A Supramolecular Nanomedicine Based on Bendamustine and MDM2‐Targeted D‐peptide Inhibitor for Breast Cancer Therapy

Abstract

Bendamustine (BEN) is a FDA-approved bifunctional DNA-alkylating chemotherapy drug, but it suffers from short half-life, instability, and poor biocompatibility in the clinical application. Due to unique biostability of d-amino acid-containing peptides (D-peptides), constructing D-peptide-small molecule drug conjugates is emerging as a promising strategy for cancer therapy. Here, a high-affinity MDM2-targeted D-peptide (peptide 5) is discovered by applying structure-based drug design (SBDD). Taking the advantages of d-amino acids, a novel self-assembling D-peptide-small molecule drug conjugate (BEN-FF-peptide 5) is developed by simultaneously conjugating small molecule drug BEN and peptide 5 to the self-assembling peptide. In vitro results demonstrate that BEN-FF-peptide 5 exhibits superior cellular uptake ability, good biostability in human serum and strong inhibitory effect on the growth of human breast cancer (MCF-7) cells. In vivo study reveals that BEN-FF-peptide 5 significantly inhibits the growth of MCF-7 cells-derived xenograft in nude mice with no obvious side effects. This work provides a useful strategy to construct D-peptide-small molecule drug conjugates for high-efficacy and low-toxicity cancer therapy.

Nanoscale bioconjugates: A review of the structural attributes of drug-loaded nanocarrier conjugates for selective cancer therapy

“…This strategy has approved higher cellular internalization, structural stability in human serum, and improved MCF-7 growth inhibition. Also, the MCF-7 cells viability impedes through p53 (target genes in MCF-7 cells) signaling regulation [ 134 ]. Advanced cancers in patients require specific therapeutic strategies.…”

Overcoming Endosomal Escape Barriers in Gene Drug Delivery Using De Novo Designed pH-Responsive Peptides

“…However, d -amino acids, which are rarely present in the body, exhibit resistance to enzymatic degradation . Studies have shown that incorporating d -peptides into l -peptide systems can enhance the enzymatic stability of their assembly structures, thereby extending their half-life in the body . Although the chiral modification of peptides has been extensively studied , as an important structural property for the development of peptide drugs such as blocking agents and antimicrobial peptides, its application in gene delivery systems remains unexplored.…”

“…16 Studies have shown that incorporating D-peptides into L-peptide systems can enhance the enzymatic stability of their assembly structures, thereby extending their half-life in the body. 17 Although the chiral modification of peptides has been extensively studied 18,19 as an important structural property for the development of peptide drugs such as blocking agents 20 and antimicrobial peptides, 21 its application in gene delivery systems remains unexplored. The chiral modification may further improve the gene drug delivery efficiency and stability of the peptide carriers.…”

Identification of novel and potent dual-targeting HDAC1/SPOP inhibitors using structure-based virtual screening, molecular dynamics simulation and evaluation of in vitro and in vivo antitumor activity

“…Structure-based virtual screening is a useful and valuable silico technique and is generally recognized as an important method for finding new drug compounds ( Zhou et al, 2021b ; Sanachai et al, 2022 ). Compared with traditional screening methods, structure-based virtual screening improves the efficiency of screening large-scale compound databases and also provides more reasonable and accurate binding modes ( Zhou et al, 2021a ; Sirous et al, 2021 ). In previous studies, kinds of research on single-targeting inhibitors of HDAC or SPOP using structure-based virtual screening has been reported ( Guo et al, 2016 ; Liu J. et al, 2020a ; Sirous et al, 2020 ).…”