In Vivo Evaluation of DMSA-Coated Magnetic Nanoparticle Toxicity and Biodistribution in Rats: A Long-Term Follow-Up
Abstract
:1. Introduction
2. Materials and Methods
2.1. Sample Preparation and Characterization
2.2. Experimental Design
2.3. Blood Sampling and Analysis
2.4. Ultrasound Analysis
2.5. Detection of Reactive Oxygen Species (ROS) and Nitrosyl Hemoglobin (HbNO) in Blood and ROS in Tissue Samples by Electron Paramagnetic Resonance (EPR)
2.6. DMSA-MNP Detection and Quantification in Organs by Ferromagnetic Resonance (FMR)
2.7. Organ Micro-Computed Tomography (Micro-CT) and Histological Analysis
2.8. Statistical Analyses
3. Results
3.1. DMSA-MNP Characterization
3.2. Clinical, Hematological, and Biochemical Analysis
3.3. Ultrasonography Analysis
3.4. HbNO and ROS Detection in Blood and Different Tissues
3.5. DMSA-MNP Detection in the Organs
3.6. Micro-CT Analysis
3.7. Histopathology
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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RBC (106/µL) | HB (g/dL) | HTC (%) | WBC (103/µL) | LP (%) | MP (%) | ||
---|---|---|---|---|---|---|---|
D0 * | 6.1–10.8 | 12.4–23.5 | 33.1–60.1 | 3.9–12.0 | 60.4–82.5 | 17.5–39.6 | |
Day after injection | Group | ||||||
D15 | Control | 10.8 ± 1.5 (10.2–11.8) | 22.2 ± 3.3 (20.8–24.7) | 60.2 ± 8.8 (43.6–66.5) | 8.9 ± 2.1 (6.2–12.2) | 70.1 ± 3.9 (64.4–74.9) | 29.9 ± 3.9 (25.1–33.1) |
T0.5 | 8.2 ± 1.8 (5.9–10.3) | 17.5 ± 3.7 (12.4–22.3) | 46.8 ± 9.7 (33.9–59.5) | 8.9 ± 2.0 (6.1–11.7) | 72.5 ± 6.1 (65.1–79.5) | 27.5 ± 6.1 (23.8–34.9) | |
T5 | 8.5 ± 1.2 (6.7–9.3) | 18.3 ± 2.5 (14.2–20.4) | 48.3 ± 6.2 (38.4–53.1) | 7.9 ± 0.8 (6.8–8.7) | 65.0 ± 8.2 (53.2–71.2) | 34.9 ± 8.2 (28.5–46.8) | |
D30 | Control | 7.8 ± 0.3 (7.3–8.1) | 15.7 ± 0.7 (14.6–16.7) | 44.1 ± 1.7 (41.9–45.8) | 10.7 ± 1.6 (8.2–12.7) | 74.1 ± 3.8 (68.5–79.7) | 25.9 ± 3.8 (20.3–27.8) |
T0.5 | 8.3 ± 0.4 (7.8–8.7) | 17.2 ± 1.1 (16.9–18.1) | 46.9 ± 2.4 (43.3–49.0) | 10.3 ± 2.2 (8.1–13.5) | 73.7 ± 3.7 (67.5–76.7) | 26.3 ± 3.7 (23.3–32.5) | |
T5 | 8.9 ± 1.2 (7.5–10.6) | 18.5 ± 2.3 (15.9–21.5 | 50.6 ± 6.0 (44.4–58.8) | 10.5 ±4.4 (5.2–15.5) | 71.5 ± 11.8 (59.1–90.8) | 28.5 ± 11.8 (9.2–40.9) | |
