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Article

Improving the Oral Bioavailability of an Anti-Glioma Prodrug CAT3 Using Novel Solid Lipid Nanoparticles Containing Oleic Acid-CAT3 Conjugates

1
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
2
Beijing Key Laboratory of Drug Delivery Technology and Novel Formulation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
*
Author to whom correspondence should be addressed.
Pharmaceutics 2020, 12(2), 126; https://doi.org/10.3390/pharmaceutics12020126
Received: 12 January 2020 / Revised: 30 January 2020 / Accepted: 1 February 2020 / Published: 3 February 2020
13a-(S)-3-pivaloyloxyl-6,7-dimethoxyphenanthro(9,10-b)-indolizidine (CAT3) is a novel oral anti-glioma pro-drug with a potent anti-tumor effect against temozolomide-resistant glioma in vivo. However, poor lipid solubility has limited the encapsulation efficacy during formulation development. Moreover, although the active metabolite of CAT3, 13a(S)-3-hydroxyl-6,7-dimethoxyphenanthro(9,10-b)-indolizidine (PF403), can penetrate the blood-brain barrier and approach the brain tissue with a 1000-fold higher anti-glioma activity than CAT3 in vitro, its bioavailability and Cmax were considerably low in plasma, limiting the anti-tumor efficacy. In this study, a novel oleic acid-CAT3 conjugate (OA-CAT3) was synthesized at the first time to increase the lipid solubility of CAT3. The OA-CAT3 loaded solid lipid nanoparticles (OA-CAT3-SLN) were constructed using an ultrasonic technique to enhance the bioavailability and Cmax of PF403 in plasma. Our results demonstrated that CAT3 was amorphous in the lipid core of OA-CAT3-SLN and the in vitro release was well controlled. Furthermore, the encapsulation efficacy and the zeta potential increased to 80.65 ± 6.79% and −26.7 ± 0.46 mV, respectively, compared to the normal CAT3 loaded SLN. As indicated by the high-performance liquid chromatography-mass spectrometry (HPLC-MS/MS) quantitation, the monolayer cellular transepithelial transport rate of OA-CAT3-SLN improved by 2.42-fold relied on cholesterol compared to the CAT3 suspension. Hence, the in vitro cell viability of OA-CAT3-SLN in C6 glioma cells decreased to 29.77% ± 2.13% and 10.75% ± 3.12% at 48 and 72 h, respectively. Finally, compared to the CAT3 suspension, the in vivo pharmacokinetics in rats indicated that the plasma bioavailability and Cmax of PF403 as afforded by OA-CAT3-SLN increased by 1.7- and 5.5-fold, respectively. Overall, the results indicate that OA-CAT3-SLN could be an efficacious delivery system in the treatment of glioma. View Full-Text
Keywords: phenanthroindolizidine; prodrug; oleic acid; conjugate; solid lipid nanoparticles; bioavailability phenanthroindolizidine; prodrug; oleic acid; conjugate; solid lipid nanoparticles; bioavailability
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MDPI and ACS Style

Wang, 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. 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

AMA Style

Wang 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. 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 Style

Wang, Hongliang, Lin Li, Jun Ye, Rubing Wang, Renyun Wang, Jinping Hu, Yanan Wang, Wujun Dong, Xuejun Xia, Yanfang Yang, Yue Gao, Lili Gao, and Yuling Liu. 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

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