Improving the Oral Bioavailability of an Anti-Glioma Prodrug CAT3 Using Novel Solid Lipid Nanoparticles Containing Oleic Acid-CAT3 Conjugates
Abstract
:1. Introduction
2. Materials and Methods
2.1. Materials
2.1.1. Cell Culture
2.1.2. Animals
2.2. Methods
2.2.1. Preparation and Spectral Analysis of OA-CAT3
2.2.2. Preparation of OA-CAT3-SLN and CAT3-SLN
2.2.3. Physicochemical Characterization of OA-CAT3-SLN and CAT3-SLN
Morphology and Particle Size
Differential Scanning Calorimetry (DSC) and Powder X-ray Diffractometry (PXRD)
Drug Loading (DL) and Encapsulation Efficiency (EE)
In Vitro Release and Releasing Mechanism
2.2.4. In Vitro and In Vivo Bio Evaluation of OA-CAT3-SLN
Transepithelial Transport Study
In vitro Cellular Uptake Study
In Vitro Cytotoxicity Analysis
In Vivo Bioavailability Studies
2.2.5. Statistical Analysis
3. Results
3.1. Characterization of OA-CAT3 by NMR, Fourier Transform Infrared Spectroscopy (FTIR), and Differential Scanning Calorimetry (DSC)
3.2. Characterizations of OA-CAT3-SLN and CAT3-SLN
3.2.1. Droplet Size, PDI, Zeta Potential, and Morphology
3.2.2. Drug Loading (DL) and Encapsulation Efficiency (EE)
3.2.3. In Vitro Controlled Release Study
3.2.4. Differential Scanning Calorimetry (DSC) and Powder X-ray Diffractometry (PXRD) Studies
3.3. In Vitro and In Vivo Bio Evaluation of OA-CAT3-SLN
3.3.1. Transepithelial Transport Study
3.3.2. In Vitro Cellular Uptake Study
3.3.3. In Vitro Cytotoxicity Analysis
3.3.4. In Vivo Pharmacokinetic Studies
4. Discussion
5. Conclusions
Author Contributions
Funding
Conflicts of Interest
Abbreviations
CAT3 | 13a-(S)-3-pivaloyloxyl-6,7-dimethoxyphenanthro(9,10-b)-indolizidine |
PF403 | 13a-(S)-3-hydroxyl-6,7-dimethoxyphenanthro(9,10-b)-indolizidine |
GBM | Glioblastoma multiforme |
TMZ | Temozolomide |
SLN | Solid lipid nanoparticles |
MDCK-MDR1 | Madin-Darby canine kidney cells transfected with the human MDR1 gene |
SD | Sprague-Dawley |
NMR | Nuclear magnetic resonance |
TMS | Tetramethylsilane |
DL | Drug loading |
EE | Encapsulation efficiency |
OA | Oleic acid |
OA-CAT3 | Oleic acid and CAT3 conjugate |
OA-CAT3-SLN | OA-CAT3 loaded SLN |
CAT3-SLN | With the same composition and contents to the OA-CAT3-SLN except the preparation of OA-CAT3 in advance |
DSC | Differential scanning calorimetry |
FTIR | Fourier transform infrared spectroscopy |
API | Active pharmaceutical ingredient |
PVDF | Polyvinylidene fluoride |
TEER | Transepithelial electrical resistance |
DI | Deionized |
PDI | Polydispersity index |
HBSS | Hanks’ balanced salt solution |
AP | Apical side |
BL | Basolateral |
LC-MS/MS | Liquid chromatography-mass spectrometry |
Papp | Apparent permeability coefficient |
HPLC | High-performance liquid chromatography |
C6-luc | Luciferase-expressing C6 cells |
DAPI | 4′,6-diamidino-2-phenylindole |
LSCM | laser scanning confocal microscopy |
MTT | 3-(4, 5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide |
MCYP | Methyl-β-Cyclodextrin |
PBS | Phosphate-buffered saline |
Cou-6 | Fluorescent Coumarin 6 |
ISTD | Internal standard |
DAS | Drug and Statistics |
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Formulation | Particle Size (nm) | PDI | Zeta Potential (mV) | DL (%) | EE (%) |
---|---|---|---|---|---|
Blank SLN | 139.2 ± 2.47 | 0.257 ± 0.003 | −41.7 ± 0.80 ** | / | / |
