Injectable ELP Depots for Drug Delivery

We have several projects in the area of injectable drug delivery depots: (1) in a project on the intratumoral delivery of radionuclides, we have covalently conjugated radionuclides to an ELP with a transition temperature below body temperature and injected these conjugates directly into tumors. Injection leads to the thermally triggered formation of a viscous "jelly-like" depot of the ELP-radionuclide depot within the tumor that can persist for a week or more, during which time it irradiates the tumor from the "inside-out". We are exploring how the transition temperature and internal microstructure of the ELP depot controls the stability of the depot and its effect on tumor regression.  The clinical application of this research is the development of an injectable alternative to surgically implanted brachytherapy seeds for treatment of prostate cancer.  (2) We  have fused peptide drugs, such as glucagon-like peptide-1 (GLP-1) to an ELP that undergoes its phase transition below body temperature upon sub-cutaneous (s.c.) injection, and have used these s.c. depots for the sustained release of the peptide drug.  This approach is promising for the delivery of peptide drugs, because they are typically proteolytically unstable and are rapidly cleared from circulation; the ELP depot protects them from premature proteolysis and increases their in vivo half-life. (3) We are investigating injectable depots for the intratumoral delivery of highly potent but systemically toxic protein drugs like immunotoxins .  (4) We are beginning to explore the use of injectable depots for the sustained and tunable release of antigens and adjuvants for the development of vaccines, building upon ourexperience with injectable depots in other therapeutic contexts.

Publications

One-week glucose control via zero-order release kinetics from an injectable depot of glucagon-like peptide-1 fused to a thermosensitive biopolymer. K.M. Luginbuhl; J.L. Schaal; B. Umstead; E.M. Mastria; X. Li; S. Banskota; S. Arnold; M. Feinglos; D.’ Alessio; A. Chilkoti. (2017).
Injectable polypeptide micelles that form radiation crosslinked hydrogels in situ for intratumoral radiotherapy. J.L. Schaal; X. Li; E. Mastria; J. Bhattacharyya; M.R. Zalutsky; A. Chilkoti; W. Liu. (2016).
Controlled release of biologics for the treatment of type 2 diabetes. C.A. Gilroy; K.M. Luginbuhl; A. Chilkoti. (2015).
Spatiotemporally Photoradiation-Controlled Intratumoral Depot for Combination of Brachytherapy and Photodynamic Therapy for Solid Tumor. R. Mukerji; J. Schaal; X. Li; J. Bhattacharyya; D. Asai; M.R. Zalutsky; A. Chilkoti; W. Liu. (2015).
Sustained intra-articular delivery of IL-1Ra from a thermally-responsive elastin-like polypeptide as a therapy for post-traumatic arthritis. K.A. Kimmerline; B.D. Furman; D.S. Mangiapani; M.A. Moverman; M.S. Sinclair; J.L. Huebner; A. Chilkoti; V.B. Kraus; L.A. Setton; F. Guilak; S.A. Olson. (2015).
A genetically engineered thermally responsive sustained release curcumin depot to treat neuroinflammation. M.S. Sinclair; J. Bhattacharyya; J.R. McDaniel; D.M. Gooden; R. Gopalaswamy; A. Chilkoti; L.A. Setton. (2013).
Brachytherapy Using Injectable Seeds That Are Self-Assembled from Genetically Encoded Polypeptides In Situ. W. Liu; J.R. McDaniel; X. Li; D. Asai; F. García Quiroz; J. Schaal; J.S. Park; M.R. Zalutsky; A. Chilkoti. (2012).
Thermal Cycling Enhances the Accumulation of a Temperature-Sensitive Biopolymer in Solid Tumors. M.R. Dreher; W. Liu; C.R. Michelich; M.W. Dewhirst; A. Chilkoti. (2007).