Host-Guest Adduct as a Stimuli-Responsive Prodrug: Enzyme-Triggered Self-Assembly Process of a Short Peptide Within Mitochondria to Induce Cell Apoptosis.

Abstract

To address the issue of nonspecific biodistribution of a chemotherapeutic drug, stable [2]pseudorotaxane complexes (PK@CAOPP and PR@CAOPP) are used to demonstrate a proof of concept. Cationic -PPh₃ ⁺ moiety in CAOPP allows specific localization of the PK@CAOPP/ PR@CAOPP in the mitochondrial membrane (MM). Electrostatic interaction between the cationic Lysine^PK or Arginine^PR moiety and the negatively charged phosphoester^CAOPP functionality in CAOPP favours strong adduct formation. The ALP-induced hydrolytic cleavage of the phosphoester moiety in cancer cells triggers dephosphorylation and releases PK/ PR moiety from PK@CAOPP/PR@CAOPP. PK or PR, derived from the Phe-Phe dipeptide, formed fibril-like molecular aggregates in the MM to induce dysfunction, depolarization, ROS generation and apoptotic MCF7 cell death. Such phenomena were not observed in ALP-negative HEK293 normal cells. These propositions were confirmed through control studies using NBDK and PE, other guest molecules. Smaller size and inclusion of the short peptides (PK or PR) within the hydrophobic interior of CAOPP, were attributed to their stability in blood serum. Thus, we have demonstrated the use of supramolecular adducts as a potential therapeutic option for treating cancer cells without affecting healthy cells. The efficacy was also established with an in-vivo MCF7 tumour xenograft model using Balb/c nude mice.