Integrated Design of a Membrane‐Lytic Peptide‐Based Intravenous Nanotherapeutic Suppresses Triple‐Negative Breast Cancer

Abstract

Membrane-lytic peptides offer broad synthetic flexibilities and design potential to the arsenal of anticancer therapeutics, which can be limited by cytotoxicity to noncancerous cells and induction of drug resistance via stress-induced mutagenesis. Despite continued research efforts on membrane-perforating peptides for antimicrobial applications, success in anticancer peptide therapeutics remains elusive given the muted distinction between cancerous and normal cell membranes and the challenge of peptide degradation and neutralization upon intravenous delivery. Using triple-negative breast cancer as a model, the authors report the development of a new class of anticancer peptides. Through function-conserving mutations, the authors achieved cancer cell selective membrane perforation, with leads exhibiting a 200-fold selectivity over non-cancerogenic cells and superior cytotoxicity over doxorubicin against breast cancer tumorspheres. Upon continuous exposure to the anticancer peptides at growth-arresting concentrations, cancer cells do not exhibit resistance phenotype, frequently observed under chemotherapeutic treatment. The authors further demonstrate efficient encapsulation of the anticancer peptides in 20 nm polymeric nanocarriers, which possess high tolerability and lead to effective tumor growth inhibition in a mouse model of MDA-MB-231 triple-negative breast cancer. This work demonstrates a multidisciplinary approach for enabling translationally relevant membrane-lytic peptides in oncology, opening up a vast chemical repertoire to the arms race against cancer.

Development of membrane‐active peptide therapeutics in oncology

“…Unlike protein targets that can mutate and gain resistance against protein binding drugs, the tumor microenvironment and lipid compositions in the cell membranes are less likely to develop mutations and resistance and can be used as biomarkers for membrane‐active peptides. Multiple studies have shown the potential use of membrane‐active peptides to eradicate drug‐resistant cancer cells, cancer stem cells, and triple‐negative breast cancer (missing the common receptors in breast cancer), 47–50 whereas the gold standard doxorubicin (small molecules) and antibodies failed to treat them. In addition, our previous study found that cancer stem cells have difficulty gaining resistance against membrane‐active peptides over 28 days, whereas the cells developed drug resistance against doxorubicin in 10 days 50 .…”

“…Multiple studies have shown the potential use of membrane‐active peptides to eradicate drug‐resistant cancer cells, cancer stem cells, and triple‐negative breast cancer (missing the common receptors in breast cancer), 47–50 whereas the gold standard doxorubicin (small molecules) and antibodies failed to treat them. In addition, our previous study found that cancer stem cells have difficulty gaining resistance against membrane‐active peptides over 28 days, whereas the cells developed drug resistance against doxorubicin in 10 days 50 . Several studies also showed that membrane‐active peptides can be utilized in combination cancer therapy to improve drug potency through enhancing membrane permeation and synergy 50–53 …”

“…In addition, our previous study found that cancer stem cells have difficulty gaining resistance against membrane‐active peptides over 28 days, whereas the cells developed drug resistance against doxorubicin in 10 days 50 . Several studies also showed that membrane‐active peptides can be utilized in combination cancer therapy to improve drug potency through enhancing membrane permeation and synergy 50–53 …”

“…CLX001 combines the features of both cationic peptide and pH‐responsive peptide and makes the targeting more specific. CLX001 has been evaluated against a panel of cancer cell lines (breast cancer, ovarian cancer, cancer stem cells, and bone cancer) and mouse models with triple‐negative breast cancer 50 …”

Synthesis and Discovery of Ligustrazine–Heterocycle Derivatives as Antitumor Agents

“…The treatment of TNBC with natural medicines has also been investigated. Despite remarkable advances in the treatment of TNBC ( Chen et al, 2022 ), the lack of efficacious anticancer drugs is still a problem ( Zhang P. et al, 2022 ). In addition, the side effects of existing drugs are a major obstacle in the treatment of TNBC ( Olivier and Prasad, 2022 ; Zhang D. et al, 2022 ).…”