We exploit the electrostatic interactions between the
positively
charged neuroprotective peptide, pituitary adenylate cyclase-activating
polypeptide (PACAP), and negatively charged poly(lactic-co-glycolic acid) (PLGA) nanoparticles to control PACAP release from
the surface of nanoparticles dispersed in a hyaluronan-methylcellulose
(HAMC) hydrogel composite. PACAP is a promising therapeutic for the
treatment of neurological disorders, yet it has been difficult to
deliver in vivo. Herein, the PACAP release rate was tuned by manipulating
peptide adsorption onto the surface of blank nanoparticles by modifying
either nanoparticle loading in the hydrogel or nanoparticle surface
charge. This peptide–nanoparticle interaction was controlled
by the pH-responsive carboxylic acid end terminal groups of PLGA.
We further validated this system with the controlled release of a
novel stabilized PACAP analog: Ac-[Ala15, Ala20]PACAP-propylamide, which masks its recognition to peptidases in
circulation. Both wild-type and stabilized PACAP released from the
vehicle increased the production of neuroprotective Interleukin-6
from cultured primary astrocytes. Using computational fluid dynamics
methods, PACAP release from the composite was predicted based on experimentally
derived adsorption isotherms, which exhibited similar release profiles
to experimental data. This versatile adsorption-based system was used
to deliver PACAP locally to the brains of stroke-injured mice over
a 10 day period in vivo, highlighting its effectiveness for the controlled
release of PACAP to the central nervous system.