Ellipticine Research Articles

Investigating the potential of monocyclic B9N9 and C18 rings for the electrochemical sensing, and adsorption of carbazole-based anti-cancer drug derivatives: DFT-based first-principle study.

For the first time, the use of monocyclic rings C18 and B9N9 as sensors for the sensing of carbazole-based anti-cancer drugs, such as tetrahydrocarbazole (THC), mukonal (MKN), murrayanine (MRY), and ellipticine (EPT), is described using DFT simulations and computational characterization. The geometries, electronic properties, stability studies, sensitivity, and adsorption capabilities of C18 and B9N9 counterparts towards the selected compounds confirm that the analytes interact through active cavities of the C18 and B9N9 rings of the complexes. Based on the interaction energies, the sensitivity of surfaces towards EPT, MKN, MRY, and THC analytes is observed. The interaction energy of EPT@B9N9, MKN@B9N9, MRY@B9N9, and THC@B9N9 complexes are observed - 20.40, - 19.49, - 20.07, and - 18.27kcal/mol respectively which is more exothermic than EPT@C18, MKN@C18, MRY@C18, and THC@C18 complexes are - 16.37, - 13.97, - 13.96, and - 11.39kcal/mol respectively. According to findings from the quantum theory of atoms in molecules (QTAIM) and the reduced density gradient (RDG), dispersion forces play a significant role in maintaining the stability of these complexes. The electronic properties including FMOs, density of states (DOS), natural bond orbitals (NBO), charge transfer, and absorption studies are carried out. In comparison of B9N9 and C18, the analyte recovery time for C18 is much shorter (9.91 × 10-11 for THC@C18) than that for B9N9 shorter recovery time value of 3.75 × 10-9 for EPT@B9N9. These results suggest that our reported sensors B9N9 and C18 make it faster to detect adsorbed molecules at room temperature. The sensor response is more prominent in B9N9 due to its fine energy gap and high adsorption energy. Consequently, it is possible to think of these monocyclic systems as a potential material for sensor applications.

Drug-Loading Content Influences Cellular Uptake of Polymer-Coated Nanocellulose.

While the effects of nanoparticle properties such as shape and size on cellular uptake are widely studied, influences exerted by drug loading have so far been ignored. In this work, nanocellulose (NC) coated by Passerini reaction with poly(2-hydroxy ethyl acrylate) (PHEA-g-NC) was loaded with various amounts of ellipticine (EPT) by electrostatic interactions. The drug-loading content was determined by UV-vis spectroscopy to range between 1.68 and 8.07 wt %. Dynamic light scattering and small-angle neutron scattering revealed an increased dehydration of the polymer shell with increasing drug-loading content, which led to higher protein adsorption and more aggregation. The nanoparticle with the highest drug-loading content, NC-EPT8.0, displayed reduced cellular uptake in U87MG glioma cells and MRC-5 fibroblasts. This also translated into reduced toxicity in these cell lines as well as the breast cancer MCF-7 and the macrophage RAW264.7 cell lines. Additionally, the toxicity in U87MG cancer spheroids was unfavorable. The nanoparticle with the best performance was found to have intermediate drug-loading content where the cellular uptake was adequately high while each nanoparticle was able to deliver a sufficiently toxic amount into the cells. Medium drug loading did not hinder uptake into cells while maintaining sufficiently toxic drug concentrations. It was concluded that while striving for a high drug-loading content is appropriate when designing clinically relevant nanoparticles, it needs to be considered that the drug can cause changes in the physicochemical properties of the nanoparticles that might cause unfavorable effects.

Ellipticine induces apoptosis and mitochondrial dysfunction in human endometriosis cell lines by activating MAPK signaling pathway

Purpose: To assess the effect of ellipticine (EPT), an alkaloid isolated from the Oleaceae family, on endometriosis, and to identify its possible mechanisms of action.
 Methods: Human endometriosis-like cell lines exposed to EPT were subjected to bromodeoxyuridine/5-bromo-2´-deoxyuridine and proliferating cell nuclear antigen staining. Flow cytometry and immunoblot analyses were used to assess the effect of EPT on cell apoptosis. Mitochondrial damage was determined by JC-1 staining and immunoblotting. Immunoblot assays were performed to determine the effects of EPT on the MAPK pathway.
 Results: Ellipticine inhibited the viability of human endometriosis cell lines and stimulated cell apoptosis (p < 0.01). It further induced mitochondrial damage in human endometriosis cell lines (p < 0.01). Mechanistically, EPT acted on MAPK pathway, and induced apoptosis and mitochondrial dysfunction (p < 0.01) in human endometriosis cells.
 Conclusion: Ellipticine is a potential treatment strategy for the management of endometriosis. However, further exploration of this potential should be explored via in vivo studies.

