An amphipathic lytic peptide for enhanced and selective delivery of ellipticine

Lu, Shan; Ding, Yong; Wu, Yan; Wang, Rong; Ran, Pan; Wan, Zizhen; Xu, Wen; Zhang, Lei; Yuan, Yongfang; Chen, P.

doi:10.1039/c6tb00529b

Cited by 5 publications

(6 citation statements)

References 39 publications

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“…Utilizing this mechanism, the NC exhibited significantly enhanced therapeutic efficacy against A549 lung cancer cells, with the IC50 decreased by up to ~90% for Dox and ~69% for PAH6 when compared to the IC50 values of the two components respectively. The synergy could originate from the enhanced cellular uptake of Dox through the permeabilized cell membranes as we proposed previously [ 10 , 17 ], as well as the multiple killing mechanisms. Furthermore, the selectivity of PAH6 conferred to the NC the improved therapeutic index of Dox from 0.22 up to 2.26 between NIH-3T3 and A549 cells, and from 0.46 to 2.48 between NIH-3T3 and HCT116 cells, which are close to the PAH6 selectivity of 2.36.…”

Section: Discussionmentioning

confidence: 75%

“…In previous studies, we proposed that the membrane disruptive ability of cationic anticancer peptides could enhance the permeability of the cell membrane in contact, facilitating the entry of small-molecule drugs and resulting in synergy [ 11 , 17 ]. After we confirmed the membrane disruptive ability of PAH6, the cell membrane permeabilization induced by PAH6 was evaluated by measuring the fluorescence intensity of DAPI permeated into A549 cells.…”

Section: Resultsmentioning

confidence: 99%

“…In particular, nanoparticles with size ranging between 10 and 100 nm are found to passively accumulate in tumor sites through enhanced permeability and retention effect [ 4 , 5 ], and reduced nanoparticle size can facilitate tumor penetration [ 6 , 7 ]; fibrous nanostructures are reported to accumulate in tumors better than their spherical counterparts [ 8 ]; and spherical nanoparticles show advantages in cellular uptake [ 9 ]. Additional functions, such as stimulus-triggered drug release [ 10 , 11 , 12 , 13 ], enhanced cell membrane translocation [ 14 , 15 , 16 ], and tuned cancer cell selectivity [ 11 , 17 ], are further engineered to equip nanoparticles for better therapeutic efficacy and reduced side effects. Numerous biomarkers have also been identified and targeting molecules are mounted on the surface of nanoparticles for improved tumor accumulation [ 18 , 19 ].…”

Section: Introductionmentioning

confidence: 99%

“…Sharing the similar membrane disruption mechanisms, we hypothesize that cationic anticancer peptides would also be able to penetrate tumor tissues. Previously, our group reported the use of cationic anticancer peptides to deliver an anticancer drug, ellipticine, and demonstrated that the systems can significantly enhance the therapeutic efficacy towards cancerous cells, but were barely enhanced towards normal cells [ 11 , 17 ]. However, the interactions between the drug and peptides rely on hydrophobic interactions, which are not stable and are nonspecific.…”

Section: Introductionmentioning

confidence: 99%

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Therapeutic Peptide Amphiphile as a Drug Carrier with ATP-Triggered Release for Synergistic Effect, Improved Therapeutic Index, and Penetration of 3D Cancer Cell Spheroids

Zhao

Zhang

et al. 2018

IJMS

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Despite the great progress in the field of drug delivery systems for cancer treatment over the last decade, many challenges still lie ahead, such as low drug loading, deep penetration of tumors, side effects, and the development of drug resistance. A class of cationic membrane lytic peptides has shown potential as an anticancer agent by inducing cancer cell death via membrane disruption; meanwhile, their intrinsic selectivity renders them as having low cytotoxicity towards noncancerous cells. Here, we report the use of a cationic peptide amphiphile (PA), named PAH6, to load doxorubicin (Dox) that is intercalated in an ATP-binding aptamer-incorporated DNA scaffold. The PA contains a cationic lytic sequence, (KLAKLAK)2, a polyhistidine segment for the “proton sponge” effect, and a hydrophobic alkyl tail to drive the self-assembly. Dox-loaded DNA was found to form a spherical nanocomplex (NC) with PAH6 with particle sizes below 100 nm at various ratios. Since the carrier PAH6 is also a therapeutic agent, the drug loadings of the NC reached up to ~86% within the ratios we tested, and Dox was released from the NC in an ATP-rich environment. In vitro studies indicate that the presence of PAH6 could permeabilize cell membranes and kill cells through fast membrane disruption and depolarization of mitochondrial membranes. The cytotoxicity tests were conducted using A549 nonsmall cell lung cancer cells and NIH-3T3 fibroblast cells. PAH6 showed selectivity towards A549 cells. Significantly, the Dox-DNA/PAH6 NC exhibited a synergistic effect against A549 cells, with the IC50 decreased up to ~90% for Dox and ~69% for PAH6 when compared to the IC50 values of the two components, respectively. Furthermore, the selectivity of PAH6 conferred to the complex an improved therapeutic index between A549 and NIH-3T3 cells. A 3D-cultured A549 spheroid model was adopted to test the capability of Dox-DNA/PAH6 for tumor penetration. The PAH6 or Dox-DNA/PAH6 complex was found to break the spheroids into pieces, while Dox-treated spheroids maintained their shapes. In summary, this work provides a new strategy for constructing nanomedicines using therapeutic agents to meet the features required by anticancer treatment.

