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Esposito, Tullio Vito Francesco

University of British Columbia

Nature presents a solution to drug resistant infections in the form of cationic host defense peptides (CHDPs), such as LL-37, that exhibit wide-ranging antimicrobial, anti-biofilm, and immunomodulatory properties. Innate defense regulators (IDRs), such as IDR-1002 and IDR-1018, are synthetic derivatives of CHDPs with enhanced effects on the host immune system but diminished direct antimicrobial activity. Many barriers exist in the development of CHDPs and IDRs. These include toxicity arising from the cationic and amphiphilic nature of the peptides, which gives them a propensity to lyse cell membranes and precipitate. Formulations have been reported, such as polymer conjugates, that improve their biocompatibility. However, a fundamental lack of knowledge exists around the pharmacokinetics of CHDPs and IDRs, whether in their native or formulated state. Understanding how these peptides are absorbed, distributed, metabolized and excreted is important to fully understand their mechanism, safety and efficacy profile, and to rationally drive their formulation and clinical translation. In this thesis, a detailed pharmacokinetic study was undertaken for LL-37, IDR-1002 and IDR-1018. The peptides were radiolabeled with gallium-67 and injected into healthy mice at doses between 1-40 mg/kg via several routes of administration— intravenous (IV), subcutaneous (SC), intratracheal (IT), intraperitoneal (IP). The peptides were then quantitatively tracked up to 48 h post-injection using nuclear techniques. At low doses, all peptides were well-tolerated across all routes of administration, rapidly absorbed from extracellular sites and rapidly cleared from the blood compartment. Higher doses of IDRs caused acute respiratory failure and death when given IV or IT. Pronounced lung distribution and disruption to the air-exchange surfaces was observed with high doses of IV IDRs. Delayed systemic absorption was noted upon dose escalation in the SC and IP cohorts, and visual signs of precipitation were observed at the SC injection site for IDR-1002. To overcome some of the toxicity and pharmacokinetic limitations observed, IDR-1002 was also reformulated in this thesis onto hyperbranched polyglycerol (HPG) via a redox-sensitive linkage. The conjugates had enhanced colloidal stability and maintained the biological profile of the IDR. Conjugates with a 5:1 peptide-to-polymer ratio, but not higher, circulated well when administered IV compared to native IDR-1002.

Text

2024-10-31

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/83079

Pharmaceutical Sciences

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/