ArticleBiophysical journal2017
Determination of the Membrane Translocation pK of the pH-Low Insertion Peptide.
Article in Biophysical journal, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed.
- Nanomaterial isolated extracellular vesicles enable high precision identification of tumor biomarkers for pancreatic cancer liquid biopsy.Journal of nanobiotechnology · 2025Article
- Selectivity of membrane-active peptides: the role of electrostatics and other membrane biophysical properties.Biophysical reviews · 2025Review
- Sequence-dependent scale for translocon-mediated insertion of interfacial helices in membranes.Science advances · 2025Article
- Neutron spin echo shows pHLIP is capable of retarding membrane thickness fluctuations.Biochimica et biophysica acta. Biomembranes · 2024Article
- Peptide-based capture-and-release purification of extracellular vesicles and statistical algorithm enabled quality assessment.bioRxiv : the preprint server for biology · 2024Article
- Article
- Recent Advances in Imaging Agents Anchored with pH (Low) Insertion Peptides for Cancer Theranostics.Molecules (Basel, Switzerland) · 2023Review
- Heterosynaptic plasticity in biomembrane memristors controlled by pH.MRS bulletin · 2023Article
- Controllable membrane remodeling by a modified fragment of the apoptotic protein Bax.Faraday discussions · 2021Article
- Theoretical and experimental comparisons of simple peptide-membrane systems; towards defining the reaction space: general discussion.Faraday discussions · 2021Article
- Roles of key residues and lipid dynamics reveal pHLIP-membrane interactions at intermediate pH.Biophysical journal · 2021Article
- Conformational Clamping by a Membrane Ligand Activates the EphA2 Receptor.Journal of molecular biology · 2021Article
- Pharmacokinetic modeling reveals parameters that govern tumor targeting and delivery by a pH-Low Insertion Peptide (pHLIP).Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Using Simulation to Understand the Role of Titration on the Stability of a Peptide-Lipid Bilayer Complex.Langmuir : the ACS journal of surfaces and colloids · 2020Article
- Tumor-Targeted, Cytoplasmic Delivery of Large, Polar Molecules Using a pH-Low Insertion Peptide.Molecular pharmaceutics · 2020Article
- Targeting Acidic Diseased Tissues by pH-Triggered Membrane-Associated Peptide Folding.Frontiers in bioengineering and biotechnology · 2020Review
- Peptide-Induced Lipid Flip-Flop in Asymmetric Liposomes Measured by Small Angle Neutron Scattering.Langmuir : the ACS journal of surfaces and colloids · 2019Article
- Ions at the Interface: Pushing the pK of pHLIP.Biophysical journal · 2019Article
- Ions Modulate Key Interactions between pHLIP and Lipid Membranes.Biophysical journal · 2019Article
- The Effect of Phosphatidylserine on a pH-Responsive Peptide Is Defined by Its Noninserting End.Biophysical journal · 2019Article
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3 authors.
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Abstract
The pH-low insertion peptide (pHLIP) is a leading peptide technology to target the extracellular acidosis that characterizes solid tumors. The pHLIP binds to lipid membranes, and responds to acidification by undergoing a coupled folding/membrane insertion process. In the final transmembrane state, the C terminus of pHLIP gets exposed to the cytoplasm of the target cell, providing a means to translocate membrane-impermeable drug cargoes across the plasma membrane of cancer cells. There exists a need to develop improved pHLIP variants to target tumors with greater efficiency. Characterization of such variants typically relies on determining the pK parameter, the pH midpoint of peptide insertion into the lipid bilayer. Here we report that the value of the pK can be strongly dependent on the method used for its determination. Membrane insertion of pHLIP involves at least four intermediate states, which are believed to be linked to the staggered titration of key acidic residues. We propose that some spectroscopic methods are influenced more heavily by specific membrane folding intermediates, and as a result yield different pK values. To address this potential problem, we have devised an assay to independently monitor the environment of the two termini of pHLIP. This approach provides insights into the conformation pHLIP adopts immediately before the establishment of the transmembrane configuration. Additionally, our data indicate that the membrane translocation of the C terminus of pHLIP, the folding step more directly relevant to drug delivery, occurs at more acidic pH values than previously considered. Consequently, such a pK difference could have substantial ramifications for assessing the translocation of drug cargoes conjugated to pHLIP.
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