Folate decorated dextran-coated magnetic nanoparticles for targeted delivery of ellipticine in cervical cancer cells

The dextran-coated superparamagnetic iron oxide nanoparticles (SPIONs) grafted with foliate (FA) were prepared and used as a nanocarrier for ellipticine (ET) delivery in cervical cancer. In this work we prepared superparamagnetic iron oxide nanoparticles by pulsed laser ablation in liquid method. The formation of the SPION@DEX-ET-FA nanosystem was performed by a reverse microemulsion process. Dynamic light scattering (DLS), atomic force microscopy (AFM), and field emission scanning electron microscope (FESEM) were used to characteristic the morphological properties of the NPs. The appropriate impact of a therapeutic dose of SPION@DEX-ET-FA on both cancer and healthy cell lines was estimated using a 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide (MTT) assay. The flow cytometry assays was used to evaluate the induction of apoptosis in Hela cervical cancer cells. The findings of the SPION@DEX-ET-FA formulated were spherical particles with an average size, polydispersity and a zeta potential of 101 ± 15.02 nm, 0.075 and −33.8 mV, respectively. The nanosystem displayed dose-dependent cytotoxic effects on Hela cells. The results showed that SPION@DEX-ET-FA retained antitumor activity and no adverse effects on healthy cells were found.

Increased Drug‐Loading Enhances the Activity of Ellipticine in Poly(N‐(2‐hydroxypropyl) Methacrylamide) PHPMA‐Based Polymeric Micelles in 2D and 3D Cancer Cell Models

AbstractPolymeric micelles are widely used as multifunctional drug carriers of poorly water‐soluble drugs, but the role of drug loading content is often overlooked. The purpose of this study is to investigate the cellular uptake and penetration of polymeric micelles with different drug loading contents and their effects on biological activities. In this study, poly(N‐(2‐hydroxypropyl) methacrylamide‐co‐methacrylic acid)‐block‐poly methyl methacrylate P(HPMA‐co‐MAA)‐b‐PMMA micelles are used as a nanocarrier for the encapsulation of the potent anticancer agent ellipticine (EPT). The micelles are loaded with various amounts of EPT and the physicochemical characteristics such as particle size, morphology, and zeta potential of blank and EPT loaded nanoparticles are studied. Moreover, fluorescent lifetime studies confirm that hydrophobic EPT is indeed in the PMMA micelle core. In vitro cytotoxicity tests using the glioma cell line U87MG reveal lower IC50 values when the cells are incubated with micelle with high drug loading content. The higher toxicity in micelles with higher drug loading content is associated with higher cellular uptake, which is monitored using laser scanning confocal microscopy and flow cytometry. Moreover, higher activity of micelles with higher drug loading is also observed in U87MG multicellular tumor spheroids although the difference is not significant.

Protective effect of Ellipticine in ovalbumin (OVA)-induced murine model of allergic rhinitis via dual inhibition of COX-2 and NF-κB

Abstract Allergic rhinitis (AR) is a serious health concern across the globe. Despite its non-fatal character, it accounts for affecting millions of people across the world and is deemed responsible to affect their quality of life and put a significant economic burden. In the current study, we aimed to assess the anti-allergic and anti-inflammatory effects and the underlying molecular mechanisms of ellipticine (ETC) against AR using ovalbumin (OVA)-induced murine model of allergic rhinitis. The ETC was administered to mice via intra-peritoneal route after suspending in 5% CMC after sensitization by OVA. Results of the study suggested that ETC causes a significant reduction the nose rubs as compared to disease control. A significant reduction in the serum level of histamine, IgG1, TNF-α, IL-1β, MIP-2, and IL-6 was found in ETC treated group in a dose-dependent manner as compared to OVA challenged mice. It also reduces eosinophils in BALF of AR mice. In western blot analysis, the expression of aberrantly activated COX-2 and NF-ĸB found significantly reduced in ETC treated group due to inhibition of TLR-4 and caspase-1 as compared to disease-control mice. ETC showed significant interaction with residues of the active site of COX-2 and NF-ĸB. Collectively, our results indicated that ETC can be used to improve present therapeutic strategies against AR.

