Impact of conjugation chemistry on the pharmacokinetics of a peptide-polymer in traumatic brain injury

Student’s name: Alondra Davila Home Institution: Arizona State University NNCI Site: SDNI @ UC San Diego REU Principal Investigator: Dr. Ester Kwon – Department of Bioengineering, UC San Diego REU Mentor: Jason Wu - Department of Bioengineering, UC San Diego Abstract: Traumatic brain injury (TBI) is caused by an impactful external force on the head, which can result in death or acute and chronic neuropathologic damage and dysfunction. Currently there are no therapeutics that treat the underlying cause of disease progression. Major obstacles preventing the clinical translation of novel therapeutics are undesirable pharmacokinetics and limited accessibility to the brain. Nanomaterials can be readily modified in their size, charge, and physicochemical properties to improve the pharmacokinetics of therapeutics to allow for greater transport into the brain. CAQK (Cys-Ala-Glu-Lys) is a peptide sequence that has been shown to have both targeting and therapeutic potential in a mouse model of TBI following systemic intravenous administration. However, the peptide pharmacokinetics are poor, thereby limiting its clinical translation. In this work, we synthesized CAQK-targeted polyethylene glycol (PEG) nanomaterials to improve the peptide pharmacokinetics. We utilized three different conjugation chemistries: maleimide-thiol, dibenzocyclooctyne (DBCO)-azide copper-free click chemistry, and N-succinimidyl-3-(2-pyridyldithio)propionate (SPDP)-thiol. We then assessed the impact of conjugation chemistry on the pharmacokinetics of the peptide in a mouse model of TBI by measuring the blood half-life and biodistribution in the injured brain parenchyma. By systematically evaluating the advantages and limitations of these conjugation strategies, we identified the optimal approach to increasing peptide accumulation and retention within the injured brain.