D60 | Control | 8.1 ± 0.2 (7.75–8.3) | 16.0 ± 0.5 (15.5–16.6) | 43.9 ± 0.8 (43.0–44.8) | 8.9 ± 1.3 (7.7–10.7) | 76.0 ± 2.1 (73.0–78.6) | 24.0 ± 2.1 (21.4–27.0) |
T0.5 | 8.5 ± 0.7 (8.1–9.4) | 17.4 ± 1.5 (16.0–18.4) | 46.7 ± 3.7 (43.4–49.3) | 9.3 ± 1.8 (6.8–11.1) | 72.7 ± 2.4 (69.1–74.7) | 27.3 ± 2.4 (24.9–28.2) | |
T5 | 8.2 ± 0.3 (7.9–8.5) | 16.6 ± 0.3 (16.2–16.9) | 45.8 ± 1.0 (44.5–46.1) | 6.3 ± 2.0 (4.7–9.0) | 68.1 ± 6.0 (59.8–76.5) | 31.9 ± 6.0 (23.5–40.2) | |
D120 | Control | 7.8 ± 0.2 (7.4–8.0) | 15.4 ± 0.5 (14.7–16.0) | 40.8 ± 1.8 (38.4–43.0) | 5.7 ± 0.6 (4.8–6.6) | 66.5 ± 7.4 (53.8–73.2) | 33.5 ± 7.4 (26.8–46.2) |
T0.5 | 7.7 ± 0.4 (7.2–8.4) | 15.7 ± 0.8 (14.4–16.7) | 42.0 ± 1.9 (39.2–44.4) | 5.2 ± 2.1 (3.4–8.3) | 65.8 ± 4.5 (61.0–71.0) | 34.2 ± 4.5 (29.0–37.7) | |
T5 | 8.3 ± 0.7 (7.9–9.6) | 16.6 ± 1.1 (15.9–18.5) | 45.2 ± 3.3 (43.2–51.1) | 5.3 ± 1.3 (4.5–7.5) | 64.0 ± 6.8 (56.3–74.8) | 36.0 ± 6.8 (25.2–43.7) | |
D180 | Control | 8.7 ± 1.2 (8.9–9.7) | 17.0 ± 2.3 (13.0–18.6) | 45.4 ± 6.1 (34.7–50.3) | 5.1 ± 0.8 (3.6–5.5) | 68.8 ± 1.9 (66.4–71.7) | 31.2 ± 1.9 (28.3–33.6) |
T0.5 | 8.9 ± 1.3 (7.5–10.8) | 17.7 ± 2.7 (15.2–21.5) | 47.5 ± 6.8 (41.0–56.5) | 4.9 ± 0.2 (4.0–7.0) | 66.0 ± 4.6 (58.7–69.6) | 34.0 ± 4.5 (30.4–41.3) | |
T5 | 8.3 ± 0.4 (7.8–8.8) | 16.6 ± 0.7 (16.2–17.3) | 44.5 ± 2.0 (41.6–46.6) | 3.7 ± 1.2 (2.9–5.8) | 64.3 ± 5.2 (56.9–69.7) | 35.7 ± 5.2 (30.3–43.1) | |
D240 | Control | 8.5 ± 0.5 (7.7–9.2) | 17.0 ± 1.1 (15.6–18.4) | 44.9 ± 2.2 (42.7–48.5) | 5.5 ± 1.0 (4.4–6.9) | 65.2 ± 2.9 (61.3–67.9) | 34.8 ± 2.9 (32.1–38.7) |
T0.5 | 7.9 ± 0.6 (7.3–8.4) | 16.1 ± 0.9 (15.0–16.9) | 42.0 ± 3.2 (38.0–47.4) | 6.1 ± 0.2 (5.9–6.3) | 68.0 ± 8.5 (56.2–76.4) | 32.1 ± 8.5 (23.6–43.8) | |
T5 | 8.0 ± 0.6 (7.0–8.5) | 16.3 ± 1.6 (13.8–17.9) | 42.7 ± 4.0 (36.4–46.7) | 4.5 ± 1.9 (2.9–7.6) | 62.4 ± 4.9 (56.8–69.1) | 37.6 ± 4.9 (30.9–43.2) | |
D300 | Control | 9.2 ± 1.3 (7.8–10.9) | 18.0 ± 2.7 (15.3–21.8) | 49.5 ± 7.6 (41.4–60.0) | 3.2 ± 0.5 (2.4–8.6) | 61.3 ± 5.5 (53.6–67.4) | 38.7 ± 5.5 (32.6–46.4) |
T0.5 | 8.5 ± 0.7 (7.7–9.3) | 17.1 ± 1.2 (16.0–18.6) | 47.1 ± 3.9 (43.1–51.4) | 2.5 ± 1.0 (1.8–3.9) | 59.3 ± 6.3 (53.0–66.7) | 40.7 ± 6.3 (33.3–47.0) | |
