Vessel visualization and inhibition of tumor growth after injection of nanosystems based on magnetic nanoparticles modified by serum albumin with free radical approach

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Abstract

BACKGROUND: Nanosystems based on magnetic nanoparticles (MNPs) of iron oxides coated with human serum albumin (HSA) have a set of unique characteristics that make their use promising in the diagnosis and treatment of tumors.

AIM: To investigate, using in vitro and in vivo models, the possibilities of using the systems we developed based on MNPs magnetite, modified by HSA using the free radical method, for contrasting tumors and slowing their growth.

MATERIALS AND METHODS: The stability and integrity of the albumin coating formed on synthesized nanoparticles as a result of protein adsorption and fixation of adsorbed albumin molecules on nanoparticles due to modification of albumin by the action of a hydroxyl radical formed in a Fenton-like reaction was controlled by a change in the apparent optical density by 450 nm with the addition of immunoglobulin G. After in vitro confirmation of the contrasting properties and possible consequences of the contact of MNPs and nanosystems with blood by agglutination test, nanosystems containing MNPs and HSA were injected intraarterially into tumors implanted in rats at a dose of 20–60 μg per animal and the contrasting properties were studied in vivo using radiography and computed tomography. The effect of nanosystems on the tumor was assessed by the tumor growth index (TGI) and by the results of a pathomorphological study.

RESULTS: To obtain nanosystems, joint incubation of MNPs and HSA was carried out for 24 hours in the presence of hydrogen peroxide, then subjected to magnetic separation. The stability and integrity of the protein coatings were confirmed with the addition of immunoglobulin G. In vitro studies have shown that the resulting nanosystem preparation in an aqueous medium with a MNPs concentration of 200 μg/ml does not lead to agglutination of blood cells and has a pronounced contrast. Vascular contrast in vivo, recorded 30 minutes after intraarterial administration, persisted for 14 days of follow-up. The tolerability study did not reveal any adverse side effects. With the introduction of nanosystems, a significant inhibition of tumor growth was noted compared with the control groups (p ≤0.05). Thus, tumors without the introduction of nanosystems reached a volume of 95,726.9±38,040.3 mm3 during the observation period — the TGI was 11±4.5. In the groups of rats treated with nanosystems at a dose of 20 micrograms of MNPs, tumors grew to 49,801±6011.2 mm3 (TGI 4.7±0.5), at a dose of 40 μg of MNPs — to 54,670.2±17 983.4 mm3 (IPO 5.5±1.4), at a dose of 60 μg of MNPs — to 43,342.5±14,637.2 mm3 (TGI 4.5±1.3).

CONCLUSION: The steady contrast of tumor vessels with the introduction of nanosystems based on MNPs and HSA and their cytotoxic effect on the tumor is shown, which gives reason to consider the nanosystems developed by us promising for tumor theranostics.

About the authors

Anna V. Bychkova

Emanuel Institute of Biochemical Physics of Russian Academy of Sciences

Author for correspondence.
Email: anna.v.bychkova@gmail.com
ORCID iD: 0000-0001-6367-0923
SPIN-code: 2180-2705

Cand. Sci. (Chemistry)

Russian Federation, Moscow

Marina N. Yakunina

N.N. Blokhin National Medical Research Center of Oncology

Email: irsovet@yandex.ru
ORCID iD: 0000-0002-5278-1641

Dr. Sci. (Vet.)

Russian Federation, Moscow

Mariia V. Lopukhova

Emanuel Institute of Biochemical Physics of Russian Academy of Sciences

Email: mahlop1@yandex.ru
ORCID iD: 0009-0002-4701-0815
SPIN-code: 9921-9170
Russian Federation, Moscow

Vadim S. Pokrovsky

Emanuel Institute of Biochemical Physics of Russian Academy of Sciences; N.N. Blokhin National Medical Research Center of Oncology; RUDN University

Email: pokrovskiy-vs@rudn.ru
ORCID iD: 0000-0003-4006-9320
SPIN-code: 4552-1226

MD, Dr. Sci. (Med.)

Russian Federation, Moscow; Moscow; Moscow

Mariia S. Veresova

Emanuel Institute of Biochemical Physics of Russian Academy of Sciences

Email: veresovamariiaa@gmail.com
ORCID iD: 0009-0004-4069-6011
Russian Federation, Moscow

Marina E. Sukhanova

RUDN University

Email: sukhanova-me@rudn.ru

Cand. Sci. (Biology)

Russian Federation, Moscow

Valery V. Kasparov

Emanuel Institute of Biochemical Physics of Russian Academy of Sciences

Email: vvkas@yandex.ru
ORCID iD: 0000-0002-0438-2451
SPIN-code: 5283-7920

Cand. Sci. (Chemistry)

Russian Federation, Moscow

Derenik S. Khachatryan

Emanuel Institute of Biochemical Physics of Russian Academy of Sciences

Email: derenik-s@yandex.ru
ORCID iD: 0000-0002-5490-5652
SPIN-code: 3221-3444

Cand. Sci. (Chemistry)

Russian Federation, Moscow

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Supplementary files

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2. Fig. 1. Hybrid nanosystems based on iron oxide nanoparticles (Fe3O4) for biomedical applications.

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3. Fig. 2. Fenton-like reaction on magnetic nanoparticles surface in the absence (1) and in the presence (2) of human serum albumin: ЧСА — human serum albumin.

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4. Fig. 3. Dependence of relative optical density on the ratio of magnetic nanoparticles (МНЧ) and human serum albumin (ЧСА) concentrations in the reaction systems after immunoglobulin G addition. Incubation time of the systems before addition of immunoglobulin G: 1 — 30 minutes, 2 — 90 minutes, 3 — 24 hours.

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5. Fig. 4. CT imaging of the tumor node from two different angles (transverse and sagittal planes) in the rat femoral muscle after 30 minutes (1, 2) and 14 days (3, 4) after the injection of nanosystems based on magnetic nanoparticles and human serum albumin (corresponding to 60 μg magnetic nanoparticles).

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6. Fig. 5. X-ray imaging after 30 minutes after injection of nanosystems corresponding to 40 μg of magnetic nanoparticles (1) and 14 days after injection of nanosystems corresponding to 20 μg (3), 40 μg (3) and 60 μg (4) of magnetic nanoparticles.

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7. Fig. 6. Microscopic imaging of whole blood and magnetic nanoparticles 1:1 (magnification ×400).

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8. Fig. 7. The effect of nanosystems injected in an amount of 60 μg by magnetic nanoparticles on the tumor growth index (TGI), characterized by the size at the beginning of treatment Vav=9.5–10.5 cm3 (1, 2) and Vav=6.0–6.5 cm3 (3, 4).

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9. Fig. 8. The effect of nanosystems injected in various quantities: group 1 — 0 μg, group 2 — 20 μg, group 3 — 40 μg, group 4 — 60 μg (by magnetic nanoparticles) on the time of doubling the volume of the tumor. The numbers above the columns represent the coefficient of treatment effectiveness in comparison with the control group where tumor growth was observed (K).

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