OA-CAT3-SLN | 151.3 ± 17.51 | 0.230 ± 0.018 | −26.7 ± 0.46 | 5.478 ± 0.346 | 80.65 ± 6.79 |
CAT3-SLN | 155.7 ± 3.03 | 0.228 ± 0.007 | −7.9 ± 0.15 ** | 4.067 ± 0.163 ** | 58.48 ± 3.35 ** |
Parameters | CAT3 | OA-CAT3 | CAT3-SLN | OA-CAT3-SLN | |
---|---|---|---|---|---|
AUC(0–t) | ng·mL−1·h | 6.39 ± 0.645 ** | 8.632 ± 3.843 * | 3.093 ± 0.133 | 3.284 ± 1.254 |
AUC(0–∞) | ng·mL−1·h | 7.23 ± 0.476 ** | 8.954 ± 3.716 * | 3.807 ± 0.441 | 4.356 ± 1.562 |
MRT(0–t) | H | 3.887 ± 0.805 | 5.113 ± 0.616 | 5.433 ± 0.82 | 6.158 ± 0.704 |
MRT(0–∞) | H | 8.779 ± 6.346 | 6.48 ± 2.444 | 13.954 ± 6.912 | 16.604 ± 2.597 |
t1/2z | H | 10.824 ± 6.769 | 4.754 ± 3.951 | 16.742 ± 11.915 | 16.902 ± 1.578 |
Tmax | H | 0.167 ± 0 | 0.25 ± 0.129 | 0.153 ± 0.034 | 0.125 ± 0.07 |
Vz/F | L/kg | 21,169.855 ± 12,087.293 | 8806.657 ± 8572.706 | 62,090.614 ± 42,268.807 | 61,307.763 ± 18,523.656 |
CLz/F | L/h/kg | 1388.185 ± 91.525 | 1268.605 ± 450.993 | 2653.874 ± 278.551 | 2576.094 ± 1027.274 |
Cmax | ng/mL | 6.618 ± 0.942 ** | 2.711 ± 1.201 | 4.539 ± 1.406 ** | 2.245 ± 0.951 |
Parameters | CAT3 | OA-CAT3 | CAT3-SLN | OA-CAT3-SLN | |
---|---|---|---|---|---|
AUC(0–t) | ng·mL−1·h | 18.778 ± 1.953 * | 13.713 ± 5.616 * | 21.723 ± 6.763 * | 32.045 ± 7.425 |
AUC(0–∞) | ng·mL−1·h | 24.42 ± 2.435 * | 30.861 ± 24.886 | 25.541 ± 9.898 * | 34.73 ± 6.178 |
MRT(0–t) | H | 9.775 ± 0.104 | 9.677 ± 1.252 | 6.649 ± 1.068 | 5.945 ± 0.889 |
MRT(0–∞) | H | 16.449 ± 0.87 | 56.077 ± 75.093 | 10.837 ± 4.978 | 7.742 ± 1.978 |
t1/2z | H | 10.121 ± 0.759 | 39.049 ± 53.163 | 8.94 ± 3.181 | 6.218 ± 1.528 |
Tmax | H | 8 ± 0 | 4.736 ± 3.834 | 0.264 ± 0.123 | 0.417 ± 0.129 |
Vz/F | L/kg | 6011.79 ± 535.387 | 15,412.451 ± 13,804.038 | 5298.387 ± 1424.022 | 2807.484 ± 748.904 |
CLz/F | L/h/kg | 412.919 ± 41.283 | 442.039 ± 193.353 | 439.687 ± 152.452 | 333.068 ± 131.27 |
Cmax | ng/mL | 1.429 ± 0.171 ** | 1.431 ± 0.315 ** | 7.884 ± 1.621 | 7.36 ± 1.694 |
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Wang, H.; Li, L.; Ye, J.; Wang, R.; Wang, R.; Hu, J.; Wang, Y.; Dong, W.; Xia, X.; Yang, Y.; et al. Improving the Oral Bioavailability of an Anti-Glioma Prodrug CAT3 Using Novel Solid Lipid Nanoparticles Containing Oleic Acid-CAT3 Conjugates. Pharmaceutics 2020, 12, 126. https://doi.org/10.3390/pharmaceutics12020126
Wang H, Li L, Ye J, Wang R, Wang R, Hu J, Wang Y, Dong W, Xia X, Yang Y, et al. Improving the Oral Bioavailability of an Anti-Glioma Prodrug CAT3 Using Novel Solid Lipid Nanoparticles Containing Oleic Acid-CAT3 Conjugates. Pharmaceutics. 2020; 12(2):126. https://doi.org/10.3390/pharmaceutics12020126
Chicago/Turabian StyleWang, Hongliang, Lin Li, Jun Ye, Rubing Wang, Renyun Wang, Jinping Hu, Yanan Wang, Wujun Dong, Xuejun Xia, Yanfang Yang, and et al. 2020. "Improving the Oral Bioavailability of an Anti-Glioma Prodrug CAT3 Using Novel Solid Lipid Nanoparticles Containing Oleic Acid-CAT3 Conjugates" Pharmaceutics 12, no. 2: 126. https://doi.org/10.3390/pharmaceutics12020126
APA StyleWang, H., Li, L., Ye, J., Wang, R., Wang, R., Hu, J., Wang, Y., Dong, W., Xia, X., Yang, Y., Gao, Y., Gao, L., & Liu, Y. (2020). Improving the Oral Bioavailability of an Anti-Glioma Prodrug CAT3 Using Novel Solid Lipid Nanoparticles Containing Oleic Acid-CAT3 Conjugates. Pharmaceutics, 12(2), 126. https://doi.org/10.3390/pharmaceutics12020126