T5 | 7.8 ± 0.3 (7.7–10.9) | 15.6 ± 0.8 (15.3–21.8) | 42.9 ± 2.0 (41.1–60.0) | 2.5 ± 0.2 (1.8–4.1) | 53.6 ± 0.6 (51.3–68.7) | 36.6 ± 0.7 (31.1–48.7) |
Creatinine (mg/dL) | Urea (mg/dL) | ALT (U/L) | AST (U/L) | Iron (μg/dL) | ||
---|---|---|---|---|---|---|
D0 * | 0.5–1.0 | 48–95 | 28–90 | 127–333 | 184–556 | |
Day after injection | Group | |||||
D15 | Control | 0.7 ± 0.1 (0.6–0.9) | 80.8 ± 9.8 (69–94) | 83.0 ± 24.0 (53–126) | 218.5 ± 51.0 (170–288) | 314.0 ± 26.9 (283–328) |
T0.5 | 0.7 ± 0.1 (0.6–0.7) | 76.1 ± 7.2 (66–84) | 79.6 ± 16.5 (65–112) | 147.2 ± 16.8 (124–174) | 349.3 ± 39.7 (294–396) | |
T5 | 0.7 ± 0.1 (0.6–0.8) | 76.4 ± 12.3 (63–92) | 76.6 ± 17.9 (62–107) | 142.8 ± 29.7 (109–178) | 479.3 ± 97.6 (376–570) | |
D30 | Control | 0.9 ± 0.3 (0.8–1.4) | 94.7 ± 9.1 (78–103) | 90.8 ± 18.7 (68–117) | 263.3 ± 84.9 (173–379) | 394.6 ± 43.8 (317–420) |
T0.5 | 0.7 ± 0.1 (0.5–0.8) | 66.0 ± 30.3 (15–87) | 78.8 ± 35.1 (51–125) | 238.0 ± 107.7 (136–336) | 319.5 ± 268.0 (130–509) | |
T5 | 0.8 ± 0.1 (0.7–0.9) | 102.8 ± 7.9 (93–107) | 69.8 ± 30.7 (26–91) | 305.5 ± 48.8 (271–340) | 403.0 ± 38.2 (376–430) | |
D60 | Control | 1.1 ± 0.6 (0.8–2.1) | 80.8 ± 8.0 (73–89) | 85.0 ± 50.6 (46–173) | 233.4 ± 85.0 (153–364) | 308.6 ± 73.7 (191–379) |
T0.5 | 0.8 ± 0.1 (0.8–0.9) | 80.4 ± 4.3 (75–86) | 74.0 ± 7.6 (66–84) | 146.4 ± 71.3 (51–251) | 347.0 ± 30.1 (317–396) | |
T5 | 0.8 ± 0.1 (0.8–0.9) | 79.8 ± 5.1 (74–85) | 65.3 ± 14.5 (53–86) | 206.8 ± 114.9 (137–378) | 345.5 ± 42.2 (294–386) | |
D120 | Control | 0.5 ± 0.1 (0.4–0.7) | 56.4 ± 10.9 (39–69) | 46.4 ± 25.5 (19–80) | 186.0 ± 53.3 (130–243) | 263.0 ± 109.5 (140–434) |
T0.5 | 0.4 ± 0.2 (0.1–0.6) | 52.2 ± 13.7 (36–70) | 70.8 ± 36.6 (51–136) | 201.2 ± 140.8 (106–445) | 236.4 ± 40.9 (167–273) | |
T5 | 0.5 ± 0.1 (0.5–0.6) | 71.0 ± 4.8 (65–78) | 67.2 ± 11.5 (56–85) | 197.4 ± 64.4 (119–271) | 254.6 ± 14.8 (239–270) | |
D180 | Control | 0.5 ± 0.1 (0.5–0.6) | 51.6 ± 6.5 (47–63) | 53.2 ± 23.9 (14–71) | 158.2 ± 63.5 (62–230) | 262.6 ± 44.3 (191–306) |
T0.5 | 0.7 ± 0.1 (0.6–0.8) | 57.6 ± 4.3 (53–63) | 58.6 ± 10.0 (44–69) | 164.2 ± 39.0 (128–226) | 280.4 ± 39.9 (223–333) | |
T5 | 0.6 ± 0.1 (0.5–0.7) | 53.8 ± 4.3 (49–60) | 55.6 ± 75.0 (49–66) | 176.0 ± 54.8 (116–266) | 271.4 ± 38.6 (212–310) | |
