: This study evaluated a biodegradable drug delivery system for local cancer radiotherapy consisting of a thermally sensitive elastin-like polypeptide (ELP) conjugated to a therapeutic radionuclide. Two ELPs (49 kDa) were synthesized using genetic engineering to test the hypothesis that injectable biopolymeric depots can retain radionuclides locally and reduce the growth of tumors. A thermally sensitive polypeptide, ELP(1), was designed to spontaneously undergo a soluble-insoluble phase transition (forming viscous microparticles) between room temperature and body temperature upon intratumoral injection, while ELP(2) was designed to remain soluble upon injection and to serve as a negative control for the effect of aggregate assembly. After intratumoral administration of radionuclide conjugates of ELPs into implanted tumor xenografts in nude mice, their retention within the tumor, spatio-temporal distribution, and therapeutic effect were quantified. The residence time of the radionuclide-ELP(1) in the tumor was significantly longer than the thermally insensitive ELP(2) conjugate. In addition, the thermal transition of ELP(1) significantly protected the conjugated radionuclide from dehalogenation, whereas the conjugated radionuclide on ELP(2) was quickly eliminated from the tumor and cleaved from the biopolymer. These attributes of the thermally sensitive ELP(1) depot improved the antitumor efficacy of iodine-131 compared to the soluble ELP(2) control. This novel injectable and biodegradable depot has the potential to control advanced-stage cancers by reducing the bulk of inoperable tumors, enabling surgical removal of de-bulked tumors, and preserving healthy tissues.
authors.affiliation: Department of Biomedical Engineering, Duke University, Durham, NC, USA.
authors.forename: Wenge
authors.initials: W
authors.lastname: Liu
authors.forename: J Andrew
authors.initials: JA
authors.lastname: MacKay
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Dreher
authors.forename: Mingnan
authors.initials: M
authors.lastname: Chen
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: McDaniel
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Simnick
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Callahan
authors.forename: Michael R
authors.initials: MR
authors.lastname: Zalutsky
authors.forename: Ashutosh
authors.initials: A
authors.lastname: Chilkoti
mesh_terms: D000818:Animals; D000941:Antigens; D001704:Biopolymers; D004304:Dosage Forms; D016503:Drug Delivery Systems / Q000379:methods*; D004549:Elastin / Q000235:genetics; D005260:Female; D006358:Hot Temperature; D007267:Injections; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms; D009385:Neoplastic Processes; D010455:Peptides / Q000235:genetics*; D011868:Radioisotopes
chemical_list: D000941:Antigens; D001704:Biopolymers; D004304:Dosage Forms; D010455:Peptides; D011868:Radioisotopes; D004549:Elastin