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

doi:10.1016/j.actbio.2017.04.009

Cited by 27 publications

(21 citation statements)

References 49 publications

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“…It demonstrated that PLL segments, due to their confinement, can adopt more ordered conformation by conjugating with a functional moiety on the side chain or a hydrophobic polypeptide on the chain end [ 38 , 39 , 40 , 41 , 42 ]. Rather, the PLL conformation exhibited little dependence on the conjugation of hydrophilic polymer on a PLL segment [ 16 , 43 ]. It is worth noting that a low percentage of α -helical conformation adopted by s -PLL- b -PLeu was detected by CD ( Table 1 ).…”

Section: Resultsmentioning

confidence: 99%

Polypeptide Composition and Topology Affect Hydrogelation of Star-Shaped Poly(L-lysine)-Based Amphiphilic Copolypeptides

Phan

Huang

Tsai

et al. 2021

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In this research, we studied the effect of polypeptide composition and topology on the hydrogelation of star-shaped block copolypeptides based on hydrophilic, coil poly(L-lysine)20 (s-PLL20) tethered with a hydrophobic, sheet-like polypeptide segment, which is poly(L-phenylalanine) (PPhe), poly(L-leucine) (PLeu), poly(L-valine) (PVal) or poly(L-alanine) (PAla) with a degree of polymerization (DP) about 5. We found that the PPhe, PLeu, and PVal segments are good hydrogelators to promote hydrogelation. The hydrogelation and hydrogel mechanical properties depend on the arm number and hydrophobic polypeptide segment, which are dictated by the amphiphilic balance between polypeptide blocks and the hydrophobic interactions/hydrogen bonding exerted by the hydrophobic polypeptide segment. The star-shaped topology could facilitate their hydrogelation due to the branching chains serving as multiple interacting depots between hydrophobic polypeptide segments. The 6-armed diblock copolypeptides have better hydrogelation ability than 3-armed ones and s-PLL-b-PPhe exhibits better hydrogelation ability than s-PLL-b-PVal and s-PLL-b-PLeu due to the additional cation–π and π–π interactions. This study highlights that polypeptide composition and topology could be additional parameters to manipulate polypeptide hydrogelation.

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Section: Resultsmentioning

confidence: 99%

Polypeptide Composition and Topology Affect Hydrogelation of Star-Shaped Poly(L-lysine)-Based Amphiphilic Copolypeptides

Phan

Huang

Tsai

et al. 2021

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“…In other words, the width of the fibril assemblies should be the length of sheetlike PLT domain plus the length of the two coil PLL ones. Based on the contour lengths of the coil PLL and sheetlike PLT, ,, the width of PLL 20 - b -PLT 8 assemblies is calculated to be about 15.0 nm. The widths of the PLL 20 - b -PLT 8 fibrils determined from the TEM image are found to be slightly smaller than the calculated ones, which can be attributed to the shrinkage of coil PLL segments upon drying.…”

Section: Resultsmentioning

confidence: 99%

“…The polypeptide was synthesized by using hexylamine (Sigma-Aldrich) as the initiator to sequentially polymerize Z - l -lysine (ZLL) and O -benzyl- l -threonine (BnT) NCAs with designated feed molar ratios between the initiator and NCAs. ZLL and BnT NCAs were synthesized through reacting triphosgene (98%, Sigma-Aldrich) with N ε - Z - l -lysine (∼99%, Sigma-Aldrich) and N -Boc-( O -benzyl)- l -threonine (>99%, Bachem), respectively. − The solvents (ACS Reagent) used for polypeptide synthesis, hexane and dichloromethane, were dried using Na metal (99.95%, Sigma-Aldrich) and calcium hydride (95%, Sigma-Aldrich), respectively. The detailed synthesis procedures of a specific block copolypeptide are given below.…”

