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Characterization and cytotoxicity of nanostructured lipid carriers formulated with olive oil, hydrogenated palm oil, and polysorbate 80

How CW, Rasedee A, Abbasalipourkabir R

IEEE Trans Nanobioscience, 2013 Jun;12(2):72-8.
PMID: 23268387 DOI: 10.1109/TNB.2012.2232937

Nanostructured lipid carriers (NLC) composed of solid and liquid lipids, and surfactants are potentially good colloidal drug carriers. Before NLC can be used as drug carriers, the cytotoxicity of their components must be ascertained. The cytotoxicity of solid lipids (trilaurin, palmitin, docosanoid acid, and hydrogenated palm oil [HPO]) and surfactants (Polysorbate 20, 80, and 85) were determined on BALB/c 3T3 cells. The HPO and Polysorbate 80 were least cytotoxic and used with olive oil in the formulation of NLC. The particle size, polydispersity index, zeta potential, specific surface area, and crystallinity index of the NLC were 61.14 nm, 0.461, -25.4 mV, and 49.07 m(2) and 27.12% respectively, while the melting point was 4.3 °C lower than of HPO. Unlike in serum-free, NLC incubated in fetal bovine serum-supplemented medium did not show particle growth, suggesting that serum proteins in medium inhibit nanoparticles aggregation. The study also showed that NLC was less toxic to BALB/c 3T3 cells than Polysorbate 80. Thus, NLC with olive oil, HPO, and Polysorbate 80 as components are potentially good drug carriers with minimal cytotoxicity on normal cells.

Matched MeSH terms: Cell Survival/drug effects
Antioxidant and cytoprotective effects of an ethanol extract of Acalypha wilkesiana var. macafeana from Malaysia

Din WM, Chu J, Clarke G, Jin KT, Bradshaw TD, Fry JR, et al.

Nat Prod Commun, 2013 Mar;8(3):375-80.
PMID: 23678815

In the annals of biomedical theory perhaps no single class of natural product has enjoyed more ingenious speculation than antioxidants formally aimed at counteracting oxidative insults which are involved in the pathophysiology of Alzheimer's and Parkinson's disease, cancer, amyotrophic lateral sclerosis, skin ageing and wound healing. In pursuing our study of Malaysian traditional medicines with antioxidant properties, we became interested in Acalypha wilkesiana var. macafeana hort., used traditionally to heal wounds. To examine whether Acalypha wilkesiana var. macafeana hort. could suppress oxidation an ethanol extract was tested by conventional chemical in vitro assays i.e., ferric reducing antioxidant potential assay (FRAP), DPPH scavenging assay and beta-carotene bleaching (BCB) assay. To explore whether Acalypha wilkesiana var. macafeana hort. protected cells against oxidative injuries, we exposed human hepatocellular liver carcinoma (HepG2) cells to tert-butylhydroperoxide (t-BHP). In all the aforementioned experiments, the ethanol extracts elicited potent antioxidant and cytoprotective activities. To gain a better understanding of the phytochemical nature of the antioxidant principle involved, five fractions (F1-F5) obtained from the ethanol extract were tested using FRAP, DPPH and BCB assays. Our results provided evidence that F5 was the most active fraction with antioxidant potentials equal to 2.090 +/- 0.307 microg/mL, 0.532 +/- 0.041 microg/mL, 0.032 +/- 0.025 microg/mL in FRAP, DPPH and BCB assay, respectively. Interestingly, F5 protected HepG2 against t-BHP oxidative insults. To further define the chemical identity of the antioxidant principle, we first performed a series of phytochemical tests, followed by liquid-chromatography and mass spectrometry (LC/MS) profiling which showed that the major compound contained in F5 was geraniin. To the best of our knowledge, this is the first report showing that the wound healing property of Acalypha wilkesiana var. macafeana hort. is mediated by a geraniin containing extract. Furthermore, our data leads us to conclude that geraniin could be used as a potential pharmaceutical and/or cosmetic topical agent.

