Targeted Delivery by Digitally Switchable ELPs

We work on genetically encoded, stimulus responsive elastin-like polypeptides (ELPs) that can be digitally switched between two states in response to a physiologically relevant trigger. In one example of the utility of ELPs for drug delivery, we have designed diblock ELPs that self-assemble into monodisperse micelles in response to a thermal trigger, wherein self-assembly in the narrow temperature range between 37 ºC (normal body temperature) and 42 ºC (highest temperature approved for mild clinical hyperthermia) results in the presentation of a functional cell penetrating peptide (CPP) motif. The presentation of a functional CPP only at 42 ºC, but not at 37 ºC opens the way to convert CPPs, which are powerful yet promiscuous agents to promote the uptake of drugs into cells, into an exquisitely targeted system for cancer drug delivery via the application of focused external hyperthermia to solid tumors.

We also work on pH-responsive polypeptide micelles that dissociate in response to the low extracellular pH of solid tumors. This system consists of a histidine-rich diblock ELP that self-assembles at 37°C into spherical micelles that are further stabilized by Zn2+ and are disrupted as the pH drops from 7.4 to 6.4. These pH-sensitive micelles demonstrate better in vivo penetration and distribution in tumors than a pH-insensitive control and provide a potential solution to the problem of limited tumor penetration of nanoparticle drug delivery vehicles. These examples illustrate the precision with which genetic engineering can be exploited for the design of peptide polymers that digitally switch between an assembled and disassembled state in response to a clinically relevant trigger, with intriguing implications for the in vivo delivery of drugs or imaging agents.

We'd like to direct your attention to 2 poems written by SR MacEwan on this research project:

1.  Extrinsically controlled intracellular drug delivery

2.  An Ode to Biopolymers

Publications

Programming molecular self-assembly of intrinsically disordered proteins containing sequences of low complexity. J.R. Simon; N.J. Carroll; M. Rubinstein; A. Chilkoti; G.P. ópez. (2017).
Characterisation of hydration and nanophase separation during the temperature response in hydrophobic/hydrophilic elastin-like polypeptide (ELP) diblock copolymers. K. Widder; S.R. MacEwan; E. Garanger; V. úñez; ébastien Lecommandoux; A. Chilkoti; D. Hinderberger. (2017).
Phase behavior and self-assembly of perfectly sequence-defined and monodisperse multi-block copolypeptides. S.R. MacEwan; I. Weitzhandler; I. Hoffmann; J. Genzer; M. Gradzielski; A. Chilkoti. (2017).
Prediction of solvent-induced morphological changes of polyelectrolyte diblock copolymer micelles. N.K. Li; W.H. Fuss; L. Tang; R. Gu; A. Chilkoti; S. Zauscher; Y.G. Yingling. (2015).
Structural Evolution of a Stimulus-Responsive Diblock Polypeptide Micelle by Temperature Tunable Compaction of its Core. E. Garanger; S.R. MacEwan; O. Sandre; A. Brûlet; L. Bataille; A. Chilkoti; S. Lecommandoux. (2015).
Elastin-like Polypeptide Diblock Copolymers Self-Assemble into Weak Micelles. W. Hassouneh; E.B. Zhulina; A. Chilkoti; M. Rubinstein. (2015).
Triple Stimulus-Responsive Polypeptide Nanoparticles That Enhance Intratumoral Spatial Distribution. D.J. Callahan; W. Liu; X. Li; M.R. Dreher; W. Hassouneh; M. Kim; P. Marszalek; A. Chilkoti. (2012).
Stimulus-responsive macromolecules and nanoparticles for cancer drug delivery. S.R. MacEwan; D.J. Callahan; A. Chilkoti. (2010).