Evaluation of biodistribution of Riboplatin, a Pt(IV) double prodrug based on cisplatin, using fluorescent visualization

Abstract

BACKGROUND: Developing new platinum-based antitumor agents with improved efficacy and reduced toxicity remains a critical challenge. One promising approach is the synthesis of Pt(IV) prodrugs, such as precursor complexes of cisplatin and its analogs, which release active Pt(II) directly into the intracellular environment of malignant cells. To determine the optimal administration route for these new platinum-based drugs in vivo, it is essential to study their acute toxicity and biodistribution in vital organs.

AIM: To evaluate the tolerability, acute toxicity, biodistribution, and accumulation in breast tumors of Riboplatin and its liposomal formulation.

MATERIALS AND METHODS: The study was conducted at Moscow Pedagogical State University in female BALB/c mice (healthy or bearing transplanted breast adenocarcinoma EMT-6) and in immunodeficient BALB/c nude mice (bearing human breast adenocarcinoma SK-BR-3). The fluorescence imaging and inductively coupled plasma mass spectrometry were used.

RESULTS: A single dose (up to 48 mg/kg) of either water solution or liposomal formulation of Riboplatin did not cause any decrease of body weight in mice. The animals tolerated the dose 48 mg/kg of the drug, whereas the body weight decreased by less than 5% within 3 days. The distribution of Riboplatin and of its liposomal formulation over the body organs was assessed in BALB/c nude mice using fluorescence imaging and inductively coupled plasma mass spectrometry. Both forms provided Riboplatin delivering to EMT-6 tumor. Riboplatin in the form of water solution was predominantly excreted through liver and kidney, while the liposomal formulation lewd to drug accumulation in the spleen.

CONCLUSION: Riboplatin is a Pt(IV) prodrug with good tolerability, reduced toxicity compared with cisplatin, with effective accumulation in malignant breast tumors. The opportunity of assessing Riboplatin biodistribution in vivo in EMT-6 and SK-BR-3 tumor lines using fluorescence imaging has been demonstrated. Significant Riboplatin accumulation in EMT-6 tumors suggests the possibility of riboflavin-specific uptake.

Keywords

cisplatin / riboflavin / combination therapy / chemotherapy / photodynamic therapy / liposomes / biodistribution

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Funding

Российский научный фондRussian Science Foundation(22-15-00182)

Министерство просвещения Российской ФедерацииMinistry of Education of the Russian Federation(073-03-2022-100/12)

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