Stimuli‐responsive zein‐based nanoparticles as a potential carrier for ellipticine: Synthesis, release, and in vitro delivery

In the present research, we have investigated a drug delivery system based on the pH‐responsive behaviors of zein colloidal nanoparticles coated with sodium caseinate (SC) and poly ethylene imine (PEI). These systematically designed nanoparticles were used as nanocarriers for encapsulation of ellipticine (EPT), as an anticancer drug. SC and PEI coatings were applied through electrostatic adsorption, leading to the increased size and improved polydispersity index of nanoparticles as well as sustained release of drug. Physicochemical characteristics such as hydrodynamic diameter, size distribution, zeta potential and morphology of nanoparticles prepared using different formulations and conditions were also determined. Based on the results, EPT was encapsulated into the prepared nanoparticles with a high drug loading capacity (5.06%) and encapsulation efficiency (94.8%) under optimal conditions. in vitro experiments demonstrated that the release of EPT from zein‐based nanoparticles was pH sensitive. When the pH level decreased from 7.4 to 5.5, the rate of drug release was considerably enhanced. The mechanism of pH‐responsive complexation in the drug encapsulation and release processes was extensively investigated. The pH‐dependent electrostatic interactions and drug state were hypothesized to affect the release profiles. Compared to the EPT‐loaded zein/PEI nanoparticles, the EPT‐loaded zein/SC nanoparticles exhibited a better drug sustained‐release profile, with a smaller initial burst release and longer release period. According to the results of in vitro cytotoxicity experiments, drug‐free nanoparticles were associated with a negligible cytotoxicity, whereas the EPT‐loaded nanoparticles displayed a high toxicity for the cancer cell line, A549. Our findings indicate that these pH‐sensitive protein‐based nanoparticles can be used as novel nanotherapeutic tools and potential antineoplastic drug carriers for cancer chemotherapy with controlled release.

Differentiation of adipose-derived stem cells into functional chondrocytes by a small molecule that induces Sox9

Osteoarthritis (OA) is a common joint disease that results from the disintegration of joint cartilage and the underlying bone. Because cartilage and chondrocytes lack the ability to self-regenerate, efforts have been made to utilize stem cells to treat OA. Although various methods have been used to differentiate stem cells into functional chondrocytes, the currently available methods cannot induce stem cells to undergo differentiation into chondrocyte-like cells without inducing characteristics of hypertrophic chondrocytes, which finally lead to cartilage disintegration and calcification. Therefore, an optimized method to differentiate stem cells into chondrocytes that do not display undesired phenotypes is needed. This study focused on differentiating adipose-derived stem cells (ASCs) into functional chondrocytes using a small molecule that regulated the expression of Sox9 as a key factor in cartilage development and then explored its ability to treat OA. We selected ellipticine (ELPC), which induces chondrocyte differentiation of ASCs, using a GFP-Sox9 promoter vector screening system. An in vivo study was performed to confirm the recovery rate of cartilage regeneration with ASC differentiation into chondrocytes by ELPC in a collagenase-induced animal model of OA. Taken together, these data indicate that ellipticine induces ASCs to differentiate into mature chondrocytes without hypertrophic chondrocytes in vitro and in vivo, thus overcoming a problem encountered in previous studies. These results indicate that ELPC is a novel chondrocyte differentiation-inducing drug that shows potential as a cell therapy for OA.

Ellipticine, its Derivatives: Re-evaluation of Clinical Suitability with the Aid of Drug Delivery Systems

Targeted drug delivery systems gave newer dimensions for safer and more effective use of therapeutic drugs, thus helping in circumventing the issues of toxicity and unintended drug accumulation. These ongoing developments in delivery systems can, in turn, bring back drugs that suffered various limitations, Ellipticine (EPT) being a candidate. EPT derivatives witnessed entry into clinical settings but failed to survive in clinics citing various toxic side effects. A large body of preclinical data deliberates the potency of drug delivery systems in increasing the efficiency of EPT/derivatives while decreasing their toxic side effects. Recent developments in drug delivery systems provide a platform to explore EPT and its derivatives as good clinical candidates in treating tumors. The present review deals with delivery mechanisms of EPT/EPT derivatives as antitumor drugs, in vitro and in vivo, and evaluates the suitability of EPT-carriers in clinical settings.

