Article

Fusions of elastin-like polypeptides to pharmaceutical proteins.

Department of Biomedical Engineering, Duke University, Durham, North Carolina, USA.
Methods in enzymology (impact factor: 1.9). 01/2012; 502:215-37. DOI:10.1016/B978-0-12-416039-2.00024-0 pp.215-37
Source: PubMed

ABSTRACT Elastin-like polypeptides (ELPs) are a class of stimulus-responsive biopolymers whose physicochemical properties and biocompatibility are particularly suitable for in vivo applications, such as drug delivery and tissue engineering. The lower critical solution temperature (LCST) behavior of ELPs allows them to be utilized as soluble macromolecules below their LCST, or as self-assembled nanoscale particles such as micelles, micron-scale coacervates, or viscous gels above their LCST, depending on the ELP architecture. As each ELP sequence is specified at its genetic level, functionalization of an ELP with peptides and proteins is simple to accomplish by the fusion of a gene encoding an ELP with that of the peptide or protein of interest. Protein ELP fusions, where the appended protein serves a therapeutic or targeting function, are suitable for applications in which the ELP can improve the systemic pharmacokinetics and biodistribution of the protein, or can be used as an injectable depot for sustained, local protein delivery. Here we describe considerations in the design of therapeutic protein ELP fusions and provide details of their gene design, expression, and purification.

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  • Article: Injectable intratumoral depot of thermally responsive polypeptide-radionuclide conjugates delays tumor progression in a mouse model.
    Wenge Liu, J Andrew MacKay, Matthew R Dreher, Mingnan Chen, Jonathan R McDaniel, Andrew J Simnick, Daniel J Callahan, Michael R Zalutsky, Ashutosh Chilkoti
    [show abstract] [hide abstract]
    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.
    Journal of Controlled Release 05/2010; 144(1):2-9. · 5.73 Impact Factor
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.

Keywords

appended protein
 
biocompatibility
 
drug delivery
 
Elastin-like polypeptides
 
ELP architecture
 
gene design
 
gene encoding
 
genetic level
 
local protein delivery
 
lower critical solution temperature
 
micron-scale coacervates
 
physicochemical properties
 
Protein ELP fusions
 
self-assembled nanoscale particles
 
soluble macromolecules
 
stimulus-responsive biopolymers
 
therapeutic protein ELP fusions
 
tissue engineering
 
viscous gels
 
vivo applications