Matched MeSH terms: Cell Survival/drug effects
New bioactive secondary metabolites from Bornean red alga, Laurencia similis (Ceramiales)

Kamada T, Vairappan CS

Nat Prod Commun, 2013 Mar;8(3):287-8.
PMID: 23678792

A Bomean red algal population of Laurencia similis Nam et Saito was analyzed for its secondary metabolite composition. Seven compounds were identified: ent-1(10)-aristolen-9beta-ol (1), (+)-aristolone (2), axinysone B (3), 9-aristolen-1alpha-ol (4), 2,3,5,6-tetrabromoindole (5), 1-methyl-2,3,5,6-tetrabromoindole (6), and 1-methyl-2,3,5-tribromoindole (7). Compound 1 was identified as a new optical isomer of 1(10)-aristolen-9beta-ol. Compounds 1, 4 and 5 exhibited good antibacterial activity against antibiotic resistant clinical bacteria and cytotoxic effects against selected cancer cell lines.

Matched MeSH terms: Cell Survival/drug effects
Anti-proliferative and anti-invasive properties of a purified fraction from Streptomyces sp. H7372

Yip WK, Cheenpracha S, Chang LC, Ho CC, Seow HF

Int J Oncol, 2010 Nov;37(5):1229-41.
PMID: 20878070

Secondary metabolites from actinomycetes especially the genus Streptomyces may be one of the most important sources for novel anticancer agents. A purified fraction from a novel actinomycete strain, Streptomyces sp. H7372, was elucidated in breast cancer cells. We have isolated three purified fractions from a novel strain, Streptomyces sp. H7372. One of the fractions, designated as 31-2, exhibited the strongest growth-inhibitory effect and thereby was selected for further studies. 31-2 exerted a growth-inhibitory effect on a panel of 15 human cancer and 2 non-malignant cell lines. In MCF-7 and MDA-MB-231 breast cancer cells, 31-2 induced a cytostatic (anti-proliferative) effect without causing cytotoxicity (cell death). Our data suggest that the cytostasis resulted from cell cycle arrest at the G1 phase in MCF-7 cells and at the S phase in MDA-MB-231 cells. Western blot analysis demonstrated a modulation of phosphorylation of the Rb and CDC2 proteins and of CDK4, cyclin D1 and cyclin D3 in the 31-2-treated breast cancer cell lines. The protein levels of CDK2, CDK6, and PCNA were not affected by 31-2 treatment. 31-2 also exhibited an anti-invasive effect in MDA-MB-231 cells. However, this effect is not attributed to the modulation of proteolytic activity in MDA-MB-231 cells as the enzymatic degradation of type IV collagen was not affected by 31-2. The 31-2 is a potent cytostatic and anti-invasive agent and modulates the cell cycle pathway. Together, these results will have important implications in searching for novel approaches to treat cancer.

Matched MeSH terms: Cell Survival/drug effects
Modulation of the benzene metabolite hydroquinone induced toxicity: evidence for an important role of fau

Inayat-Hussain SH, Ibrahim HA, Siew EL, Rajab NF, Chan KM, G T Williams, et al.

Chem Biol Interact, 2010 Mar 19;184(1-2):310-2.
PMID: 20025857 DOI: 10.1016/j.cbi.2009.12.009
Matched MeSH terms: Cell Survival/drug effects
Erythrocarpines A-E, new cytotoxic limonoids from Chisocheton erythrocarpus

Awang K, Lim CS, Mohamad K, Morita H, Hirasawa Y, Takeya K, et al.

Bioorg Med Chem, 2007 Sep 1;15(17):5997-6002.
PMID: 17576066

Five new cytotoxic limonoids, erythrocarpines A-E (1-5), were isolated from the bark of Chisocheton erythrocarpus Hiern. Chemical structures, stereochemistry, and conformation were fully elucidated and characterized by 2D NMR, MS, and computational methods.

