Anticancer Ruthenium(III) Complexes and Ru(III)-Containing Nanoformulations: An Update on the Mechanism of Action and Biological Activity
Abstract
:1. Introduction
1.1. From Platinum(II) to Ruthenium(III)-based Complexes: The Importance of Nanoformulations in Metallo Drug Delivery
1.2. Anticancer Activity and Mechanism of Action of the Lead Low Molecular Weight Ru(III)-Based Compounds
1.3. Nucleolipid and Aminoacyl Lipid-based Structures Incorporating AziRu, a NAMI-A-Like Ruthenium Compound
2. Ru(III)-Containing Formulations as Efficient Drug Delivery Systems
2.1. KP1019-Hosting Nanosystems
2.2. NAMI-A-Hosting Nanosystems
2.3. AziRu-Hosting Nanosystems
2.4. Mononuclear and Dinuclear Ru(III)-Dithiocarbamato Complexes Encapsulated in Nanosized Carriers
2.5. Liposome-Based Systems Containing Nucleolipid or Aminoacyl Lipid-Based Ru(III) Complexes
3. Antiproliferative Effects of Liposome-Based Systems Containing Nucleolipid or Aminoacyl Lipid-Based Ru(III) Complexes: Insight into Their Mode of Action
3.1. In Vitro Bioactivity
3.2. Cellular Uptake Studies on Ru(III)-Containing Liposomes by Fluorescence Microscopy
3.3. Sub-Cellular Accumulation of the Ru(III) Complexes
3.4. Cell Morphological Changes Induced by in Vitro Treatment with Ru(III)-Containing Liposomes
3.5. Insight into the Ru(III)-Containing Liposomes Mode of Action: Identification of Molecular Cell Death Pathways
3.5.1. Pro-Apoptotic Effects in Breast Cancer Cells Evaluated by FACS Analysis
3.5.2. DNA Fragmentation Assay
3.5.3. Apoptotic-Related Protein Expression in Breast Cancer Cells
3.5.4. Autophagy Activation in Breast Cancer Cells
3.5.5. Autophagy-Related Proteins Expression in Breast Cancer Cells
3.6. In Vivo Anticancer Efficacy of Ru(III)-Containing Liposomes in Mice BCC Xenografts
4. Improved Ru(III)-Containing Nanosystems: Introduction of Targeting and/or Diagnostic Agents for Theranostic Applications
4.1. Niosome-Based Systems Containing Nucleolipid-Based Ru(III) Complexes
4.2. Nanoparticle-Based Systems Containing Nucleolipid-Based Ru(III) Complexes
5. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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IC50 (μM) | ||||||
---|---|---|---|---|---|---|
MCF-7 | WiDr | C6 | HeLa | L6 | HaCaT | |
NAMI-A [78] | 620 ± 30 | - | - | 626 ± 45 | - | - |
AziRu [77,79] | 305 ± 16 [77] | 441 ± 20 [77] | 318 ± 12 [77] | 382 ± 19 [79] | > 500 [79] | > 500 [79] |
POPC-based formulations | ||||||
ToThyRu/POPC [77,134] | 27.8 ± 0.1 [134] | 75 ± 4 [77] | 36 ± 8 [77] | - | - | - |
HoThyRu/POPC [77] | 7 ± 4 | 40 ± 5 | 81 ± 7 | - | - | - |
DoHuRu/POPC [77,134] | 18.9 ± 0.1 [134] | 99 ± 5 [77] | 24 ± 5 [77] | - | - | - |
ToThyCholRu/POPC [79,105] | 70 ± 12 [105] | 165 ± 10 [105] | - | - | >500 [79] | >500 [79] |
HoUrRu/POPC [107] | 14 ± 7 | 20 ± 8 | - | - | - | - |
DOTAP-based formulations | ||||||
ToThyRu/DOTAP [106,134] | 10.1 ± 0.1 [134] | 50 ± 11 [106] | 54 ± 8 [106] | - | - | - |
HoThyRu/DOTAP [100,106] | 13 ± 4 [100] | 65 ± 8 [106] | 43 ± 11 [106] | - | - | - |
DoHuRu/DOTAP [106,134] | 10.3 ± 0.2 [134] | 41 ± 10 [106] | 34 ± 9 [106] | - | - | - |
ToThyCholRu/DOTAP [79] | 13 ± 2 | 23 ± 8 | - | 34 ± 4 | 187 ± 1 | 377 ± 3 |
HoUrRu/DOTAP [107] | 8 ± 5 | 12 ± 5 | - | - | - | - |
I/DOTAP [110] | 31.2 ± 2.7 | - | 35.4 ± 2.7 | 45.6 ± 3 | - | >150 |
The Composite Sustainability Indicator (CSI) | Average Score① | Growth Rate② | ||||||
---|---|---|---|---|---|---|---|---|
2011 | 2012 | 2013 | 2014 | 2015 | 2016 | |||
Beijing | 0.565 | 0.59 | 0.609 | 0.605 | 0.588 | 0.634 | 0.598 | 2.44% |
