Polyurethane–polyurea hybrid nanocapsules as efficient delivery systems of anticancer Ir(<scp>iii</scp>) metallodrugs

Bonelli, Joaquín; Ortega-Forte, Enrique; Vigueras, Gloria; Bosch, Manel; Cutillas, Natalia; Rocas, Josep; Ruiz, José; Marchán, Vicente

doi:10.1039/d1qi01542g

Cited by 12 publications

(21 citation statements)

References 81 publications

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“…Based on the results obtained with OncoIr1 and OncoIr2 [ 14 ], we maintained two of the cyclometalating ligands fixed and modified the benzimidazole core of the third ligand for the molecular construction of the new iridium compound OncoIr3 (Fig. 1 a).…”

Section: Resultsmentioning

confidence: 99%

“…Very recently, some of us reported two new iridium compounds, namely OncoIr1 and OncoIr2 (Fig. 1 a), which also induced oncosis-like cell death [ 14 ]. However, these two compounds were unable to enter human cells, and only displayed their anticancer activity upon nanoparticle encapsulation [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

“…1 a), which also induced oncosis-like cell death [ 14 ]. However, these two compounds were unable to enter human cells, and only displayed their anticancer activity upon nanoparticle encapsulation [ 14 ]. Based on these results, we decided to redesign the chemical structure of OncoIr1 and OncoIr2 to improve cellular uptake into cancer cells and induce cell death via oncosis.…”

Section: Introductionmentioning

confidence: 99%

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Potent anticancer activity of a novel iridium metallodrug via oncosis

Ortega-Forte

Hernández-García

Vigueras

et al. 2022

Cell. Mol. Life Sci.

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Oncosis (from Greek ónkos, meaning “swelling”) is a non-apoptotic cell death process related to energy depletion. In contrast to apoptosis, which is the main form of cell death induced by anticancer drugs, oncosis has been relatively less explored but holds potential to overcome drug resistance phenomena. In this study, we report a novel rationally designed mitochondria-targeted iridium(III) complex (OncoIr3) with advantageous properties as a bioimaging agent. OncoIr3 exhibited potent anticancer activity in vitro against cancer cells and displayed low toxicity to normal dividing cells. Flow cytometry and fluorescence-based assays confirmed an apoptosis-independent mechanism involving energy depletion, mitochondrial dysfunction and cellular swelling that matched with the oncotic process. Furthermore, a Caenorhabditis elegans tumoral model was developed to test this compound in vivo, which allowed us to prove a strong oncosis-derived antitumor activity in animals (with a 41% reduction of tumor area). Indeed, OncoIr3 was non-toxic to the nematodes and extended their mean lifespan by 18%. Altogether, these findings might shed new light on the development of anticancer metallodrugs with non-conventional modes of action such as oncosis, which could be of particular interest for the treatment of apoptosis-resistant cancers. Graphical abstract

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Potent anticancer activity of a novel iridium metallodrug via oncosis

Ortega-Forte

Hernández-García

Vigueras

et al. 2022

Cell. Mol. Life Sci.

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“…The results from these experiments are in good agreement with our previous observations by TEM, which demonstrated that NCs loaded with iridium(III) complexes were selectively degraded in the presence of glutathione, while they remained completely stable after incubation at 37 °C in PBS and in serum AB. 27 …”

Section: Results and Discussionmentioning

confidence: 99%

“… 26 In this context, we have recently described polyurethane-polyurea hybrid NCs loaded with two cell impermeable cyclometalated Ir(III) complexes whose anticancer activity could be investigated, thanks to their nanoencapsulation. 27 Such Ir(III)-loaded nanoparticles were found to be completely stable in complete human AB serum but degradable in the presence of glutathione owing to the incorporation of disulfide bonds in the polymeric wall. Moreover, in vivo safety and biodistribution assays have been carried out using this type of NCs by system injection through the tail vein, in order to elucidate associated toxicity and preferential accumulation in ectopic and orthotopic lung cancer tumors, respectively, yielding very good results in both models.…”

Section: Introductionmentioning

confidence: 98%

Improving Photodynamic Therapy Anticancer Activity of a Mitochondria-Targeted Coumarin Photosensitizer Using a Polyurethane–Polyurea Hybrid Nanocarrier

et al. 2022

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Integration of photosensitizers (PSs) within nanoscale delivery systems offers great potential for overcoming some of the “Achiles’ heels” of photodynamic therapy (PDT). Herein, we have encapsulated a mitochondria-targeted coumarin PS into amphoteric polyurethane–polyurea hybrid nanocapsules (NCs) with the aim of developing novel nanoPDT agents. The synthesis of coumarin-loaded NCs involved the nanoemulsification of a suitable prepolymer in the presence of a PS without needing external surfactants, and the resulting small nanoparticles showed improved photostability compared with the free compound. Nanoencapsulation reduced dark cytotoxicity of the coumarin PS and significantly improved in vitro photoactivity with red light toward cancer cells, which resulted in higher phototherapeutic indexes compared to free PS. Importantly, this nanoformulation impaired tumoral growth of clinically relevant three-dimensional multicellular tumor spheroids. Mitochondrial photodamage along with reactive oxygen species (ROS) photogeneration was found to trigger autophagy and apoptotic cell death of cancer cells.

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Towards Selective Delivery of a Ruthenium(II) Polypyridyl Complex‐Containing Bombesin Conjugate into Cancer Cells

et al. 2023

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An increasing number of novel Ru(II) polypyridyl complexes have been successfully applied as photosensitizers (PSs) for photodynamic therapy (PDT). Despite recent advances in optimized PSs with refined photophysical properties, the lack of tumoral selectivity is often a major hurdle for their clinical development. Here, classical maleimide and versatile NHS‐activated acrylamide strategies were employed to site‐selectively conjugate a promising Ru(II) polypyridyl complex to the N‐terminally Cys‐modified Bombesin (BBN) targeting unit. Surprisingly, the decreased cell uptake of these novel Ru‐BBN conjugates in cancer cells did not hamper the high phototoxic activity of the Ru‐containing bioconjugates and even decreased the toxicity of the constructs in the absence of light irradiation. Overall, although deceiving in terms of selectivity, our new bioconjugates could still be useful for advanced cancer treatment due to their nontoxicity in the dark.

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Polyurethane–polyurea hybrid nanocapsules as efficient delivery systems of anticancer Ir(iii) metallodrugs

Abstract: Cyclometalated Ir(III) complexes hold great promise as an alternative to platinum metallodrugs for therapy and diagnosis of cancer. However, low aqueous solubility and poor cell membrane permeability difficult in vivo...

Cited by 12 publications

References 81 publications

Potent anticancer activity of a novel iridium metallodrug via oncosis

Potent anticancer activity of a novel iridium metallodrug via oncosis

Improving Photodynamic Therapy Anticancer Activity of a Mitochondria-Targeted Coumarin Photosensitizer Using a Polyurethane–Polyurea Hybrid Nanocarrier

Towards Selective Delivery of a Ruthenium(II) Polypyridyl Complex‐Containing Bombesin Conjugate into Cancer Cells

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