A manganese (II)-based coordinative dendrimer with robust efficiency in intracellular peptide delivery

Abstract

Peptides have gained increasing interests as drug candidates in modern pharmaceutical industry, however, the development of peptide drugs acting on intracellular targets is limited due to their membrane impermeability. Here, we reported the use of metal-terpyridine based coordinative dendrimer for cytosolic peptide delivery. Among the investigated transition metal ions, Mn 2+ -coordinated polymer showed the highest delivery efficiency due to balanced peptide binding and release. It showed robust efficiency in the delivery of peptides with different charge property and hydrophobicity into various primary cells. The efficiency of Mn 2+ -terpyridine based polymer is superior to cell penetrating peptides such as oligoarginines. The material also delivered an autophagy-inducing peptide derived from Beclin-1 into cells and efficiently induced autophagy in the cells. This study provides a promising alternative to cell penetrating peptides for cytosolic peptide delivery.

Development of an autophagy activator from Class III PI3K complexes, Tat-BECN1 peptide: Mechanisms and applications

“…Other elements can be introduced simultaneously to facilitate targeted delivery, which will be discussed in the next session. Beclin 1 peptide can be directly packaged into metal (Mn 2+ )-terpyridine based coordinative dendrimer and released after cellular internalization with high efficiency compared to 11mer-Tat ( Ren et al, 2022 ). The last strategy develops soluble Beclin 1 peptide-containing fusion proteins, where thioredoxin (Trx) confers solubility and thermal stability, pH low insertion peptide (pHLIP) triggers the fusion protein translocation across the plasma membrane in a tumor acidic environment ( Ding et al, 2018 ).…”

Effects of polymer carriers on the occurrence and development of autophagy in drug delivery

“…Beclin1, encoded by BECN1 gene, is a mammalian homolog of Atg6 and takes part in the initiation of autophagosomes formation through binding to PI3K 65 . It could be a success strategy to induce autophagy that Beclin1 or its derived peptide are delivered into cell by nano-carriers, which can promote the LC3-I conversion and p62 degradation 66 . Polymer-peptide has a longer blood circulation for tumor-targeted delivery and enhances therapeutic effects.…”

“… 65 It could be a successful strategy to induce autophagy in which Beclin1 or its derived peptide are delivered into cells by nano-carriers, which can promote the LC3-I conversion and p62 degradation. 66 Polymer-peptide has longer blood circulation for tumor-targeted delivery and enhances therapeutic effects. Beclin1 was covalently grafted onto pH-sensitive polymers (poly(β-amino ester)), which self-assemble into nanoparticles (P-Bec1) with a PEG shell.…”

“…40,65 It is also applied in posterior capsular opacification in which abnormal organelles or proteins are degraded by autophagy. 86 There have been advances in endometriosis, 66 mitochondrial responses, 94 anti-inflammatory platform, 44,53,74 and antimicrobial activities. 82…”

Amphipathic poly-β-peptides for intracellular protein delivery

“…The first one introduced protein binding ligands, i.e. guanidinium, [29][30][31] boronate containing compounds 32,33 or metal chelates 2,34 to the polymer. These ligands could interact with amino acid residues on the cargo proteins via salt bridge, boronate-nitrogen or metal-nitrogen coordination interactions.…”