Identification of an IKKβ inhibitor for inhibition of inflammation in vivo and in vitro

Targeting on the IKKβ to discover anti-inflammatory drugs has been launched for ten years, due to its predominant role in canonical NF-κB signaling. In the current study, we identified a novel IKKβ inhibitor, ellipticine (ELL), an alkaloid isolated from Ochrosia elliptica and Rauvolfia sandwicensis. We found that ELL reduced the secretion and mRNA expression of TNF-α and IL-6 and decreased the protein expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) in bone marrow derived macrophages (BMDMs) stimulated with LPS. In coincided with the results, ELL suppressed PGE2 and NO production in BMDMs. Underlying mechanistic study showed that ELL inhibited IκBα phosphorylation and degradation as well as NF-κB nuclear translocation, which was attributed to suppression of IKKα/β activation. Furthermore, kinase assay and binding assay results indicated that ELL inhibited IKKβ activity via directly binding to IKKβ and in turn resulted in suppression of NF-κB signaling. To identify the binding sites of ELL on IKKβ, IKKβC46A plasmid was prepared and the kinase assay was performed. The results demonstrated that the inhibitory effect of ELL on IKKβ activity was impaired in the mutation, implying that anti-inflammatory effect of ELL was partially attributed to binding on cysteine 46. Furthermore, ELL up-regulated LC3 II expression and reduced p62 expression, suggesting that autophagy induction contributed to the anti-inflammatory effect of ELL as well. In coincided with the in vitro results, ELL increased the survival and antagonized the hypothermia in the mice with LPS-induced septic shock. Consistently, ELL reduced TNF-α and IL-6 production in the serum of the mice treated with LPS. Collectively, our study provides evidence that ELL is an IKKβ inhibitor and has potential to be developed as a lead compound for treatment inflammatory diseases in the future.

Histidine-Rich Cell-Penetrating Peptide for Cancer Drug Delivery and Its Uptake Mechanism.

In this work, we report a drug delivery system based on the pH-responsive self-assembly and -disassembly behaviors of peptides. Here, a systematically designed histidine-rich lipidated peptide (NP1) is presented to encapsulate and deliver an anticancer drug ellipticine (EPT) into two model cells: non-small-cell lung carcinoma and Chinese hamster ovary cells. The mechanism of pH-responsive peptide self-assembly and -disassembly involved in the drug encapsulation and release process are extensively investigated. We found that NP1 could self-assemble as a spherical nanocomplex (diameter = 34.43 nm) in a neutral pH environment with EPT encapsulated and positively charged arginine amino acids aligned outward and EPT is released in an acidic environment due to the pH-triggered disassembly. Furthermore, the EPT-encapsulating peptide could achieve a mass loading ability of 18% (mass of loaded-EPT/mass of NP1) with optimization. More importantly, it is revealed that the positively charged arginine on the periphery of the NP1 peptides could greatly facilitate their direct translocation through the negatively charged plasma membrane via electrostatic interaction, instead of via endocytosis, which provides a more efficient uptake pathway.

Apoferritine-encapsulated ellipticine – construction and properties

Apoferritine-encapsulated ellipticine – construction and properties

Molecular interactions of the anticancer agent ellipticine with glycosaminoglycans by in silico analysis

The anticancer agent ellipticine (ELP) functions as a DNA intercalating drug. Depending on the pH of the medium, it exists both in a neutral and a protonated form. In acidic extracellular microenvironment characteristic to malignant tissues, charged ELP molecules can also bind to glycosaminoglycans (GAGs), linear anionic periodic polysaccharides, which interact with various protein targets affecting diverse cellular events. Although a previous experimental work indicated specific GAG binding of protonated ELP, the underlying molecular mechanisms remain to be elucidated. From a computational point of view, analysis of molecular systems containing GAGs is challenging due to their high flexibility, variability in sulfation patterns and a key role of electrostatics and solvent-mediated interactions. In the present study, molecular dynamics-based approaches were employed to model ELP-GAG interactions in order to unveil the atomistic details of this biologically relevant molecular system. We characterized dynamic and energetic properties of three kinds of ELP-GAG complexes to rationalize and complement the available experimental data. The results reported herein provide insight into possible molecular pathways by which biological actions of ELP are mediated.

