Attachment Triggered Self-Assembly of Drugs into Nanoparticles

We have explored the capacity of ELPs to self-assemble into nanostructures in response to a range of stimuli. In one example, we designed a chimeric polypeptide that consists of two segments: (VPGXG)n repeats followed by a short (GGY)n segment, and showed that attachment of multiple copies of a hydrophobic molecule at the Y position can impart sufficient amphiphilicity to the polypeptide and thereby drive its self-assembly into near-monodisperse nanoparticles with the attached hydrophobic small molecule embedded in the core of the nanoparticle. This is an interesting finding, because it appears that any molecule with a hydrophobicity that is greater than a threshold value appears to drive attachment-triggered self-assembly of the chimeric polypeptide into a nanoparticle. Because many cancer chemotherapeutics are insoluble hydrophobic small molecules with poor bioavailability, this approach of attachment-triggered encapsulation of small hydrophobic molecules into soluble nanoparticles has great utility to increase the solubility, plasma-half-life and tumor accumulation of cancer chemotherapeutics.

Publications

Recombinant synthesis of hybrid lipid-peptide polymer fusions that self-assemble and encapsulate hydrophobic drugs. K.M. Luginbuhl; D. Mozhdehi; M. Dzuricky; P. Yousefpour; F.C. Huang; N.R. Mayne; K. Buehne; A. Chilkoti. (2017).
Niclosamide-conjugated polypeptide nanoparticles inhibit Wnt signaling and colon cancer growth. J. Bhattacharyya; Xrong Ren; R. Mook; J. Wang; I. Spasojevic; R. Premont; X. Li; W. Chen; A. Chilkoti. (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).
Encapsulating a Hydrophilic Chemotherapeutic into Rod-Like Nanoparticles of a Genetically Encoded Asymmetric Triblock Polypeptide Improves Its Efficacy. J. Bhattacharyya; I. Weitzhandler; S.Bryan Ho; J.R. McDaniel; X. Li; L. Tang; J. Liu; M. Dewhirst; A. Chilkoti. (2017).
Development of an Injectable Brachytherapy Using Self-Assembly Polypeptides. W. Liu; J.R. McDaniel; X. Li; J. Schaal; M. Zalutsky; A. Chilkoti. (2016).
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).
Developing Precisely Defined Drug-Loaded Nanoparticles by Ring-Opening Polymerization of a Paclitaxel Prodrug. J. Liu; Y. Pang; J. Bhattacharyya; W. Liu; I. Weitzhandler; X. Li; A. Chilkoti. (2016).
Maleimide-Functionalized Poly(2-Oxazoline)s and Their Conjugation to Elastin-Like Polypeptides. J.F. Nawroth; J.R. McDaniel; A. Chilkoti; R. Jordan; R. Luxenhofer. (2016).
A paclitaxel-loaded recombinant polypeptide nanoparticle outperforms Abraxane in multiple murine cancer models. J. Bhattacharyya; J.J. Bellucci; I. Weitzhandler; J.R. McDaniel; I. Spasojevic; X. Li; C.C. Lin; J.T.A. Chi; A. Chilkoti. (2015).
Bioinspired Reversibly Cross-linked Hydrogels Comprising Polypeptide Micelles Exhibit Enhanced Mechanical Properties. A. Ghoorchian; J.R. Simon; B. Bharti; W. Han; X. Zhao; A. Chilkoti; G.P. López. (2015).
Doxorubicin-conjugated polypeptide nanoparticles inhibit metastasis in two murine models of carcinoma. E.M. Mastria; M. Chen; J.R. McDaniel; X. Li; J. Hyun; M.W. Dewhirst; A. Chilkoti. (2015).
Ring-Opening Polymerization of Prodrugs: A Versatile Approach to Prepare Well-Defined Drug-Loaded Nanoparticles. J. Liu; W. Liu; I. Weitzhandler; J. Bhattacharyya; X. Li; J. Wang; Y. Qi; S. Bhattacharjee; A. Chilkoti. (2014).
Rational Design of “Heat Seeking” Drug Loaded Polypeptide Nanoparticles That Thermally Target Solid Tumors. J.R. McDaniel; S.R. MacEwan; X. Li; C.D. Radford; C.D. Landon; M.W. Dewhirst; A. Chilkoti. (2014).
Self-Assembly of Thermally Responsive Nanoparticles of a Genetically Encoded Peptide Polymer by Drug Conjugation. J.R. McDaniel; J. Bhattacharyya; K.B. Vargo; W. Hassouneh; D.A. Hammer; A. Chilkoti. (2013).
Doxorubicin-conjugated chimeric polypeptide nanoparticles that respond to mild hyperthermia. J.R. McDaniel; S.R. MacEwan; M.W. Dewhirst; A. Chilkoti. (2012).
Self-assembling chimeric polypeptide–doxorubicin conjugate nanoparticles that abolish tumours after a single injection. J.A. MacKay; M. Chen; J.R. McDaniel; W. Liu; A.J. Simnick; A. Chilkoti. (2009).