Matched MeSH terms: Cell Survival/drug effects
Cryopreservation of scalps of Malaysian bananas using a pre-growth method

Sipen P, Anthony P, Davey MR

Cryo Letters, 2011 May-Jun;32(3):197-205.
PMID: 21766149

The effect of preculture with different sugars and mannitol on cryopreservation of scalps of the banana (Musa) cvs. Pisang Mas, Pisang Nangka, Pisang Berangan and Pisang Awak was investigated. Scalps (0.3 square cm) were precultured on semi-solid MS-based medium, containing 0.4 or 0.5 M sucrose, glucose, fructose, trehalose or mannitol, for 14 days under a 16 h light and 8 h dark photoperiod prior to rapid cooling and storage in liquid nitrogen. Explants were rewarmed rapidly in a water bath at 40 degree C for 1 min, followed by recovery on two layers of sterile filter paper overlaying 25 ml aliquots of semi-solid MS-based medium with 5 mg per liter benzylaminopurine, 0.2 mg per liter indole acetic acid and 10 mg per liter ascorbic acid (PM8 medium) for 2 days in the dark. Subsequently, scalps were transferred onto 25 ml aliquots of semi-solid PM8 medium and incubated in the dark for 1 week prior to incubation in the light. Shoot regeneration from 5 - 48 percent of cryopreserved scalps of all the banana cvs., was observed only following preculture with 0.4 or 0.5 M glucose or fructose, and with 0.4 M trehalose for the cvs. Pisang Berangan and Pisang Awak. Preculture with 0.4 M glucose resulted in maximum shoot regeneration of cryopreserved scalps of 10 percent, 13 percent, 42 percent and 48 percent for the cvs. Pisang Mas, Pisang Nangka, Pisang Berangan and Pisang Awak, respectively. Concentrations of 0.5 M trehalose, or 0.4 and 0.5 M sucrose or mannitol were extremely toxic to scalps of all the cvs. investigated.

Matched MeSH terms: Cell Survival/drug effects
Neolamarckines A and B, new indole alkaloids from Neolamarckia cadamba

Qureshi AK, Mukhtar MR, Hirasawa Y, Hosoya T, Nugroho AE, Morita H, et al.

Chem Pharm Bull (Tokyo), 2011;59(2):291-3.
PMID: 21297315

Two new indole alkaloids, neolamarckines A and B (1, 2) were isolated from the leaves of Neolamarckia cadamba (Rubiaceae). Structural elucidation of 1 and 2 was performed by combination of 2D-NMR and circular dichroism (CD) spectra, and chemical correlations. Neolamarckine A (1) showed inhibition of inducible nitric oxide synthase (iNOS) dose dependently.

Matched MeSH terms: Cell Survival/drug effects
In vitro cytotoxicity evaluation of biomaterials on human osteoblast cells CRL-1543; hydroxyapatite, natural coral and polyhydroxybutarate

Shamsuria O, Fadilah AS, Asiah AB, Rodiah MR, Suzina AH, Samsudin AR

Med J Malaysia, 2004 May;59 Suppl B:174-5.
PMID: 15468874

The aim of this study was to evaluate the in vitro cytotoxicity of biomaterials; Hydroxyapatite (HA), Natural coral (NC) and Polyhydroxybutarate (PHB). Three different materials used in this study; HA (Ca10(PO4)6(OH)2), NC (CaCO3) and PHB (Polymer) were locally produced by the groups of researcher from Universiti Sains Malaysia. The materials were separately extracted in the complete culture medium (100mg/ml) for 72h and introduced to the osteoblast cells CRL-1543. The viability of osteoblast CRL-1543 cultivated with these extraction materials after 72h incubation period was compared to negative control with neutral red assay by using spectrophotometer at 540nm. The results showed the non-cytotoxicity of the materials. After 72h of incubation period, HA showed 123% viable cells, NC was 99.43% and PHB was 176.75%. In this study, cytotoxicity test dealt mainly with the substances that leached out from the biomaterial. The results obtained showed that the materials were not toxic and also promoted cells growth in the sense of biofunctionality.

