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

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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.

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About the authors

Daniil V. Spektor

Chemistry Department, Lomonosov Moscow State University

Email: danspector@yandex.ru
ORCID iD: 0000-0002-2726-2671

Cand. Sci (Chemistry)

Russian Federation, Moscow

Roman A. Akasov

Moscow Pedagogical State University

Email: romanakasov@gmail.com
ORCID iD: 0000-0001-6486-8114
SPIN-code: 8383-0004

Cand. Sci (Chemistry)

Russian Federation, Moscow

Evgeny V. Khaidukov

Moscow Pedagogical State University; Mendeleev University of Chemical Technology of Russia

Email: khaydukov@mail.ru
ORCID iD: 0000-0002-3900-2949
SPIN-code: 2097-1680

Dr. Sci. (Physis and Math)

Russian Federation, Moscow; Moscow

Polina A. Demina

Moscow Pedagogical State University

Email: polidemina1207@yandex.ru
ORCID iD: 0000-0001-6349-2979
SPIN-code: 6974-2981

Cand. Sci (Chemistry)

Russian Federation, Moscow

Maksim E. Stepanov

Moscow Pedagogical State University

Email: stepanov_me@mail.ru
ORCID iD: 0000-0002-0332-1235
SPIN-code: 9652-6151

Cand. Sci (Chemistry)

Russian Federation, Moscow

Gulyalek Babayeva

Blokhin Oncology Research Center

Email: babaevagulyalek@gmail.com
ORCID iD: 0000-0001-5781-7925
SPIN-code: 8547-6770

Cand. Sci. (Biology)

Russian Federation, Moscow

V. S. Pokrovsky

Blokhin Oncology Research Center

Email: vadimpokrovsky@yandex.ru
ORCID iD: 0000-0003-4006-9320
SPIN-code: 4552-1226

MD, Dr. Sci. (Medicine), Professor

Russian Federation, Moscow

Anna D. Lapanik

Lomonosov Moscow State University

Email: anya73anya@gmail.com
ORCID iD: 0009-0003-9847-4609

student

Russian Federation, Moscow

Alena D. Naumova

Lomonosov Moscow State University

Email: naumovaaaalena@gmail.com
ORCID iD: 0009-0003-9727-1615

Master

Russian Federation, Moscow

Anton V. Lopukhov

Lomonosov Moscow State University

Email: lopukhov@enzyme.chem.msu.ru
ORCID iD: 0000-0002-3517-505X
SPIN-code: 7232-5120

Cand. Sci. (Chemistry)

Russian Federation, Moscow

Natalia L. Klyachko

Lomonosov Moscow State University

Email: nlklyachko@gmail.com
ORCID iD: 0000-0002-9357-8236
SPIN-code: 3680-6329

Dr. Sci. (Chemistry), Professor

Russian Federation, Moscow

Ilya A. Kuzmichev

Serbsky National Medical Research Center for Psychiatry and Narcology

Email: lolopededin@gmail.com
ORCID iD: 0009-0004-7092-1777

Researcher

Russian Federation, Moscow

Alevtina S. Semkina

Serbsky National Medical Research Center for Psychiatry and Narcology

Email: alevtina.semkina@gmail.com
ORCID iD: 0000-0003-3617-4830
SPIN-code: 6071-3394

Cand. Sci. (Biology)

Russian Federation, Moscow

Aleksander S. Dubenskiy

Geological Institute of RAS

Email: alexchem206@gmail.com
ORCID iD: 0000-0001-9364-5876
SPIN-code: 2261-3382

Cand. Sci. (Chemistry)

Russian Federation, Moscow

Elena K. Beloglazkina

Chemistry Department, Lomonosov Moscow State University

Email: beloglazki@mail.ru
ORCID iD: 0000-0001-6796-8241

Dr. Sci. (Chemistry), Professor

Russian Federation, Moscow

Olga O. Krasnovskaya

Chemistry Department, Lomonosov Moscow State University

Author for correspondence.
Email: krasnovskayao@gmail.com
ORCID iD: 0000-0002-4948-2747
SPIN-code: 4925-6432

Cand. Sci (Chemistry)

Russian Federation, Moscow

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2. Fig. 1. Organ fluorescence 1 h and 10 min after injection of Riboplatin solution. Healthy BALB/c mouse.

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3. Fig. 2. Organ fluorescence 1 h and 10 min after injection of liposomal formulation of Riboplatin. Healthy BALB/c mouse.

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4. Fig. 3. BALB/c mouse with inoculated EMT-6 tumor. a. Fluorescence of mouse organs and tumor sections 1 h and 10 min after Riboplatin injection; b. Fluorescence of organs and mouse tumor sections 1 h and 10 min after Riboplatin injection. Hereafter: internal tumor cross-section refers to that adjacent to body tissues; external cross-section refers to that adjacent to skin and coat.

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5. Fig. 4. BALB/c mouse with inoculated EMT-6 tumor. a. Fluorescence of mouse organs and tumor 1 h and 10 min after administration of liposomal formulation of Riboplatin; b. Fluorescence of mouse organs and tumor sections 1 h and 10 min after administration of liposomal formulation of Riboplatin.

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6. Fig. 5. Organ emission of BALB/c nude mice with inoculated SK-BR-3 xenografted mammary tumor. a. 30 min after intravenous injection of Riboplatin solution; b. 24 h after intravenous injection of liposomal formulation of Riboplatin.

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7. Fig. 6. Distribution of Riboplatin in organs of BALB/c mice with SK-BR-3 tumor after administration of a, C. 25,6 mg/kg aqueous solution of Riboplatin. b, D 86 mg/kg liposomal formulation of Riboplatin. a, b. Organ Pt content (ICP-MS analysis). c, d. Fluorescence analysis. There are no error bars for time t=80 min since one mouse in was used in the experiment.

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