Mitochondria targeting molecular transporters: synthesis, lipophilic effect, and ionic complex

Abstract

As mitochondria are potential therapeutic targeting sites for the treatment of human diseases, delivering cytotoxic drugs, antioxidants, and imaging molecules to mitochondria can provide new therapeutic opportunities. In an attempt to develop a new mitochondria-targeting vector, we synthesized sorbitol-based molecular transporters with multiple guanidines, measured their partition coefficients, compared their targeting efficiency using fluorescent images and Pearson's correlation coefficients, and studied cellular uptake mechanisms. To increase the targeting ability of these molecular transporters to mitochondria, alanine-naphthalene as a lipophilic group was attached to the molecular transporter, which improved translocation across cellular membranes and led to higher accumulation in mitochondria. The molecular transporter was able to form an ionic complex with antibiotics, resulting in low cell viability. These data demonstrate that the molecular transporter with a lipophilic group could be utilized as a potential drug delivery vector for treating mitochondrial dysfunction.

Circumventing challenges in mitochondrial targeting for cancer treatment: leveraging nanoplatforms for effective solutions

“…59 To overcome this, lipophilic molecules are preferred due to their membrane permeability, facilitated by hydrophobic interactions. 60…”

Dynamic responsiveness of self‐assembling peptide‐based nano‐drug systems

“…Delivering cytotoxic drugs, antioxidants, and other agents to mitochondria can be a novel strategy for treating intractable diseases. [153][154][155][156][157][158] Xu et al demonstrated perimitochondrial enzymatic peptide self-assembly to target mitochondria in liver cancer cells selectively (Figure 4B). Here, enterokinase in the mitochondria cleaved the peptide-lipid conjugates and delivered encapsulated chloramphenicol to cancer cell mitochondria to avoid inactivation, inhibiting mitochondrial protein synthesis, thereby inducing cell death and resensitizing drugresistant cells to cisplatin.…”

“…Several research groups have successfully achieved the in situ self‐assembly of peptide derivatives at the tumor tissue and even at cancer cell subcellular organelle levels. Delivering cytotoxic drugs, antioxidants, and other agents to mitochondria can be a novel strategy for treating intractable diseases 153–158 . Xu et al.…”

The role of sphingosine-1-phosphate in the development and progression of Parkinson’s disease

“…One particularly intriguing observation is that the activity of complex (I, II, III, or IV) remained unchanged before and after treatment ( Shults et al, 1995 ). At present, data from the literature show that not only are mitochondrial deficiencies present before drug treatment ( Punzi et al, 2018 ), but also that current drug therapy do not inhibit mitochondrial damage and resolve abnormal mitochondrial functions ( Murthy et al, 2022 ). These findings suggest that targeting the S1P pathway might be therapeutically important for PD patients through regulating mitochondrial function.…”