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Anionic linear-globular dendrimer-cis-platinum (II) conjugates promote cytotoxicity in vitro against different cancer cell lines.

Haririan I, Alavidjeh MS, Khorramizadeh MR, Ardestani MS, Ghane ZZ, Namazi H - Int J Nanomedicine (2010)

Bottom Line: Due to their unique properties, Anticancer dendrimer-based drugs have been displaying promising results in both in vitro and in vivo in the treatment of cancerous cells, as compared to the traditional polymers.In summary, the G2+Pt conjugate had greater toxicity than the G1+Pt conjugate and cisplatin, based on the in vitro results.In conclusion, these conjugates with such high potency and minimum hemolysis would be suitable candidates for use against these cancerous cell lines as efficient and novel antitumor agents.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran. haririan@tums.ac.ir

ABSTRACT
Due to their unique properties, Anticancer dendrimer-based drugs have been displaying promising results in both in vitro and in vivo in the treatment of cancerous cells, as compared to the traditional polymers. In this report, two conjugates (G1+Pt and G2+Pt) of cisplatin [cis-diaminedichloroplatinum; (CDDP)] with two generations (G1, G2) of a biocompatible anionic dendrimer were prepared in an aqueous media. Their potential cytotoxic effects, in two sensitive cancer cell lines HT1080 and CT26 together with one resistant cancer cell line SKOV3, using MTT (methyl thiazolyl tetrazolium) assay were examined. Hemolytic impacts and cell death mechanisms of the conjugates on human blood and HT1080 cell line were also investigated. The conjugate G2+Pt showed greater toxicity up to 9x and 2x in the sensitive and resistant cell lines (IC(50) comparison, inhibitory concentration) respectively when compared to the parent drug. The G1+Pt conjugate showed greater toxicity only in the sensitive HT1080 (2x) and CT26 (3.7x) cell lines. Moreover, the G1+Pt conjugate was less toxic approximately one third of the cisplatin in SKOV3 after 48 hrs of incubation. In summary, the G2+Pt conjugate had greater toxicity than the G1+Pt conjugate and cisplatin, based on the in vitro results. Approximately the same hemolysis behavior was observed for both conjugates and cisplatin. Both apoptosis and necrosis mechanisms (about 2x more than cisplatin) were attributed to conjugates and cisplatin in a direct correlation between the concentration and the degree of cell death. In conclusion, these conjugates with such high potency and minimum hemolysis would be suitable candidates for use against these cancerous cell lines as efficient and novel antitumor agents.

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Related in: MedlinePlus

Dot plot diagrams related to the amount of apoptosis-necrosis assays. Impact of the conjugates and free cisplatin (CDDP) at two concentrations on the percentage of apoptosis and necrosis. The data were analyzed with a version 2.4 of Flomax software. (A) negative control, (B) G1(0.75 μg/ml), (C) G1(1.5 μg/ml), (D) G2 (0.75 μg/ml), (E) G2 (1.5 μg/ml). (F) Platinum (0.75 μg/ml), (G) Platinum (1.5 μg/ml). Lower right: apoptotic cells, Upper right: necrotic and secondary apoptotic cells, Lower left: viable cells, Upper left: damaged cells.
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f8-ijn-5-063: Dot plot diagrams related to the amount of apoptosis-necrosis assays. Impact of the conjugates and free cisplatin (CDDP) at two concentrations on the percentage of apoptosis and necrosis. The data were analyzed with a version 2.4 of Flomax software. (A) negative control, (B) G1(0.75 μg/ml), (C) G1(1.5 μg/ml), (D) G2 (0.75 μg/ml), (E) G2 (1.5 μg/ml). (F) Platinum (0.75 μg/ml), (G) Platinum (1.5 μg/ml). Lower right: apoptotic cells, Upper right: necrotic and secondary apoptotic cells, Lower left: viable cells, Upper left: damaged cells.

Mentions: Apoptosis-necrosis assay was carried out at two moderately toxic concentrations (0.75 and 1.5 μg/mL) in order to determine and differentiate between the two cell death mechanisms induced by the conjugates and free cisplatin. These death mechanisms are considered crucial in determining the final treatment, eradication, and recurrence of the tumor cells.23 From the results, a direct correlation between the concentration and cell death was observed for the derivatives and free cisplatin; ie, the higher the concentration the greater the degree of cell death. Greater toxicity was observed for the G2+Pt complex, and increased necrosis was also seen for this conjugate. Generally, the amount of apoptosis and necrosis, was higher nearly 8%, (~2×) for the conjugates than those of cisplatin. The detailed results are presented in the Figure 8.