Matched MeSH terms: Cell Survival/drug effects*
DNA damage evaluation of hydroxyapatite on fibroblast cell L929 using the single cell gel electrophoresis assay

Rajab NF, Yaakob TA, Ong BY, Hamid M, Ali AM, Annuar BO, et al.

Med J Malaysia, 2004 May;59 Suppl B:170-1.
PMID: 15468872

Hydroxyapatite is the main component of the bone which is a potential biomaterial substance that can be applied in orthopaedics. In this study, the biocompatibility of this biomaterial was assessed using an in vitro technique. The cytotoxicity and genotoxicity effect of HA2 and HA3 against L929 fibroblast cell was evaluated using the MTT Assay and Alkaline Comet Assay respectively. Both HA2 and HA3 compound showed low cytotoxicity effect as determined using MTT Assay. Cells viability following 72 hours incubation at maximum concentration of both HA2 and HA3 (200 mg/ml) were 75.3 +/- 8.8% and 86.7 +/- 13.1% respectively. However, the cytotoxicity effect of ZnSO4.7H2O as a positive control showed an IC50 values of 46 mg/ml (160 microM). On the other hand, both HA2 and HA3 compound showed a slight genotoxicity effect as determined using the Alkaline Comet Assay following incubation at the concentration 200 mg/ml for 72 hours. This assay has been widely used in genetic toxicology to detect DNA strand breaks and alkali-labile site. The percentage of the cells with DNA damage for both substance was 27.7 +/- 1.3% and 15.6 +/- 1.0% for HA2 and HA3 respectively. Incubation of the cells for 24 hours with 38 microg/ml (IC25) of positive control showed an increase in percentage of cells with DNA damage (67.5 +/- 0.7%). In conclusion, our study indicated that both hydroxyapatite compounds showed a good biocompatibility in fibroblast cells.

Matched MeSH terms: Cell Survival/drug effects
Chromosome aberration test for hydroxyapatite in sheep

Kannan TP, Nik Ahmad Shah NL, Azlina A, Samsudin AR, Narazah MY, Salleh M

Med J Malaysia, 2004 May;59 Suppl B:168-9.
PMID: 15468871

The present study is aimed at finding the mutagenicity and cytotoxicity of dense form of synthetic hydroxyapatite (Source: School of Materials and Mineral Resources Engineering, Universiti Sains Malaysia) in the blood of sheep. The biomaterial was implanted in the tibia of Malin, an indigenous sheep breed of Malaysia. Blood was collected from the sheep before implantation of the biomaterial, cultured and a karyological study was made. Six weeks after implantation, blood was collected from the same animal, cultured and screened for chromosome aberrations. The mitotic indices and karyological analysis indicated that the implantation of synthetic hydroxyapatite (dense form) did not produce any cytotoxicity or chromosome aberrations in the blood of sheep.

Matched MeSH terms: Cell Survival/drug effects
In vitro cytotoxicity testing on valued added hydroxyapatite as bone replacement material

Shaari R, Samsudin AR

Med J Malaysia, 2004 May;59 Suppl B:109-10.
PMID: 15468842

The present in vitro evaluation indicated that the value added hydroxyapatite (HA) was more toxic than pure HA but the toxicity of value added HA was slight compared to the positive control. In this testing, the conclusion can be made that value added HA is less biocompatible than commercialized pure HA. This toxicity may be caused by both the particle size and degradation (leaching). Further studies should be carried out to determine whether there is particle size effect or leaching effect when using powder as compared to the block materials. The in vivo evaluation should be done to assess the reaction to this value added HA as compared to the pure HA.