Density functional theory calculations and molecular dynamics simulations of the adsorption of ellipticine anticancer drug on graphene oxide surface in aqueous medium as well as under controlled pH conditions

In this study, the solvent effects on the geometric structures and electronic properties of ellipticine (EPT) anticancer drug on the surface of graphene oxide nanosheet (GONS) as adsorbents are studied by density functional theory calculation. To study of the solvent effects, three polar solvents (water with ɛ=78.39 as a green and natural solvent, dimethyl sulfoxide (DMSO) with ɛ=46.7 and ethanol with ɛ=24. 5) have been selected using the polarizable continuum model (PCM). The results show that the adsorption of ellipticine onto GONS is exothermic and energetically more favorable. Moreover, solvation energy values demonstrate that the stability is more in the water among the selected solvents. The theory of Atoms in Molecules (AIM) analysis indicates closed shell (non-covalent) interactions between EPT and GO nanosheet. The calculation of charge transfer by employing NBO method shows that EPT is donor and GO nanosheet is acceptor. These results illustrate that GONS may be a promising candidate as an appropriate adsorbent for adsorbing. Moreover, molecular dynamic simulations are examined to understand the effect of pH on the EPT loading and release on graphene oxide. Our results confirm the favorable drug loading at the neutral blood pH level and its release at acidic pH levels of the environment surrounding a cancerous tumor. The results would motivate the researchers to examine the molecular mechanisms of EPT loading and release under the influence of pH.

Construction of an apoferritin nanocarrier with encapsulated ellipticine and examination of its properties

Construction of an apoferritin nanocarrier with encapsulated ellipticine and examination of its properties

Candidate cytochrome P450 genes for ethoxyresorufin O-deethylase activity in oyster Crassostrea gigas

Vertebrate cytochrome P450 1 (CYP1) enzymes metabolize endogenous and xenobiotic compounds and usually demonstrate a substrate-inducible response. Ethoxyresorufin O-deethylase activity (EROD) is a common method to quantify CYP1 enzymes activity in these organisms. Despite the absence of this gene family in protostomes, CYP1-like genes were identified in several species, even though no evolutionary relationship has been established with the vertebrate CYP1 family. In the present study, EROD activity was evaluated in microsomal fraction of gills, digestive gland and mantle of Crassostrea gigas. Enzyme activity was quantified in gills, although no activity was detected in digestive gland and mantle. EROD kinetic characterization in gills using typical Michaelis-Menten equation demonstrated an apparent Km of 1.15μM and Vmax of 229.2 fmol.min−1mg.protein −1. EROD activity was analyzed in the presence of CYP1 inhibitors, ellipticine (ELP), furafylline (FRF), clotrimazole (CTZ), α-naphthoflavone (ANF), and the non-ionic surfactant Triton X-100. CTZ inhibited EROD activity in all tested concentrations while Triton X-100 (0.5mM) caused 16% inhibition. Transcript levels of four CYP1-like genes were determined in gills, digestive gland and mantle. In general, CYP1-like genes showed higher transcript levels in gills compared to other tissues. The transcript levels of CYP1-like 1 and 2, analyzed together, positively correlated with EROD activity observed in gills, suggesting the possible involvement of these two gene products in EROD activity in this tissue. Homology models of translated CYP1-like 1 and 2 were generated based on human CYP1A1 structure and were similar to the general canonical cytochrome P450 fold. Molecular docking analysis showed that the two putative oyster CYP1-like structures have the potential to metabolize 7-ethoxyresorufin (7-ER), although the contribution of other CYP1-like genes needs to be investigated. Proteins encoded by CYP1-like 1 and 2 genes are plausible candidates for EROD activity observed in gills of C. gigas.

Characterization of ethoxyresorufin O-deethylase activity (EROD) in oyster Crassostrea brasiliana.

Cytochrome P450 family 1 (CYP1) is involved in polycyclic aromatic hydrocarbons (PAHs) biotransformation. PAHs can induce CYP1 protein expression and enzyme activity, the latter being usually quantified as 7-ethoxyresorufin O-deethylase activity (EROD). The aim of this study was to characterize EROD activity in the bivalve mollusk Crassostrea brasiliana. EROD activity was evaluated in cytosolic and microsomal fractions of gills, digestive gland and mantle of C. brasiliana. No EROD activity was detected in mantle, but it was present in microsomal fraction of gills and digestive gland with NADPH as coenzyme. Optima temperature and pH for EROD assay were 30°C and 7.4, respectively. EROD apparent Km (Kmapp) was 4.32μM for gills and 5.56μM for digestive gland. EROD Vmax was 337.3fmol·min-1·mg of protein-1 in gills and 297.7fmol·min-1·mg of protein-1 in digestive gland. Compared to other bivalves, a higher Kmapp and a lower Vmax was found in oyster which may suggest that oyster CYP1-like enzyme has lower affinity for substrate 7-ethoxyresorufin (7-ER) than those species. CYP1 inhibitor ellipticine (ELP) inhibited EROD activity in all tested concentrations in both tissues. The higher ELP concentration, 100μM, inhibited 78% of EROD activity in gills and 47% in digestive gland. The CYP1 inhibitors α-naphthoflavone and furafylline did not inhibited EROD activity in microsomes of both tissues. In conclusion, EROD activity can be used to determine CYP1-like activity in oysters and possibly a CYP1A1/A2-like enzyme is responsible for this catalysis.

