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Publikation

Edeler, D.; Kaluđerović, M. R.; Dojčinović, B.; Schmidt, H.; Kaluđerović, G. N.; SBA-15 mesoporous silica particles loaded with cisplatin induce senescence in B16F10 cells RSC Adv. 6, 111031-111040, (2016) DOI: 10.1039/C6RA22596A

The anticancer drug cisplatin (CP) is loaded into SBA-15 mesoporous silica (SBA-15|CP) and its release from the nanomaterial is studied. The CP-loaded SBA-15 is tested against four tumor cell lines: mouse malignant melanoma B16F10, human adenocarcinoma HeLa, colon HT-29 and prostate PC3. Most importantly, the superiority of this novel material in comparison to CP arises from the fact that the CP-grafted nanomaterial SBA-15 (→SBA-15|CP) is enhancing cessation of proliferation along with induction of senescence in B16F10 in approximately 3.5 times lower concentration. The control material loaded with therapeutically inactive K2[PtCl4] (→SBA-15|TC) showed no antitumor activity. To a large extent, SBA-15|CP-induced senescence might present a safe approach in tumor treatment. Such cells can be cleared by immune cells resulting in efficient tumor regression. So far only apoptotic agents are being exploited in clinics, thus an understanding of the chemotherapeutic-induced senescence will allow oncologists to explore this essential tumor suppressor mechanism.
Publikation

Momčilović, M.; Eichhorn, T.; Blazevski, J.; Schmidt, H.; Kaluđerović, G. N.; Stosic-Grujicic, S.; In vitro effects of binuclear (η6-p-cymene)ruthenium(II) complex containing bridging bis(nicotinate)-polyethylene glycol ester ligand on differentiation pathways of murine Th lymphocytes activated by T cell mitogen J. Biol. Inorg. Chem. 20, 575-583, (2015) DOI: 10.1007/s00775-015-1242-x

T cell differentiation into distinct T helper (Th) subpopulations is crucial in governing acquired immune responses as well as some inflammatory and autoimmune disorders. This study investigated potential of the novel neutral binuclear ruthenium(II) complexes 1–8 with general formula [{RuCl2(η6-p-cym)}2μ-(N∩N)] (N∩N = bis(nicotinate)- and bis(iso-nicotinate)-polyethylene glycol esters; (3-py)COO(CH2CH2O) n CO(3-py) and (4-py)COO(CH2CH2O) n CO(4-py); n = 1–4), as well as [RuCl2(η6-p-cym)(nic)] (R1, nic = nicotinate) and [RuCl2(η6-p-cym)(inic)] (R2, inic = isonicotinate) as an immunomodulatory agents capable to direct Th cell differentiation. From all investigated complexes, [{RuCl2(η6-p-cym)}2μ-{(3-py)COO(CH2CH2O)4CO(3-py)}] (4) was selected for further study because it did not affect splenocyte viability (in concentration up to 50 μM), but significantly reduced secretion of representative Th1 cytokine, IFN-γ induced by T cell mitogen. Besides IFN-γ, 4 inhibited dose dependently expression and production of representative Th17 cytokine, IL-17, in these cells. Otherwise, the production of anti-inflammatory cytokines IL-4 and IL-10 was upregulated. Also, 4 significantly increased CD4+CD25+FoxP3+ Treg cell frequency in the activated splenocytes. Moreover, ConA-induced expression of Th1 transcription factors, T-bet and STAT1, as well as of Th17-related protein STAT3 was attenuated upon exposure to 4, while the expression of Th2-related transcription factor GATA3 remained stable. In conclusion, ruthenium(II) complex 4 modulates immune system cell functions in vitro by inhibiting T cell differentiation towards pathogenic Th1/Th17 phenotype and inducing a regulatory phenotype characterized by IL-10 and IL-4 production, which may provide novel therapeutic opportunities for immune-inflammatory and/or autoimmune disorders.
Publikation

Bulatović, M. Z.; Maksimović-Ivanić, D.; Bensing, C.; Gómez-Ruiz, S.; Steinborn, D.; Schmidt, H.; Mojić, M.; Korać, A.; Golić, I.; Pérez-Quintanilla, D.; Momčilović, M.; Mijatović, S.; Kaluđerović, G. N.; Organozinn(IV)-beladenes mesoporöses SiO2 als biokompatible Strategie bei der Krebstherapie Angew. Chem. 126, 6092-6097, (2014) DOI: 10.1002/ange.201400763

Das große therapeutische Potenzial eines Organozinn(IV)‐beladenen nanostrukturierten SiO2 (SBA‐15pSn) wird am Beispiel der Rückbildung eines durch B16‐Zellen induzierten Melanoms bei syngenen C57BL/6‐Mäusen demonstriert. Neben Apoptose als grundlegendem Mechanismus der Antitumorwirkung einer Vielzahl von Chemotherapeutika ist der entscheidende Vorteil dieses mesoporösen zinnhaltigen Materials das Auslösen der Zelldifferenzierung – ein Effekt, der weder für metallbasierte Zytostatika noch für mesoporöse Materialien alleine bisher beobachtet wurde. Dieser nichtaggressive Wirkungsmechanismus ist hochwirksam gegen Tumorzellen aber im gewählten Konzentrationsbereich nichttoxisch für normales Gewebe. JNK‐unabhängige Apoptose (JNK: Jun amino‐terminal kinase), begleitet von der Bildung des melanozytenartigen nichtproliferativen Phänotyps der überlebenden Zellen demonstriert das außergewöhnliche Potenzial von SBA‐15pSn zur Unterdrückung von Tumorwachstum ohne eine unerwünschte kompensatorische Proliferation der erkrankten Zellen als Antwort auf den Zelltod in ihrer Nachbarschaft.
Publikation

Bulatović, M. Z.; Maksimović-Ivanić, D.; Bensing, C.; Gómez-Ruiz, S.; Steinborn, D.; Schmidt, H.; Mojić, M.; Korać, A.; Golić, I.; Pérez-Quintanilla, D.; Momčilović, M.; Mijatović, S.; Kaluđerović, G. N.; Organotin(IV)-Loaded Mesoporous Silica as a Biocompatible Strategy in Cancer Treatment Angew. Chem. Int. Ed. 53, 5982-5987, (2014) DOI: 10.1002/anie.201400763

The strong therapeutic potential of an organotin(IV) compound loaded in nanostructured silica (SBA‐15pSn) is demonstrated: B16 melanoma tumor growth in syngeneic C57BL/6 mice is almost completely abolished. In contrast to apoptosis as the basic mechanism of the anticancer action of numerous chemotherapeutics, the important advantage of this SBA‐15pSn mesoporous material is the induction of cell differentiation, an effect unknown for metal‐based drugs and nanomaterials alone. This non‐aggressive mode of drug action is highly efficient against cancer cells but is in the concentration range used nontoxic for normal tissue. JNK (Jun‐amino‐terminal kinase)‐independent apoptosis accompanied by the development of the melanocyte‐like nonproliferative phenotype of survived cells indicates the extraordinary potential of SBA‐15pSn to suppress tumor growth without undesirable compensatory proliferation of malignant cells in response to neighboring cell death.

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