Matched MeSH terms: Cell Survival/drug effects*
Cytotoxicity analysis of poly (carbonate-siloxane-urea) urethane

Kannan RY, Sales KM, Salacinski HJ, Butler PE, Seifalian AM

Med J Malaysia, 2004 May;59 Suppl B:99-100.
PMID: 15468837
Matched MeSH terms: Cell Survival/drug effects*
Challenges associated with the synthesis of unusual o-carboxamido stilbenes by the Heck protocol: Intriguing substituent effects, their toxicological and chemopreventive implications

Kee CH, Ariffin A, Awang K, Takeya K, Morita H, Hussain SI, et al.

Org Biomol Chem, 2010 Dec 21;8(24):5646-60.
PMID: 20941451 DOI: 10.1039/c0ob00296h

The syntheses of fourteen unusual o-carboxamido stilbenes by the Heck protocol revealed surprising complexity related to intriguing substituent effects with mechanistic implications. The unexpected cytotoxic and chemopreventive properties also seem to be substituent dependent. For example, although stilbene 15d (with a 4-methoxy substituent) showed cytotoxicity on HT29 colon cancer cells with an IC(50) of 4.9 μM, the 3,4-dimethoxy derivative (15c) is inactive. It is interesting to observe that the 3,5-dimethoxy derivative (15e) showed remarkable chemopreventive activity in WRL-68 fetal hepatocytes, surpassing the gold standard, resveratrol. The resveratrol concentration needed to be 5 times higher than that of 15e to produce comparable elevation of NQO1.

Matched MeSH terms: Cell Survival/drug effects
Biocompatibility of bio based calcium carbonate nanocrystals aragonite polymorph on NIH 3T3 fibroblast cell line

Kamba AS, Ismail M, Ibrahim TA, Zakaria ZA

Afr J Tradit Complement Altern Med, 2014;11(4):31-8.
PMID: 25392577

BACKGROUND: Currently, there has been extensive research interest for inorganic nanocrystals such as calcium phosphate, iron oxide, silicone, carbon nanotube and layered double hydroxide as a drug delivery system especially in cancer therapy. However, toxicological screening of such particles is paramount importance before use as delivery carrier. In this study we examine the biocompatibility of CaCO3 nanocrystal on NIH 3T3 cell line.
MATERIAL AND METHODS: Transmission and field emission scanning electron microscopy (TEM and FESEM) were used for the characterisation of CaCO3 nanocrystals. Cytotoxicity and genotoxic effect of calcium carbonate nanocrystals in cultured mouse embryonic fibroblast NIH 3T3 cell line using various bioassays including MTT, and Neutral red/Trypan blue double-staining assays. LDH, BrdU and reactive oxygen species were used for toxicity analysis. Cellular morphology was examined by scanning electron microscopy (SEM) and confocal fluorescence microscope.
RESULTS: The outcome of the analyses revealed a clear rod-shaped aragonite polymorph of calcium carbonate nanocrystal. The analysed cytotoxic and genotoxicity of CaCO3 nanocrystal on NIH 3T3 cells using different bioassays revealed no significance differences as compared to control. A slight decrease in cell viability was noticed when the cells were exposed to higher concentrations of 200 to 400 µg/ml, while increase in ROS generation and LDH released at 200 and 400 µg/ml was observed.
CONCLUSIONS: The study has shown that CaCO3 nanocrystal is biocompatible and non toxic to NIH 3T3 fibroblast cells. The analysed results offer a promising potential of CaCO3 nanocrystal for the development of intracellular drugs, genes and other macromolecule delivery systems.

