A smart tumor targeting peptide–drug conjugate, pHLIP-SS-DOX: synthesis and cellular uptake on MCF-7 and MCF-7/Adr cells

Abstract

Doxorubicin (DOX) is a potent anticancer drug for the treatment of tumors, but the poor specificity and multi-drug resistance (MDR) on tumor cells have restricted its application. Here, a pH and reduction-responsive peptide-drug conjugate (PDC), pHLIP-SS-DOX, was synthesized to overcome these drawbacks. pH low insertion peptide (pHLIP) is a cell penetrating peptide (CPP) with pH-dependent transmembrane ability. And because of the unique cell membrane insertion pattern, it might reverse the MDR. The cellular uptake study showed that on both drug-sensitive MCF-7 and drug-resistant MCF-7/Adr cells, pHLIP-SS-DOX obviously facilitated the uptake of DOX at pH 6.0 and the uptake level on MCF-7/Adr cells was similar with that on MCF-7 cells, indicating that pHLIP-SS-DOX had the ability to target acidic tumor cells and reverse MDR. In vitro cytotoxicity study mediated by GSH-OEt demonstrated that the cytotoxic effect of pHLIP-SS-DOX was reduction responsive, with obvious cytotoxicity at pH 6.0; while it had poor cytotoxicity at pH 7.4, no matter with or without GSH-OEt pretreatment. This illustrated that pHLIP could deliver DOX into tumor cells with acidic microenvironment specifically and could not deliver drugs into normal cells with neutral microenvironment. In summary, pHLIP-SS-DOX is a promising strategy to target drugs to tumors and provides a possibility to overcome MDR.

Targeting Acidic Diseased Tissues by pH-Triggered Membrane-Associated Peptide Folding

“…Targeted pHLIP-mediated delivery of moderately hydrophobic small molecule drugs has proven to be successful as well. Among the drugs that have been delivered are potent inhibitors of tubulin, such as monomethyl auristatin E, poly (ADP-ribose) polymerase inhibitors (PARPi's) including rucaparib and talazoparib, and other molecules (Burns et al, 2015(Burns et al, , 2017Song et al, 2016). A notable property is that pHLIP delivery has been shown to reduce bone marrow accumulation and toxicity, which is a significant issue in the use of many potent cytotoxic molecules.…”

Co-delivery of docetaxel and bortezomib based on a targeting nanoplatform for enhancing cancer chemotherapy effects

“…Stimuli responsive drug delivery systems are considered to be promising for the control of drug release in vivo (Liu et al, 2017b). Given the pH values variations from physiological pH to slightly acidic pH in normal tissues versus neoplastic tissues (Dai et al, 2011), a pH-triggered strategy is particularly attractive for the design of an anticancer drug delivery system (Luo et al, 2012;Song et al, 2016;Liu et al, 2017a). Su et al (2011) described a novel pH responsive mechanism based on facile conjugation of the anticancer drug BTZ to catechol containing polymeric carriers.…”

Applications of pHLIP Technology for Cancer Imaging and Therapy

“…At low pH (pH <6.5), pHLIPs promote delivery of cell-permeable therapeutic cargoes such as the tubulin -binding toxin monomethyl auristatin E (MMAE) and the DNA intercalator doxorubicin, and reduces the cellular entry of these cargoes into healthy tissue at normal physiological pH [57, 58]. pHLIP MMAE conjugates have cytotoxic effects at low pH, inhibiting cell growth by more than 90%, and targeted triple-negative breast cancer tumors in mice [58].…”