期刊
出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2016605118
关键词
pHLIP; pH-Low Insertion Peptide; pharmacokinetic modeling; tumor-targeted drug delivery; tumor acidity
资金
- NIH [R01 GM073857-13]
- NIH National Research Service Award [F30CA196020]
- Yale University's NIH Medical Scientist Training Program [T32GM007205]
The study investigates the determinants of pHLIP insertion, targeting, and delivery through computational modeling. It develops a mathematical model to describe the transmembrane insertion process and integrates it into a pharmacokinetic model to predict the biodistribution of pHLIPs. The analysis explores how changing pHLIP properties can influence tumor targeting and delivery efficacy, predicting optimal pHLIP phenotypes for superior tumor targeting and delivery capabilities.
A pH-Low Insertion Peptide (pHLIP) is a pH-sensitive peptide that undergoes membrane insertion, resulting in transmembrane helix formation, on exposure to acidity at a tumor cell surface. As a result, pHLIPs preferentially accumulate within tumors and can be used for tumor-targeted imaging and drug delivery. Here we explore the determinants of pHLIP insertion, targeting, and delivery through a computational modeling approach. We generate a simple mathematical model to describe the transmembrane insertion process and then integrate it into a pharmacokinetic model, which predicts the tumor vs. normal tissue biodistribution of the most studied pHLIP, wild-type pHLIP, over time after a single intravenous injection. From these models, we gain insight into the various mechanisms behind pHLIP tumor targeting and delivery, as well as the various biological parameters that influence it. Furthermore, we analyze how changing the properties of pHLIP can influence the efficacy of tumor targeting and delivery, and we predict the properties for optimal pHLIP phenotypes that have superior tumor targeting and delivery capabilities compared with wild-type pHLIP.
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