One-dimensional poly(L-lysine)-block-poly(L-threonine) assemblies exhibit potent anticancer activity by enhancing membranolysis

Yu Fon Chen, Ai Li Shiau, Sue-Joan Chang, Nai Shin Fan, Chung Teng Wang, Chao Liang Wu, Jeng Shiung Jan

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Herein, we report the oncolytic activity of cationic, one-dimensional (1D) fibril assemblies formed from coil-sheet poly(L-lysine)-block-poly(L-threonine) (PLL-b-PLT) block copolypeptides for cancer therapy. The 1D fibril assemblies can efficiently interact with negatively charged cellular and mitochondrial membranes via electrostatic interactions, leading to necrosis via membrane lysis and apoptosis via the mitochondria-lytic effect. The concept is analogous to that of 1D drug carriers that exhibit enhanced cell penetration. In comparison to free PLL chains, PLL-b-PLT fibril assemblies exhibit selective cytotoxicity toward cancer cells, low hemolysis activity, enhanced membranolytic activity, and a different apoptosis pathway, which may be due to differences in the peptide-membrane interactions. Antitumor studies using a metastatic LL2 lung carcinoma model indicate that the fibril assemblies significantly inhibited tumor growth, improved survival in tumor-bearing mice and suppressed lung metastasis without obvious body weight loss. An additive efficacy was also observed for treatment with both PLL-b-PLT and cisplatin. These results support the feasibility of using 1D fibril assemblies as potential apoptotic anticancer therapeutics. Statement of Significance We report that cationic, one-dimensional (1D) fibril assemblies formed by coil-sheet poly(L-lysine)-block-poly(L-threonine) (PLL-b-PLT) block copolypeptides exhibited potent anticancer activity by enhancing membranolysis. The 1D fibril assemblies can efficiently interact with negatively charged cellular and mitochondrial membranes via electrostatic interactions, leading to necrosis via membrane lysis and apoptosis via mitochondria-lytic effect. Moreover, the fibril assemblies exhibited low hemolytic activity and selective cytotoxicity toward cancer cell, which is advantageous as compared to PLL and most antimicrobial/anticancerous peptides. This study provides a new concept of using cationic, 1D fibril assemblies for cancer therapy.

Original languageEnglish
Pages (from-to)283-295
Number of pages13
JournalActa Biomaterialia
Volume55
DOIs
Publication statusPublished - 2017 Jun 1

Fingerprint

Threonine
Lysine
Neoplasms
Membranes
Mitochondrial Membranes
Cell death
Apoptosis
Static Electricity
Mitochondria
Necrosis
Phase locked loops
Cytotoxicity
Coulomb interactions
Lung
Peptides
Drug Carriers
Tumors
Bearings (structural)
Therapeutics
Hemolysis

All Science Journal Classification (ASJC) codes

  • Biotechnology
  • Biomaterials
  • Biochemistry
  • Biomedical Engineering
  • Molecular Biology

Cite this

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title = "One-dimensional poly(L-lysine)-block-poly(L-threonine) assemblies exhibit potent anticancer activity by enhancing membranolysis",
abstract = "Herein, we report the oncolytic activity of cationic, one-dimensional (1D) fibril assemblies formed from coil-sheet poly(L-lysine)-block-poly(L-threonine) (PLL-b-PLT) block copolypeptides for cancer therapy. The 1D fibril assemblies can efficiently interact with negatively charged cellular and mitochondrial membranes via electrostatic interactions, leading to necrosis via membrane lysis and apoptosis via the mitochondria-lytic effect. The concept is analogous to that of 1D drug carriers that exhibit enhanced cell penetration. In comparison to free PLL chains, PLL-b-PLT fibril assemblies exhibit selective cytotoxicity toward cancer cells, low hemolysis activity, enhanced membranolytic activity, and a different apoptosis pathway, which may be due to differences in the peptide-membrane interactions. Antitumor studies using a metastatic LL2 lung carcinoma model indicate that the fibril assemblies significantly inhibited tumor growth, improved survival in tumor-bearing mice and suppressed lung metastasis without obvious body weight loss. An additive efficacy was also observed for treatment with both PLL-b-PLT and cisplatin. These results support the feasibility of using 1D fibril assemblies as potential apoptotic anticancer therapeutics. Statement of Significance We report that cationic, one-dimensional (1D) fibril assemblies formed by coil-sheet poly(L-lysine)-block-poly(L-threonine) (PLL-b-PLT) block copolypeptides exhibited potent anticancer activity by enhancing membranolysis. The 1D fibril assemblies can efficiently interact with negatively charged cellular and mitochondrial membranes via electrostatic interactions, leading to necrosis via membrane lysis and apoptosis via mitochondria-lytic effect. Moreover, the fibril assemblies exhibited low hemolytic activity and selective cytotoxicity toward cancer cell, which is advantageous as compared to PLL and most antimicrobial/anticancerous peptides. This study provides a new concept of using cationic, 1D fibril assemblies for cancer therapy.",
author = "Chen, {Yu Fon} and Shiau, {Ai Li} and Sue-Joan Chang and Fan, {Nai Shin} and Wang, {Chung Teng} and Wu, {Chao Liang} and Jan, {Jeng Shiung}",
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One-dimensional poly(L-lysine)-block-poly(L-threonine) assemblies exhibit potent anticancer activity by enhancing membranolysis. / Chen, Yu Fon; Shiau, Ai Li; Chang, Sue-Joan; Fan, Nai Shin; Wang, Chung Teng; Wu, Chao Liang; Jan, Jeng Shiung.

In: Acta Biomaterialia, Vol. 55, 01.06.2017, p. 283-295.

Research output: Contribution to journalArticle

TY - JOUR

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AU - Chen, Yu Fon

AU - Shiau, Ai Li

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AU - Fan, Nai Shin

AU - Wang, Chung Teng

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AU - Jan, Jeng Shiung

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