Mitochondria targeting peptides for highly efficient cancer therapy

Abstract

Synthesis of Cyclic mitochondria penetrating peptides (MPPs) coordinated with Ir(III) complex and pH-responsive charge conversion MPPs , 2016, Jae-Hyeong Park, Graduate Program of Chemistry, Ulsan National Institute of Science and Technology(UNIST). Selectively targeting and accumulating the photosensitizers (PS) inside the cancer cells have considerable interest. Herein, we report simple, biocompatible and robust technique for the conjugation of iridium to the MPPs complexes to target the mitochondria of cancer cells. While considering the organelle specific targeting, the mitochondria have received vital merits, upon their ability to induce apoptosis and they become an ideal target for several PDT agents. Cyclic [HK(Fxr)nH] and corresponding linear peptide [K(Fxr)nHH] were conjugated with Ir(III) complexes[Red and Green]. Ir(III) complexes and histidine (His) which has positively charged amino acid can easily bind through coordination between imidazole side chain of histidine (His) and metal which is highly efficient and easily synthesized through cyclization procedure. As a result, this effectively develop designed strategy for PDT agent based on Ir(III) complexes, which specifically targeted the mitochondria. Moreover, this cyclic modified complexes showed an improved PDT effect compared to linear one, meaning of a potent mitochondria-targeted PDT agents in antitumor therapy. Although both forms possess abundant charge, cyclic structure with rigidity is ability to result in an ideal interface for interaction with membrane constituent more than flexible structure. Stimuli responsive degradation of chemical bonds are useful tools for the development of ‘smart materials’ which have remarkable applications in stimuli responsive drug delivery system. The pH is commonly applied to the cancer specific drug delivery system, because the pH near the tumor or in the tumor extracellular environment significantly acidic as pH 6-6.5 while the normal physiological pH is around 7.4. In this study, we designed and developed mitochondria targeting short peptide with charge conversion depending on pH values. The peptide sequences consists of FxrFxKK, possess positive charge and lipophilic character for targeting mitochondria. We conjugated drug (PU-10-COOH) as an inhibitor of HSP90 and maleic derivatives which are play a role of hydrolyzed in MPPs. Once maleic conjugated MPP extravagates into cell membrane through highly permeability, amide bonds within conjugate occur hydrolysis, reproducing intrinsic properties of MPP in the acidic tumor extracellular fluids (pH < 7) for cellular uptake and mitochondria targeting. Moreover, this platforms shows anticancer effect at 20 μM concentration. Therefore, we hope that this model conjugated peptides have a potent of cancer therapy agent.