Anionic linear-globular dendrimer-cis-platinum (II) conjugates promote cytotoxicity in vitro against different cancer cell lines.

Haririan I, Alavidjeh MS, Khorramizadeh MR, Ardestani MS, Ghane ZZ, Namazi H - Int J Nanomedicine (2010)

Dot plot diagrams related to the amount of apoptosis-necrosis assays. Impact of the conjugates and free cisplatin (CDDP) at two concentrations on the percentage of apoptosis and necrosis. The data were analyzed with a version 2.4 of Flomax software. (A) negative control, (B) G1(0.75 μg/ml), (C) G1(1.5 μg/ml), (D) G2 (0.75 μg/ml), (E) G2 (1.5 μg/ml). (F) Platinum (0.75 μg/ml), (G) Platinum (1.5 μg/ml). Lower right: apoptotic cells, Upper right: necrotic and secondary apoptotic cells, Lower left: viable cells, Upper left: damaged cells.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2819903&req=5

f8-ijn-5-063: Dot plot diagrams related to the amount of apoptosis-necrosis assays. Impact of the conjugates and free cisplatin (CDDP) at two concentrations on the percentage of apoptosis and necrosis. The data were analyzed with a version 2.4 of Flomax software. (A) negative control, (B) G1(0.75 μg/ml), (C) G1(1.5 μg/ml), (D) G2 (0.75 μg/ml), (E) G2 (1.5 μg/ml). (F) Platinum (0.75 μg/ml), (G) Platinum (1.5 μg/ml). Lower right: apoptotic cells, Upper right: necrotic and secondary apoptotic cells, Lower left: viable cells, Upper left: damaged cells.
Mentions: Apoptosis-necrosis assay was carried out at two moderately toxic concentrations (0.75 and 1.5 μg/mL) in order to determine and differentiate between the two cell death mechanisms induced by the conjugates and free cisplatin. These death mechanisms are considered crucial in determining the final treatment, eradication, and recurrence of the tumor cells.23 From the results, a direct correlation between the concentration and cell death was observed for the derivatives and free cisplatin; ie, the higher the concentration the greater the degree of cell death. Greater toxicity was observed for the G2+Pt complex, and increased necrosis was also seen for this conjugate. Generally, the amount of apoptosis and necrosis, was higher nearly 8%, (~2×) for the conjugates than those of cisplatin. The detailed results are presented in the Figure 8.

Bottom Line: Due to their unique properties, Anticancer dendrimer-based drugs have been displaying promising results in both in vitro and in vivo in the treatment of cancerous cells, as compared to the traditional polymers.In summary, the G2+Pt conjugate had greater toxicity than the G1+Pt conjugate and cisplatin, based on the in vitro results.In conclusion, these conjugates with such high potency and minimum hemolysis would be suitable candidates for use against these cancerous cell lines as efficient and novel antitumor agents.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran. haririan@tums.ac.ir

ABSTRACT
Due to their unique properties, Anticancer dendrimer-based drugs have been displaying promising results in both in vitro and in vivo in the treatment of cancerous cells, as compared to the traditional polymers. In this report, two conjugates (G1+Pt and G2+Pt) of cisplatin [cis-diaminedichloroplatinum; (CDDP)] with two generations (G1, G2) of a biocompatible anionic dendrimer were prepared in an aqueous media. Their potential cytotoxic effects, in two sensitive cancer cell lines HT1080 and CT26 together with one resistant cancer cell line SKOV3, using MTT (methyl thiazolyl tetrazolium) assay were examined. Hemolytic impacts and cell death mechanisms of the conjugates on human blood and HT1080 cell line were also investigated. The conjugate G2+Pt showed greater toxicity up to 9x and 2x in the sensitive and resistant cell lines (IC(50) comparison, inhibitory concentration) respectively when compared to the parent drug. The G1+Pt conjugate showed greater toxicity only in the sensitive HT1080 (2x) and CT26 (3.7x) cell lines. Moreover, the G1+Pt conjugate was less toxic approximately one third of the cisplatin in SKOV3 after 48 hrs of incubation. In summary, the G2+Pt conjugate had greater toxicity than the G1+Pt conjugate and cisplatin, based on the in vitro results. Approximately the same hemolysis behavior was observed for both conjugates and cisplatin. Both apoptosis and necrosis mechanisms (about 2x more than cisplatin) were attributed to conjugates and cisplatin in a direct correlation between the concentration and the degree of cell death. In conclusion, these conjugates with such high potency and minimum hemolysis would be suitable candidates for use against these cancerous cell lines as efficient and novel antitumor agents.

Show MeSH
Related in: MedlinePlus