Matched MeSH terms: Cell Survival/drug effects*
Fulltext Protective effect of arachidonic acid and linoleic acid on 1-methyl-4-phenylpyridinium-induced toxicity in PC12 cells

Tang KS

Lipids Health Dis, 2014 Dec 19;13:197.
PMID: 25522984 DOI: 10.1186/1476-511X-13-197

BACKGROUND: Parkinson's disease is a neurodegenerative disorder that is being characterized by the progressive loss of dopaminergic neurons of the nigrostriatal pathway in the brain. The protective effect of omega-6 fatty acids is unclear. There are lots of contradictions in the literature with regard to the cytoprotective role of arachidonic acid. To date, there is no solid evidence that shows the protective role of omega-6 fatty acids in Parkinson's disease. In the current study, the potential of two omega-6 fatty acids (i.e. arachidonic acid and linoleic acid) in alleviating 1-methyl-4-phenylpyridinium (MPP+)-induced cytotoxicity in PC12 cells was examined.
METHODS: Cultured PC12 cells were either treated with MPP+ alone or co-treated with one of the omega-6 fatty acids for 1 day. Cell viability was then assessed by using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay.
RESULTS: Cells treated with 500 μM MPP+ for a day reduced cell viability to ~70% as compared to control group. Linoleic acid (50 and 100 μM) significantly reduced MPP+-induced cell death back to ~85-90% of the control value. The protective effect could be mimicked by arachidonic acid, but not by ciglitazone.
CONCLUSIONS: Both linoleic acid and arachidonic acid are able to inhibit MPP+-induced toxicity in PC12 cells. The protection is not mediated via peroxisome proliferator-activated receptor gamma (PPAR-γ). Overall, the results suggest the potential role of omega-6 fatty acids in the treatment of Parkinson's disease.

Matched MeSH terms: Cell Survival/drug effects
In vitro degradation and cell viability assessment of Zn-3Mg alloy for biodegradable bone implants

Dambatta MS, Murni NS, Izman S, Kurniawan D, Froemming GR, Hermawan H

Proc Inst Mech Eng H, 2015 May;229(5):335-42.
PMID: 25991712 DOI: 10.1177/0954411915584962

This article reports the in vitro degradation and cytotoxicity assessment of Zn-3Mg alloy developed for biodegradable bone implants. The alloy was prepared using casting, and its microstructure was composed of Mg2Zn11 intermetallic phase distributed within a Zn-rich matrix. The degradation assessment was done using potentiodynamic polarization and electrochemical impedance spectrometry. The cell viability and the function of normal human osteoblast cells were assessed using 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium and alkaline phosphatase extracellular enzyme activity assays. The results showed that the degradation rate of the alloy was slower than those of pure Zn and pure Mg due to the formation of a high polarization resistance oxide film. The alloy was cytocompatible with the normal human osteoblast cells at low concentrations (<0.5 mg/mL), and its alkaline phosphatase activity was superior to pure Mg. This assessment suggests that Zn-3Mg alloy has the potential to be developed as a material for biodegradable bone implants, but the toxicity limit must be carefully observed.

Matched MeSH terms: Cell Survival/drug effects
Comparison of free amino acids, antioxidants, soluble phenolic acids, cytotoxicity and immunomodulation of fermented mung bean and soybean

Ali NM, Yeap SK, Yusof HM, Beh BK, Ho WY, Koh SP, et al.

J Sci Food Agric, 2016 Mar 30;96(5):1648-58.
PMID: 26009985 DOI: 10.1002/jsfa.7267

BACKGROUND: Mung bean and soybean have been individually reported previously to have antioxidant, cytotoxic and immunomodulatory effects, while fermentation is a well-known process to enhance the bioactive compounds that contribute to higher antioxidant, cytotoxic and immunomodulation effects. In this study, the free amino acids profile, soluble phenolic acids content, antioxidants, cytotoxic and immunomodulatory effects of fermented and non-fermented mung bean and soybean were compared.
RESULTS: Fermented mung bean was recorded to have the highest level of free amino acids, soluble phenolic acids (especially protocatechuic acid) and antioxidant activities among all the tested products. Both fermented mung bean and soybean possessed cytotoxicity activities against breast cancer MCF-7 cells by arresting the G0/G1 phase followed by apoptosis. Moreover, fermented mung bean and soybean also induced splenocyte proliferation and enhanced the levels of serum interleukin-2 and interferon-γ.
CONCLUSION: Augmented amounts of free amino acids and phenolic acids content after fermentation enhanced the antioxidants, cytotoxicity and immunomodulation effects of mung bean and soybean. More specifically, fermented mung bean showed the best effects among all the tested products. This study revealed the potential of fermented mung bean and soybean as functional foods for maintenance of good health.