Arginine-rich ionic complementary peptides as potential drug carriers: Impact of peptide sequence on size, shape and cell specificity

Ionic complementary peptides have shown potential in delivering hydrophobic anticancer drugs. In this study, a series of four ionic complementary peptides, EAR16-II, EAR8-II, EAR8-IIa and ELR8-IIa, is derived from the most studied ionic complementary peptide EAK16-II. The purpose is to investigate the impact of peptide sequence on nanostructure formation, delivery efficacy and cell specificity of the peptide-drug complex. We show that the peptide length has a pronounced impact on the morphology of peptide complex with the anticancer drug ellipticine (EPT), and the amino acid arrangement affects the complex size. Cytotoxicity studies show that the complexes are effective at inhibiting the growth of A549 lung cancer cells and EAR16-II-EPT is the most effective. Interestingly, the complexes formulated with EAR16-II and EAR8-II become less active against MCF-7 breast cancer cells, but more hemolytic than the other two complexes. This work provides essential information to optimize self-assembling peptide-based drug delivery for cancer therapy.

Loading of an anti-cancer drug into mesoporous silica nano-channels and its subsequent release to DNA.

Mesoporous silica nano-channel (MCM-41) based molecular switching of a biologically important anticancer drug, namely, ellipticine (EPT) has been utilized to probe its efficient loading onto MCM-41, and its subsequent release to intra-cellular biomolecules, like DNA. By exploiting various spectroscopic techniques (like, steady state fluorescence, time-resolved fluorescence and circular dichroism), it has been shown that EPT can be easily translocated from MCM-41 to DNA without using any external stimulant. Blue emission of EPT in a polar aprotic solvent, i.e., dichloromethane (DCM), completely switches to green upon loading inside MCM-41 due to the conversion from a neutral to a protonated form of the drug inside nano-pores. Powder X-ray diffraction (PXRD), N2 gas adsorption and confocal fluorescence microscopy results confirm the adsorption of EPT inside the nano-pores of MCM-41. Here, the lysozyme (Lyz) protein has been utilized as a pore blocker of MCM-41 in order to prevent premature drug release. Interestingly, EPT is released to DNA even from the EPT-MCM-Lyz composite system, and results in intensification of green fluorescence. Electron microscopy results reveal the formation of a distinctive garland kind of morphology involving MCM-41 and DNA probably through non-covalent interactions, and this is believed to be responsible for the DNA assisted release of drug molecules from silica nano-pores. Confocal laser scanning microscopy (CLSM) imaging revealed that EPT-MCM is successfully internalized into the HeLa cervical cancer cells and localized into the nucleus. Cell viability assay results infer that EPT-MCM and EPT-MCM-Lyz showed much improved efficacy in HeLa cancer cells compared to free ellipticine.

An amphipathic lytic peptide for enhanced and selective delivery of ellipticine.

Cationic lytic peptides (CLPs) have shown promise in treating bacterial infection and cancer via selective disruption of bacterial or cancer cell membranes. In this work, we used a CLP, C6, as a nanocarrier for a hydrophobic anticancer agent, ellipticine (EPT). The size of the resulting C6-EPT complex was ∼190 nm. The in vitro studies using A549 lung cancer cells showed an enhanced anticancer activity of the C6-EPT complex compared to that of C6 or the EPT control. This enhancement was found to correlate with the membrane disruption induced by C6, which facilitated the entry of EPT into cells. More importantly, the C6-EPT complex showed a higher selectivity than that of C6 towards cancer cells upon comparison of their cytotoxicities against A549 cells and NIH-3T3 fibroblast cells. The enhanced therapeutic activity was also found in in vivo studies using an A549 tumor-bearing BALB/c nude mice model. This study provides a new CLP strategy for the development of multifunctional drug delivery systems.