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J Nanosci Nanotechnol. 2018 Oct 1;18(10):6732-6739. doi: 10.1166/jnn.2018.15502.

Glutaryl Polyamidoamine Dendrimer for Overcoming Cisplatin-Resistance of Breast Cancer Cells.

Abstract

OBJECTIVE:

Cisplatin has limited clinical applications due to drug resistance. PAMAM dendrimer was chosen as a vehicle to counteract cisplatin-resistance and its mechanism was assessed.

METHODS:

Generation 5 Polyamidoamine dendrimer (G5) was modified by glutaric anhydride (GA) and then conjugated with cisplatin. The cisplatin release of G5-GA-cisplatin was evaluated at pH 5.5 and pH 7.4. The cytotoxicity of G5-GA-cisplatin and free cisplatin was compared in cisplatin-resistant breast cancer cell line MCF-7R. The intracellular platinum content of MCF-7R was determined using ICP-MS. The expression of Ctr1 and ATP7B of MCF-7R cells was also evaluated.

RESULTS:

An average of 75 amino groups present in the G5 PAMAM surface were converted into glutaric acid (G5-GA75) and platinum loading was 350±21 μg per 1 mg of G5-GA75. G5-Ac75-cisplatin complex exhibited controlled release of cisplatin at different pH over a period of 96 h. After 96 h incubation with G5-Ac75-cisplatin, cell viability was 27.47±2.53%, 12.18±0.65% and 11.62±0.84% using platinum concentration of 1 μg/ml, 3 μg/ml and 5 μg/ml, respectively. Meanwhile, 46.33±5.06% cells survived even in the high platinum concentration of 5 μg/ml after 96 h incubation with free cisplatin. G5-GA75 led to 3-6 times higher cisplatin accumulation than free cisplatin in MCF-7R cells, because MCF-7R cells exhibited lower Ctr1 expression and higher ATP7B expression than MCF-7 cells.

CONCLUSION:

The G5-GA75-cisplatin complex displayed greater anticancer activity than free cisplatin in the cisplatin-resistant breast cancer cell line MCF-7R. The low levels of Ctr1 and high levels of ATP7B in MCF-7R caused G5-GA75 to allow the accumulation of cisplatin, which in turn increased the cytotoxicity. Results indicated that glutaryl G5 PAMAM may be a potential carrier for cisplatin targeting in breast cancer.

PMID:
29954488
DOI:
10.1166/jnn.2018.15502

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