Matched MeSH terms: Cell Survival/drug effects
Silver Nanoparticle Coated Bioactive Glasses--Composites with Dex/CMC Hydrogels: Characterization, Solubility, and In Vitro Biological Studies

Wren AW, Hassanzadeh P, Placek LM, Keenan TJ, Coughlan A, Boutelle LR, et al.

Macromol Biosci, 2015 Aug;15(8):1146-58.
PMID: 25923463 DOI: 10.1002/mabi.201500109

Silver (Ag) coated bioactive glass particles (Ag-BG) were formulated and compared to uncoated controls (BG) in relation to glass characterization, solubility and microbiology. X-ray diffraction (XRD) confirmed a crystalline AgNP surface coating while ion release studies determined low Ag release (<2 mg/L). Cell culture studies presented increased cell viability (127 and 102%) with lower liquid extract (50 and 100 ml/ml) concentrations. Antibacterial testing of Ag-BG in E. coli, S. epidermidis and S. aureus significantly reduced bacterial cell viability by 60-90%. Composites of Ag-BG/CMC-Dex Hydrogels were formulated and characterized. Agar diffusion testing was conducted where Ag-BG/hydrogel composites produced the largest inhibition zones of 7 mm (E. coli), 5 mm (S. aureus) and 4 mm (S. epidermidis).

Matched MeSH terms: Cell Survival/drug effects*
Fulltext Synergistic effect of pH-responsive folate-functionalized poloxamer 407-TPGS-mixed micelles on targeted delivery of anticancer drugs

Butt AM, Mohd Amin MC, Katas H

Int J Nanomedicine, 2015;10:1321-34.
PMID: 25709451 DOI: 10.2147/IJN.S78438

BACKGROUND: Doxorubicin (DOX), an anthracycline anticancer antibiotic, is used for treating various types of cancers. However, its use is associated with toxicity to normal cells and development of resistance due to overexpression of drug efflux pumps. Poloxamer 407 (P407) and vitamin E TPGS (D-α-tocopheryl polyethylene glycol succinate, TPGS) are widely used polymers as drug delivery carriers and excipients for enhancing the drug retention times and stability. TPGS reduces multidrug resistance, induces apoptosis, and shows selective anticancer activity against tumor cells. Keeping in view the problems, we designed a mixed micelle system encapsulating DOX comprising TPGS for its selective anticancer activity and P407 conjugated with folic acid (FA) for folate-mediated receptor targeting to cancer cells.
METHODS: FA-functionalized P407 was prepared by carbodiimide crosslinker chemistry. P407-TPGS/FA-P407-TPGS-mixed micelles were prepared by thin-film hydration method. Cytotoxicity of blank micelles, DOX, and DOX-loaded micelles was determined by alamarBlue(®) assay.
RESULTS: The size of micelles was less than 200 nm with encapsulation efficiency of 85% and 73% for P407-TPGS and FA-P407-TPGS micelles, respectively. Intracellular trafficking study using nile red-loaded micelles indicated improved drug uptake and perinuclear drug localization. The micelles show minimal toxicity to normal human cell line WRL-68, enhanced cellular uptake of DOX, reduced drug efflux, increased DOX-DNA binding in SKOV3 and DOX-resistant SKOV3 human ovarian carcinoma cell lines, and enhanced in vitro cytotoxicity as compared to free DOX.
CONCLUSION: FA-P407-TPGS-DOX micelles show potential as a targeted nano-drug delivery system for DOX due to their multiple synergistic factors of selective anticancer activity, inhibition of multidrug resistance, and folate-mediated selective uptake.

Matched MeSH terms: Cell Survival/drug effects

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