Applications of pHLIP Technology for Cancer Imaging and Therapy

• Published in: Trends in biotechnology (Regular ed.) Vol. 35; no. 7; pp. 653 - 664
• Main Authors: Wyatt, Linden C., Lewis, Jason S., Andreev, Oleg A., Reshetnyak, Yana K., Engelman, Donald M.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.07.2017; Elsevier Limited
• Subjects: Acidification; Acidity; Acidosis; Amino acids; Animals; antibodies; Antibodies, Neoplasm - therapeutic use; Biochemistry; Biomarkers; Biomarkers, Tumor - metabolism; Cancer; Cancer therapies; Cell growth; Cell-Penetrating Peptides - pharmacokinetics; Cell-Penetrating Peptides - therapeutic use; chemical elements; Clonal selection; Cytoplasm; Diagnosis; drug delivery; Drug Delivery Systems - methods; Effectiveness; Folding; Head & neck cancer; Humans; Hydrogen-Ion Concentration; image analysis; Imaging; Insertion; Internal Medicine; Membranes; Metabolism; Metastases; metastasis; Nanoparticles; nanotechnology; neoplasm cells; neoplasms; Neoplasms - diagnostic imaging; Neoplasms - drug therapy; Neoplasms - metabolism; Neoplasms - pathology; Optical Imaging - methods; Peptides; Permeability; Physiology; therapeutics; Therapy; tissues; Tumor cells; tumor targeting; Tumors; nanotechnology; tumor targeting; acidity; drug delivery; imaging
• ISSN: 0167-7799; 1879-3096; 1879-3096
• DOI: 10.1016/j.tibtech.2017.03.014

Acidity is a biomarker of cancer that is not subject to the blunting clonal selection effects that reduce the efficacy of other biomarker technologies, such as antibody targeting. The pH (low) insertion peptides (pHLIP®s) provide new opportunities for targeting acidic tissues. Through the physical mechanism of membrane-associated folding, pHLIPs are triggered by the acidic microenvironment to insert and span the membranes of tumor cells. The pHLIP platform can be applied to imaging acidic tissues, delivering cell-permeable and impermeable molecules to the cytoplasm, and promoting the cellular uptake of nanoparticles. Since acidosis is a hallmark of tumor development, progression, and aggressiveness, the pHLIP technology may prove useful in targeting cancer cells and metastases for tumor diagnosis, imaging, and therapy. pHLIP®s target cancer cells in primary tumors as well as metastases based on the acidic environment that is universal to tumor tissues. Acidity-based targeting is not diminished by the phenomena that blunt the efficacy of other biomarker-based targeting methods. pHLIPs exist as monomers and remain anchored across the membrane, leaving it intact, which distinguishes them from pore-forming and cell-penetrating peptides. A growing family of pHLIP variants gives choices for the delivery of various cargoes, including imaging agents for nuclear diagnostic imaging and fluorescence guided surgery, cell-permeable and impermeable therapeutic agents for intracellular delivery, and different types of nanoparticles. pHLIPs show promise for many medical applications, and the clinical translation of several pHLIP conjugates is currently underway.