Repozytorium publikacji - Politechnika Gdańska

Hematopoietic cell transplantation (HCT) is often considered a last resort leukemia treatment, fraught with limited success due to microbial infections, a leading cause of mortality in leukemia patients. To address this critical issue, we explored a novel approach by synthesizing antileukemic agents containing antibacterial substances. This innovative strategy involves conjugating fluoroquinolone antibiotics, such as ciprofloxacin (CIP) or levofloxacin (LVX), with the cell-penetrating peptide (CPP) transportan 10 (TP10). Here, we demonstrate that the resultant compounds display promising biological activities in preclinical studies. These novel conjugates not only exhibit potent antimicrobial effects but are also selective against leukemia cells. The cytotoxic mechanism involves rapid disruption of cell membrane asymmetry leading to membrane damage. Importantly, these conjugates penetrated mammalian cells, accumulating within the nuclear membrane without significant effect on cellular architecture or mitochondrial function. Molecular simulations elucidated the aggregation tendencies of TP10 conjugates within lipid bilayers, resulting in membrane disruption and permeabilization. Moreover, mass spectrometry analysis confirmed efficient reduction of disulfide bonds within TP10 conjugates, facilitating release and activation of the fluoroquinolone derivatives. Intriguingly, these compounds inhibited human topoisomerases, setting them apart from traditional fluoroquinolones. Remarkably, TP10 conjugates generated lower intracellular levels of reactive oxygen species (ROS) compared to CIP and LVX. The combination of antibacterial and antileukemic properties, coupled with selective cytostatic effects and minimal toxicity towards healthy cells, positions TP10 derivatives as promising candidates for innovative therapeutic approaches in the context of antileukemic HCT. This study highlights their potential in search of more effective leukemia treatments.

Autorzy

• dr Jan Lica,
• Mateusz Heldt,
• dr inż. Miłosz Wieczór link otwiera się w nowej karcie ,
• Paweł Chodnicki link otwiera się w nowej karcie ,
• Natalia Ptaszyńska,
• Anna Łęgowska,
• dr Wioletta Brankiewicz link otwiera się w nowej karcie ,
• Dr inż. Katarzyna Gucwa,
• dr inż. Anna Stupak link otwiera się w nowej karcie ,
• dr inż. Natalia Maciejewska link otwiera się w nowej karcie ,
• Bhaskar Pradhan,
• Agata Gitlin-Domagalska,
• Dawid Dębowski,
• prof. dr hab. inż. Sławomir Milewski link otwiera się w nowej karcie ,
• Maria Bieniaszewska link otwiera się w nowej karcie ,
• dr Grzegorz Jan Grabe,
• prof. dr hab. n. med. Andrzej Hellmann,
• Rolka Krzysztof