D240 | Control | 0.7 ± 0.1 (0.6–0.8) | 44.5 ± 3.1 (42–48) | 51.0 ± 28.2 (18–89) | 154.8 ± 34.3 (127–210) | 286.8 ± 51.5 (250–375) |
T0.5 | 0.8 ± 0.2 (0.5–1.0) | 52.8 ± 8.8 (39–61) | 60.2 ± 11.6 (43–71) | 213.4 ± 111.0 (122–374) | 240.2 ± 49.9 (163–295) | |
T5 | 0.8 ± 0.1 (0.7–0.9) | 47.6 ± 6.4 (44–59) | 60.4 ± 14.5 (53–80) | 129.8 ± 40.7 (101–201) | 348.6 ± 85.5 (243–465) | |
D300 | Control | 0.3 ± 0.3 (0.1–0.7) | 39.8 ± 10.1 (23–50) | 42.8 ± 22.8 (10–71) | 192.2 ± 50.3 (118–232) | 296,6 ± 131.5 (142–478) |
T0.5 | 0.5 ± 0.1 (0.4–0.6) | 42.0 ± 12.0 (28–57) | 52.5 ± 14.6 (35–65) | 201.3 ± 52.2 (133–260) | 343.5 ± 103.0 (235–474) | |
T5 | 0.5 ± 0.4 (0.1–0.9) | 49.2 ± 9.3 (43–64) | 62.2 ± 37.8 (39–129) | 185.4 ± 49.9 (126–226) | 303.8 ± 139.0 (205–542) |
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Paulini, F.; Marangon, A.R.M.; Azevedo, C.L.; Brito, J.L.M.; Lemos, M.S.; Sousa, M.H.; Veiga-Souza, F.H.; Souza, P.E.N.; Lucci, C.M.; Azevedo, R.B. In Vivo Evaluation of DMSA-Coated Magnetic Nanoparticle Toxicity and Biodistribution in Rats: A Long-Term Follow-Up. Nanomaterials 2022, 12, 3513. https://doi.org/10.3390/nano12193513
Paulini F, Marangon ARM, Azevedo CL, Brito JLM, Lemos MS, Sousa MH, Veiga-Souza FH, Souza PEN, Lucci CM, Azevedo RB. In Vivo Evaluation of DMSA-Coated Magnetic Nanoparticle Toxicity and Biodistribution in Rats: A Long-Term Follow-Up. Nanomaterials. 2022; 12(19):3513. https://doi.org/10.3390/nano12193513
Chicago/Turabian StylePaulini, Fernanda, Aline R. M. Marangon, Carolina L. Azevedo, Juliana L. M. Brito, Marcelle S. Lemos, Marcelo H. Sousa, Fabiane H. Veiga-Souza, Paulo E. N. Souza, Carolina M. Lucci, and Ricardo B. Azevedo. 2022. "In Vivo Evaluation of DMSA-Coated Magnetic Nanoparticle Toxicity and Biodistribution in Rats: A Long-Term Follow-Up" Nanomaterials 12, no. 19: 3513. https://doi.org/10.3390/nano12193513
APA StylePaulini, F., Marangon, A. R. M., Azevedo, C. L., Brito, J. L. M., Lemos, M. S., Sousa, M. H., Veiga-Souza, F. H., Souza, P. E. N., Lucci, C. M., & Azevedo, R. B. (2022). In Vivo Evaluation of DMSA-Coated Magnetic Nanoparticle Toxicity and Biodistribution in Rats: A Long-Term Follow-Up. Nanomaterials, 12(19), 3513. https://doi.org/10.3390/nano12193513