Inhibition of cancer cell proliferation and breast tumor targeting of pHLIP-monomethyl auristatin E conjugates.
Localized delivery is vital for the successful development of novel and effective therapeutics for the treatment of cancer. The targeting and delivery described herein is based on the pH (low) insertion peptide (pHLIP), a unique delivery peptide that can selectively target tumors in mice and translocate and release cargo molecules intracellularly based solely on the low extracellular pH intrinsic to cancer cells. In this study, we investigate the efficacy of pHLIP to target and deliver the highly potent and clinically validated microtubule inhibitor monomethyl auristatin E (MMAE) to cancer cells and breast tumors. We show that pHLIP-MMAE conjugates induce a potent cytotoxic effect (>90% inhibition of cell growth) in a concentration- and pH-dependent manner after only 2 h incubation without any apparent disruption of the plasma membrane. pHLIP-MMAE conjugates exhibit between an 11- and 144-fold higher antiproliferative effect at low pH than that at physiological pH and a pronounced pH-dependent cytotoxicity as compared to that of free drug. Furthermore, we demonstrate that a pHLIP-MMAE drug conjugate effectively targets triple-negative breast tumor xenografts in mice. These results indicate that pHLIP-based auristatin conjugates may have an enhanced therapeutic window as compared to that of free drug, providing a targeting mechanism to attenuate systemic toxicity.
†Department of Chemistry, Lehigh University, 6 East Packer Avenue, Bethlehem, Pennsylvania 18015, United States.
Kelly E
KE
Burns
‡Molecular Therapeutics Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, Pennsylvania 19111, United States.
Matthew K
MK
Robinson
†Department of Chemistry, Lehigh University, 6 East Packer Avenue, Bethlehem, Pennsylvania 18015, United States.
Damien
D
Thévenin
D062365:Aminobenzoates / Q000737:chemistry; D000818:Animals; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D049109:Cell Proliferation; D002626:Chemistry, Pharmaceutical / Q000379:methods; D002942:Circular Dichroism; D016503:Drug Delivery Systems; D005260:Female; D006367:HeLa Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008565:Membrane Proteins / Q000737:chemistry*; D051379:Mice; D009368:Neoplasm Transplantation; D009842:Oligopeptides / Q000737:chemistry*; D010455:Peptides / Q000737:chemistry; D010713:Phosphatidylcholines / Q000737:chemistry; D013050:Spectrometry, Fluorescence; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy*; D014364:Tryptophan / Q000737:chemistry
D062365:Aminobenzoates; D008565:Membrane Proteins; D009842:Oligopeptides; D010455:Peptides; D010713:Phosphatidylcholines; C543533:auristatin; C533201:pHLIP protein; D014364:Tryptophan; C028694:1-palmitoyl-2-oleoylphosphatidylcholine; C495575:monomethyl auristatin E
cytotoxicity; in vivo imaging; peptide; targeted drug delivery; tumor acidity