An injectable and in situ-gelling biopolymer for sustained drug release following perineural administration.
METHODS
This study evaluated whether the aggregation behavior of a thermally responsive elastin-like polypeptide (ELP) prolongs protein residence time at the dorsal root ganglion (DRG). This work involves development of a sustained-release drug delivery vehicle to provide high and sustained levels of biologic therapeutics to the dorsal root ganglion while minimizing systemic exposure.


OBJECTIVE
To study the potential of the ELP biopolymer to sustain release and lower systemic exposure of bioactive peptides following perineural administration.


BACKGROUND
Anticytokine treatment for lumbar radiculopathy may offer clinical improvement, but exposes patients to systemic toxicities of immunosuppression. ELPs are environmentally responsive polypeptides that undergo a phase transition on heating to form an insoluble aggregate. Drug conjugates with ELP exhibit both temperature-sensitivity and in vitro bioactivity. Monomer resolubilization yields solution-phase molecules, and this reversible aggregation behavior may create a perineural drug depot to sustain drug delivery to an inflamed nerve.


METHODS
This experiment involved 48 rats in which radiolabeled ELPs (aggregating or soluble) were injected overlying the L5 dorsal root ganglion. Animals were killed at 6 different time points, and radioactivity associated with the injected segment, serum, and other tissues was evaluated.


RESULTS
The aggregating ELP demonstrated a 7-fold longer perineural half-life compared with the soluble ELP. This supports the hypothesis that the aggregating ELP forms a depot from which slow resolubilization and clearance provides sustained, local protein release. Furthermore, serum radioactivity reached a lower peak for the aggregating group, demonstrating slower absorption of the aggregating protein into the systemic circulation.


CONCLUSIONS
These results suggest that ELP aggregation confer the benefit of perineural compartment longevity for bioactive therapeutics delivered fused with this carrier. This may sustain release of potent immunomodulator therapeutics to treat local neuroinflammation. Desirable features include delivery of high local doses and protection against systemic exposure and associated toxicity.
Shamji
Mohammed F
MF
Department of Biomedical Engineering, Duke University, Durham, North Carolina 27708, USA.
Whitlatch
Lyman
L
Friedman
Allan H
AH
Richardson
William J
WJ
Chilkoti
Ashutosh
A
Setton
Lori A
LA
D000704:Analysis of Variance; D000818:Animals; D001704:Biopolymers / Q000493:pharmacokinetics*; D003692:Delayed-Action Preparations / Q000493:pharmacokinetics; D004549:Elastin / Q000493:pharmacokinetics*; D005782:Gels; D007267:Injections; D016018:Least-Squares Analysis; D008159:Lumbar Vertebrae; D010455:Peptides / Q000493:pharmacokinetics*; D011843:Radiculopathy / Q000188:drug therapy*; D051381:Rats; D014018:Tissue Distribution
D001704:Biopolymers; D003692:Delayed-Action Preparations; D005782:Gels; D010455:Peptides; D004549:Elastin