Section: Experimental Sectionmentioning

confidence: 99%

“…PLL 30 - b -PLT 12 block copolypeptide was obtained by removing the Z and benzyl protecting groups on PZLL 30 - b -PBnT 12 using HBr (33 wt % in acetic acid, Sigma-Aldrich) and iodotrimethylsilane (TMSiI, Sigma-Aldrich). , In a 100 mL flask, excess HBr with 5-fold of the moles of Z group was added to a solution containing 0.3 g of PZLL 30 - b -PBnT 12 polypeptide dissolved in 30 mL of trifluoroacetic acid (Sigma-Aldrich) via syringe. After stirring for 30 min, TMSiI with the volume based on 150 μL of TMSiI per 1 mmol of benzyl group was added to the flask via syringe, and the resultant solution was stirred for an additional 120 min.…”

Section: Experimental Sectionmentioning

confidence: 99%

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Self-Assembly and Hydrogelation of Coil–Sheet Poly(l-lysine)-block-poly(l-threonine) Block Copolypeptides

et al. 2018

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This study reports the self-assembly and hydrogelation of coil−sheet poly(L-lysine)-block-poly(L-threonine) (PLLb-PLT) block copolypeptides. Our experiments showed that the PLL-b-PLT block copolypeptides with degrees of polymerization (DPs) between 30 and 60 can self-assemble to form fibrils due to the packing of sheetlike PLT at low polymer concentrations; moreover, further increasing the polymer concentration can result in the formation of transparent hydrogels due to fibril entanglements. The hydrogelation was determined by the orientation and packing of the fibril assemblies, which aremainly dictated by the balance between the intermolecular hydrogen bonding interactions and charge repulsion exerted respectively by sheetlike PLT and positively charged, coil PLL segments. The noncovalent interactions can be manipulated by varying the polypeptide chain length and composition, which would result in these block copolypeptides exhibiting different critical gelation concentrations (CGCs), gel molecular assemblies, and mechanical properties.

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“…The PFAs’ in vitro inhibition of lung cancer cell migration and clonogenesis, as well as in vivo antimetastatic activity on lung cancer cells, was thus evaluated. Based on our previous study, Lys 40 - b -Thr 20 PFAs presented an anticancer effect through the enhancing of the membranolytic effects . However, the possible inhibition of metastasis by PFAs has not been explored in detail.…”

Section: Introductionmentioning

confidence: 99%

Peptide Fibrillar Assemblies Exhibit Membranolytic Effects and Antimetastatic Activity on Lung Cancer Cells

et al. 2020

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Cancer metastasis is a central oncology concern that worsens patient conditions and increases mortality in a short period of time. During metastatic events, mitochondria undergo specific physiological alterations that have emerged as notable therapeutic targets to counter cancer progression. In this study, we use drug-free, cationic peptide fibrillar assemblies (PFAs) formed by poly(L-Lysine)-block-poly(L-Threonine) (Lysb-Thr) to target mitochondria. These PFAs interact with cellular and mitochondrial membranes via electrostatic interactions, resulting in membranolysis. Charge repulsion and hydrogen-bonding interactions exerted by Lys and Thr segments dictate the packing of the peptides and enable the PFAs to display enhanced membranolytic activity toward cancer cells. Cytochrome c (cyt c), endonuclease G, and apoptosis-inducing factor were released from mitochondria after treatment of lung cancer cells, subsequently inducing caspase-dependent and caspase-independent apoptotic pathways. A metastatic xenograft mouse model was used to show how the PFAs significantly suppressed lung metastasis and inhibited tumor growth, while avoiding significant body weight loss and mortality. Antimetastatic activities of PFAs are also demonstrated by in vitro inhibition of lung cancer cell migration and clonogenesis. Our results imply that the cationic PFAs achieved the intended and targeted mitochondrial damage, providing an efficient antimetastatic therapy.

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

Cited by 27 publications

References 49 publications

Polypeptide Composition and Topology Affect Hydrogelation of Star-Shaped Poly(L-lysine)-Based Amphiphilic Copolypeptides

Polypeptide Composition and Topology Affect Hydrogelation of Star-Shaped Poly(L-lysine)-Based Amphiphilic Copolypeptides

Self-Assembly and Hydrogelation of Coil–Sheet Poly(l-lysine)-block-poly(l-threonine) Block Copolypeptides

Peptide Fibrillar Assemblies Exhibit Membranolytic Effects and Antimetastatic Activity on Lung Cancer Cells

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