Hypoxia-targeted cupric-tirapazamine liposomes potentiate radiotherapy in prostate cancer spheroids

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A1 Alkuperäisartikkeli tieteellisessä aikakauslehdessä
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Date
2021-09-25
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Language
en
Pages
11
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International Journal of Pharmaceutics, Volume 607
Abstract
In this study, novel cupric-tirapazamine [Cu(TPZ)2]-liposomes were developed as an effective hypoxia-targeted therapeutic, which potentiated radiotherapy in a three dimensional (3D) prostate cancer (PCa) model. To overcome the low water solubility of the Cu(TPZ)2, a remote loading method was developed to efficiently load the lipophilic complex into different liposomal formulations. The effect of pH, temperature, PEGylation, lipid composition, liposome size, lipid: complex ratio on the liposome properties, and drug loading was evaluated. The highest loading efficiency was obtained at neutral pH, which was independent of lipid composition and incubation time. In addition, enhanced drug loading was achieved upon decreasing the lipid:complex molar ratio with minimal effects on liposomes’ morphology. Interestingly, the in vitro potency of the developed liposomes was easily manipulated by changing the lipid composition. The hydrophilic nature of our liposomal formulations improved the complex's solubility, leading to enhanced cellular uptake and toxicity, both in PCa monolayers and tumour spheroids. Moreover, Cu(TPZ)2-loaded liposomes combined with radiation, showed a significant reduction in PCa spheroids growth rate, compared to the free complex or radiation alone, which could potentiate radiotherapy in patients with localised advanced PCa.
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Funding Information: V.L.S is grateful for her PhD studentship awarded by the University of East Anglia (studentship ref. 100099479). This work was also supported by the Prostate Cancer UK (CDF-12-002 Fellowship), the Engineering and Physical Sciences Research Council (EPSRC) (EP/M008657/1) and Queen's University Belfast. Funding Information: V.L.S is grateful for her PhD studentship awarded by the University of East Anglia (studentship ref. 100099479). This work was also supported by the Prostate Cancer UK (CDF-12-002 Fellowship), the Engineering and Physical Sciences Research Council (EPSRC) (EP/M008657/1) and Queen’s University Belfast. Publisher Copyright: © 2021
Keywords
Copper complexes, Hypoxia, Hypoxia pro-drugs, Liposomes, Prostate cancer, Radiation, Spheroids, Tirapazamine
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Citation
Silva , V L , Ruiz , A , Ali , A , Pereira , S , Seitsonen , J , Ruokolainen , J , Furlong , F , Coulter , J & Al-Jamal , W T 2021 , ' Hypoxia-targeted cupric-tirapazamine liposomes potentiate radiotherapy in prostate cancer spheroids ' , International Journal of Pharmaceutics , vol. 607 , 121018 . https://doi.org/10.1016/j.ijpharm.2021.121018