Peptides of pHLIP family for targeted intracellular and extracellular delivery of cargo molecules to tumors
Significance Targeted delivery has been limited by reliance on tumor cell biomarkers. The emergence of the pH (low) insertion peptide (pHLIP) technology provides an alternative by targeting a metabolic marker, tumor cell surface acidity. We report several new pHLIPs, including a new concept, pHLIP bundles, and we evaluate these constructs alongside a new generation of pHLIPs. We also discuss challenges inherent to the design and accurate evaluation of pHLIPs. Our research elucidates the strengths and weaknesses of existing pHLIPs, proposes future peptide modifications that could further improve tumor targeting, and discusses the applicability of this new generation of pHLIPs for specific areas of drug delivery. The principles and new constructs promise to advance applications to tumor therapy.