Abstract
The delivery of cancer therapeutics can be limited by pharmacological issues such as poor bioavailability and high toxicity to healthy tissue. pH-low insertion peptides (pHLIPs) represent a promising tool to overcome these limitations. pHLIPs allow for the selective delivery of agents to tumors on the basis of pH, taking advantage of the acidity of the hypoxic tumor microenvironment. This review article highlights the various applications in which pHLIPs have been utilized for targeting and treating diseases in hypoxic environments, including delivery of small molecule inhibitors, toxins, nucleic acid analogs, fluorescent dyes, and nanoparticles.
Highlights
Toxicity to healthy tissue can limit the dose and timing of several therapeutics especially cancer therapeutics, impacting quality of life and causing delays in treatments.the development of tumor-specific agents would represent an important step towards overcoming these limitations
Delivery of this construct occurs via three modes, where tumor targeting occurs due to enhanced permeation and retention (EPR) effect, pH-low insertion peptides (pHLIPs) mediated membrane internalization as a consequence of acidic environment due to hypoxic conditions, and nanoparticle uptake by adsorption mediated endocytosis [29]
PHLIP was used to renally deliver a Peptide Nucleic Acids (PNAs) targeting miR-33, a microRNA that plays a key role in inflammation, in a mouse model of kidney injury induced by the administration of folinic acid [71]
Summary
Toxicity to healthy tissue can limit the dose and timing of several therapeutics especially cancer therapeutics, impacting quality of life and causing delays in treatments. The development of tumor-specific agents would represent an important step towards overcoming these limitations. Much of the effort to develop targeted agents with relative tumor specificity has relied on the surface expression of tumor-specific antigens or cancer-specific dependence on signaling pathways. While these approaches have all led to important and meaningful improvements in cancer therapy, by nature of their design they are limited to specific cancer types and subtypes. PH-low insertion peptides (pHLIPs) represent a potential system to target tumors, and importantly do not rely on the surface expression of tumor-specific antigens. This review article outlines pHLIP function and describes the numerous ways that pHLIP has been used in experimental models to demonstrate efficacy for cancer therapy and/or imaging
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