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

Ismaeil Haririan^1,6, Mohammad Shafiee Alavidjeh¹, Mohammad Reza Khorramizadeh², Mehdi Shafiee Ardestani³, Zohre Zarei Ghane⁴, Hassan Namazi⁵

¹Department of Pharmaceutics, Faculty of Pharmacy, ²Department of Medical Biotechnology, School of Advanced Medical Biotechnology, ³Department of Medicinal Chemistry, Faculty of Pharmacy, ⁴Department of Pathobiology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran; ⁵Faculty of Chemistry, Laboratory of Natural Carbohydrates and Biopolymer, University of Tabriz, Tabriz, Iran; ⁶Biomaterials Research Center (BRC), Tehran, Iran

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 9× and 2× in the sensitive and resistant cell lines (IC₅₀ comparison, inhibitory concentration) respectively when compared to the parent drug. The G1+Pt conjugate showed greater toxicity only in the sensitive HT1080 (2×) and CT26 (3.7×) 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 2× 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.

Keywords: cis-platinum (II), dendrimer, in vitro cytotoxicity, hemolysis, apoptosis-necrosis