Biodistribution and Biosafety of a Poly(Phosphorhydrazone) Dendrimer, an Anti-Inflammatory Drug-Candidate
Abstract
:1. Introduction
2. Materials and Methods
2.1. Dendrimers
Zeta Potential of the Dendrimers
2.2. Biodistribution
2.2.1. Biodistribution Using the ABP-Julolidine Dendrimer
2.2.2. Biodistribution Using the ABP-NIR Dendrimer
2.3. Hematological Safety
2.4. Genotoxicity
2.4.1. BN Ames’ Test
2.4.2. In Vitro Micronucleus Test
2.5. Maximal Tolerated Dose (MTD)
2.5.1. Single Injection in Mice and Rats
2.5.2. Repeated Injections in Rats
2.6. In Vitro Cardiac Safety
2.7. Statistical Analyses
2.7.1. Biodistribution Using the ABP-NIR Dendrimer
2.7.2. Hematological Safety
2.7.3. Genotoxicity
3. Results
3.1. Biodistribution
3.2. Hematological Safety
3.3. Genotoxicity
3.3.1. BN Ames’ Test
- for the strain TA 1537, a compound that induces a dose-dependent increase in the number of reverse mutations along at least three consecutive doses, with the greatest increase being greater than or equal to three times that of the untreated control (which gives the number of spontaneous reverse mutations) is considered positive to the test;
- for the strains TA 100 and TA 98, a compound that induces a dose-dependent increase in the number of reverse mutations along at least three consecutive doses, with the greatest increase being greater than or equal to twice that of the untreated control (which gives the number of spontaneous reverse mutations) is considered positive to the test.
3.3.2. In Vitro Micronucleus Test
3.4. Maximal Tolerated Dose (MTD)
3.4.1. Single Injection in Mice and Rats
3.4.2. Repeated Injections in Rat
3.5. In Vitro Cardiac Safety
4. Discussion
5. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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TA 1537 | TA 100 | TA 98 | |||||
---|---|---|---|---|---|---|---|
Dose (µg/Dish) | Mutants/Dish | Ratio | Mutants/Dish | Ratio | Mutants/Dish | Ratio | |
without metabolic activation | untreated | 6.5 | 111.5 | 24 | |||
control + 1 | 681.7 | 105 ** | 2380.3 | 21.3 | 636.3 | 26.5 ** | |
0.39 | 7 | 1.1 | 110.3 | 1 | 21.3 | 0.9 | |
0.78 | 9.7 | 1.5 | 128.7 | 1.2 | 26 | 1.1 | |
1.56 | 7 | 1.1 | 133 | 1.2 | 26.7 | 1.1 | |
3.13 | 7 | 1.1 | 132.3 | 1.2 | 32 | 1.3 | |
6.25 | 6.7 | 1 | 119.3 | 1.1 | 27.7 | 1.2 | |
12.5 | 9 | 1.4 | 126 | 1.1 | 28 | 1.2 | |
25 | 9.3 | 1.4 | 124.3 | 1.1 | 29.3 | 1.2 | |
50 | 7.7 | 1.2 | 115.7 | 1 | 33 | 1.4 | |
100 | 7 | 1.1 | 114.3 | 1 | 27.7 | 1.2 | |
200 | 11.3 | 1.7 | 123.3 | 1.1 | 37.3 | 1.6 ** | |
with metabolic activation (S9 mix) | untreated | 7.8 | 106.3 | 28.4 | |||
control + 2 | 177.3 | 22.7 ** | 1498.3 | 14.1 ** | 1686.7 | 59.4 ** | |
0.39 | 7.7 | 1 | 125.7 | 1.2 | 28.7 | 1 | |
0.78 | 7 | 0.9 | 105.3 | 1 | 35.3 | 1.2 | |
1.56 | 7.7 | 1 | 118.3 | 1.1 | 32.3 | 1.1 | |
3.13 | 7 | 0.9 | 113.3 | 1.1 | 33 | 1.2 | |
6.25 | 7.7 | 1 | 138.3 | 1.3 ** | 30.3 | 1.1 | |
12.5 | 5.3 | 0.7 | 123.3 | 1.2 | 31.3 | 1.1 | |
25 | 8 | 1 | 111.3 | 1 | 35.7 | 1.3 | |
50 | 5.3 | 0.7 | 113.7 | 1.1 | 38 | 1.3 | |
100 | 6.7 | 0.9 | 115.7 | 1.1 | 33 | 1.2 | |
200 | 4.3 | 0.6 | 127.7 | 1.2 | 26.7 | 0.9 |
Dose (µM) | Relative % of Survival | Total Number of Micronuclei for 2000 Mononuclear Cells | Relative % of Survival | Total Number of Micronuclei for 2000 Mononuclear Cells | |
---|---|---|---|---|---|
without recovery | with recovery | ||||
without metabolic activation | untreated | 100 | 3 | 100 | 3 |
control + 1 | 88.9 | 40 *** | 90.8 | 75 *** | |
430 | 31.1 | nd 2 | 51.2 | 17 ** | |
215 | 79.2 | 9 * | 99.9 | 12 * | |
107 | 69.8 | 4 | 96.2 | 4 | |
53.7 | 80.3 | 3 | 111 | nd 2 | |
with metabolic activation (S9 mix) | untreated | 100 | 3 | ||
control + 3 | 85.1 | 239 *** | |||
773 | 127 | 4 | |||
387 | 145 | 2 | |||
193 | 119 | 3 |
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Fruchon, S.; Bellard, E.; Beton, N.; Goursat, C.; Oukhrib, A.; Caminade, A.-M.; Blanzat, M.; Turrin, C.-O.; Golzio, M.; Poupot, R. Biodistribution and Biosafety of a Poly(Phosphorhydrazone) Dendrimer, an Anti-Inflammatory Drug-Candidate. Biomolecules 2019, 9, 475. https://doi.org/10.3390/biom9090475
Fruchon S, Bellard E, Beton N, Goursat C, Oukhrib A, Caminade A-M, Blanzat M, Turrin C-O, Golzio M, Poupot R. Biodistribution and Biosafety of a Poly(Phosphorhydrazone) Dendrimer, an Anti-Inflammatory Drug-Candidate. Biomolecules. 2019; 9(9):475. https://doi.org/10.3390/biom9090475
Chicago/Turabian StyleFruchon, Séverine, Elisabeth Bellard, Nicolas Beton, Cécile Goursat, Abdelouahd Oukhrib, Anne-Marie Caminade, Muriel Blanzat, Cédric-Olivier Turrin, Muriel Golzio, and Rémy Poupot. 2019. "Biodistribution and Biosafety of a Poly(Phosphorhydrazone) Dendrimer, an Anti-Inflammatory Drug-Candidate" Biomolecules 9, no. 9: 475. https://doi.org/10.3390/biom9090475