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Section: Discussionmentioning

confidence: 75%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Therapeutic Peptide Amphiphile as a Drug Carrier with ATP-Triggered Release for Synergistic Effect, Improved Therapeutic Index, and Penetration of 3D Cancer Cell Spheroids

Zhao

Zhang

et al. 2018

IJMS

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show abstract

“…We also found that, without forming supramolecular nanostructures, neither lysine nor arginine‐rich amphiphilic peptide exhibited a significant difference in cytotoxicity in the presence of either NaCl or Urea (Figure S12). Therefore, the differentiated functions of PA self‐assemblies could result from the combinational impact of their surface chemistry and internal status on the collective behaviors of the interactions between PA supramolecular structures and biological membranes.…”

Section: Resultsmentioning

confidence: 95%

Functional Control of Peptide Amphiphile Assemblies via Modulation of Internal Cohesion and Surface Chemistry Switch

Cui

et al. 2018

Chemistry A European J

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Understanding the impacts of the internal cohesion and surface chemistry of supramolecular systems on the collective behaviors in the contacts between the systems and biomolecules can greatly expand the functional diversity and adaptivity of supramolecular nanostructures. Here we show how the tuned molecular interactions modulate the morphologies and internal cohesion of peptide amphiphile (PA) self-assemblies and their resultant functions. Circular dichroism spectroscopy, fluorescence probing, atomic force and electron microscopy, along with molecular dynamics simulations, revealed that the PA self-assembly formed compact long fibers when surface charge repulsion was screened, but formed loose short fibers or micelle-like assemblies when hydrogen bonding was disrupted or hydrophobic core was enhanced. More importantly, depending on the strength of the phospholipid affinity for the cationic segment of the PA, the same internal cohesion of PA nanostructures can lead to either cell death or cell survival, providing unique insights into the design of supramolecular materials.

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Simultaneous membrane interaction of amphipathic peptide monomers, self-aggregates and cargo complexes detected by fluorescence correlation spectroscopy

Vasconcelos¹,

Lehto²,

Madani³

et al. 2018

Biochimica et Biophysica Acta (BBA) - Biomembranes

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Peptides able to translocate cell membranes while carrying macromolecular cargo, as cell-penetrating peptides (CPPs), can contribute to the field of drug delivery by enabling the transport of otherwise membrane impermeable molecules. Formation of non-covalent complexes between amphipathic peptides and oligonucleotides is driven by electrostatic and hydrophobic interactions. Here we investigate and quantify the coexistence of distinct molecular species in multiple equilibria, namely peptide monomer, peptide self-aggregates and peptide/oligonucleotide complexes. As a model for the complexes, we used a stearylated peptide from the PepFect family, PF14 and siRNA. PF14 has a cationic part and a lipid part, resembling some characteristics of cationic lipids. Fluorescence correlation spectroscopy (FCS) and fluorescence cross-correlation spectroscopy (FCCS) were used to detect distinct molecular entities in solution and at the plasma membrane of live cells. For that, we labeled the peptide with carboxyrhodamine 6G and the siRNA with Cyanine 5. We were able to detect fluorescent entities with diffusional properties characteristic of the peptide monomer as well as of peptide aggregates and peptide/oligonucleotide complexes. Strategies to avoid peptide adsorption to solid surfaces and self-aggregation were developed and allowed successful FCS measurements in solution and at the plasma membrane. The ratio between the detected molecular species was found to vary with pH, peptide concentration and the proximity to the plasma membrane. The present results suggest that the diverse cellular uptake mechanisms, often reported for amphipathic CPPs, might result from the synergistic effect of peptide monomers, self-aggregates and cargo complexes, distributed unevenly at the plasma membrane.

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An amphipathic lytic peptide for enhanced and selective delivery of ellipticine

Cited by 5 publications

References 39 publications

Therapeutic Peptide Amphiphile as a Drug Carrier with ATP-Triggered Release for Synergistic Effect, Improved Therapeutic Index, and Penetration of 3D Cancer Cell Spheroids

Therapeutic Peptide Amphiphile as a Drug Carrier with ATP-Triggered Release for Synergistic Effect, Improved Therapeutic Index, and Penetration of 3D Cancer Cell Spheroids

Functional Control of Peptide Amphiphile Assemblies via Modulation of Internal Cohesion and Surface Chemistry Switch

Simultaneous membrane interaction of amphipathic peptide monomers, self-aggregates and cargo complexes detected by fluorescence correlation spectroscopy

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