Tianjin | 0.562 | 0.555 | 0.553 | 0.513 | 0.522 | 0.515 | 0.537 | −1.66% |
Hebei | 0.403 | 0.401 | 0.414 | 0.426 | 0.467 | 0.503 | 0.436 | 4.93% |
Shanxi | 0.407 | 0.419 | 0.442 | 0.434 | 0.437 | 0.482 | 0.437 | 3.70% |
Inner Mongolia | 0.522 | 0.523 | 0.532 | 0.556 | 0.558 | 0.598 | 0.548 | 2.89% |
Liaoning | 0.474 | 0.486 | 0.515 | 0.509 | 0.509 | 0.453 | 0.491 | −0.91% |
Jilin | 0.406 | 0.442 | 0.455 | 0.466 | 0.467 | 0.517 | 0.459 | 5.46% |
Heilongjiang | 0.393 | 0.397 | 0.432 | 0.431 | 0.432 | 0.46 | 0.424 | 3.42% |
Shanghai | 0.45 | 0.455 | 0.449 | 0.477 | 0.496 | 0.556 | 0.48 | 4.69% |
Jiangsu | 0.53 | 0.517 | 0.555 | 0.547 | 0.566 | 0.586 | 0.55 | 2.11% |
Zhejiang | 0.534 | 0.545 | 0.576 | 0.588 | 0.594 | 0.613 | 0.575 | 2.96% |
Anhui | 0.412 | 0.43 | 0.503 | 0.483 | 0.51 | 0.582 | 0.486 | 8.25% |
Fujian | 0.487 | 0.525 | 0.537 | 0.547 | 0.574 | 0.586 | 0.543 | 4.03% |
Jiangxi | 0.403 | 0.42 | 0.45 | 0.423 | 0.45 | 0.507 | 0.442 | 5.20% |
Shandong | 0.537 | 0.537 | 0.572 | 0.574 | 0.561 | 0.588 | 0.561 | 1.90% |
Henan | 0.33 | 0.337 | 0.351 | 0.382 | 0.402 | 0.484 | 0.381 | 9.30% |
Hubei | 0.421 | 0.446 | 0.458 | 0.501 | 0.518 | 0.574 | 0.486 | 7.27% |
Hunan | 0.398 | 0.431 | 0.433 | 0.464 | 0.508 | 0.551 | 0.464 | 7.70% |
Guangdong | 0.474 | 0.451 | 0.482 | 0.471 | 0.514 | 0.534 | 0.488 | 2.54% |
Guangxi | 0.415 | 0.431 | 0.436 | 0.443 | 0.477 | 0.522 | 0.454 | 5.18% |
Hainan | 0.547 | 0.596 | 0.595 | 0.585 | 0.569 | 0.598 | 0.582 | 1.87% |
Chongqing | 0.496 | 0.531 | 0.541 | 0.571 | 0.572 | 0.604 | 0.553 | 4.36% |
Sichuan | 0.388 | 0.401 | 0.407 | 0.417 | 0.46 | 0.512 | 0.431 | 6.41% |
Guizhou | 0.393 | 0.427 | 0.422 | 0.452 | 0.473 | 0.518 | 0.448 | 6.35% |
Yunnan | 0.427 | 0.432 | 0.446 | 0.457 | 0.449 | 0.504 | 0.452 | 3.58% |
Tibet | 0.534 | 0.55 | 0.56 | 0.582 | 0.582 | 0.558 | 0.561 | 0.92% |
Shaanxi | 0.483 | 0.521 | 0.532 | 0.526 | 0.545 | 0.568 | 0.529 | 3.53% |
Gansu | 0.421 | 0.429 | 0.442 | 0.442 | 0.43 | 0.474 | 0.44 | 2.49% |
Qinghai | 0.476 | 0.485 | 0.49 | 0.504 | 0.502 | 0.549 | 0.501 | 3.06% |
Ningxia | 0.457 | 0.481 | 0.501 | 0.512 | 0.503 | 0.551 | 0.501 | 4.15% |
Xinjiang | 0.5 | 0.494 | 0.498 | 0.515 | 0.546 | 0.567 | 0.52 | 2.68% |
East China③ | 0.509 | 0.517 | 0.534 | 0.533 | 0.545 | 0.571 | 0.535 | 2.45% |
Middle China | 0.395 | 0.414 | 0.439 | 0.448 | 0.471 | 0.53 | 0.449 | 6.83% |
West China | 0.459 | 0.475 | 0.484 | 0.498 | 0.508 | 0.544 | 0.495 | 3.68% |
Northeastern China | 0.424 | 0.442 | 0.467 | 0.469 | 0.469 | 0.477 | 0.458 | 2.46% |
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Riccardi, C.; Musumeci, D.; Trifuoggi, M.; Irace, C.; Paduano, L.; Montesarchio, D. Anticancer Ruthenium(III) Complexes and Ru(III)-Containing Nanoformulations: An Update on the Mechanism of Action and Biological Activity. Pharmaceuticals 2019, 12, 146. https://doi.org/10.3390/ph12040146
Riccardi C, Musumeci D, Trifuoggi M, Irace C, Paduano L, Montesarchio D. Anticancer Ruthenium(III) Complexes and Ru(III)-Containing Nanoformulations: An Update on the Mechanism of Action and Biological Activity. Pharmaceuticals. 2019; 12(4):146. https://doi.org/10.3390/ph12040146
Chicago/Turabian StyleRiccardi, Claudia, Domenica Musumeci, Marco Trifuoggi, Carlo Irace, Luigi Paduano, and Daniela Montesarchio. 2019. "Anticancer Ruthenium(III) Complexes and Ru(III)-Containing Nanoformulations: An Update on the Mechanism of Action and Biological Activity" Pharmaceuticals 12, no. 4: 146. https://doi.org/10.3390/ph12040146