期刊
AAPS PHARMSCITECH
卷 21, 期 8, 页码 -出版社
SPRINGER
DOI: 10.1208/s12249-020-01855-1
关键词
paclitaxel; solid SEDDS; breast cancer; Akt; mTOR pathway; apoptosis
资金
- Department of Biotechnology, Government of India [BT/PR14769/NNT/28/996/2015]
A solid self-emulsifying drug delivery system (SEDDS) of paclitaxel (PTX) was developed that could enhance its oral bioavailability and neutralize other niggles associated with conventional delivery systems of PTX. TPGS-centered SEDDS containing PTX was optimized by Box-Behnken experimental design and then formulated as fumed colloidal silica-based solid SEDDS microparticles (Si-PTX-S-SEDDS). AFM analysis exhibited round-shaped microparticles of approximately 2-3 mu M diameter, whereas after reconstitution, particle size measurement showed nanoemulsion droplets of 30.00 +/- 2.00 nm with a zeta potential of 17.38 +/- 2.88 mV. Si-PTX-S-SEDDS displayed improved efficacy proven by reduced IC50 of 0.19 +/- 0.03 mu M against MDA-MB-231 cells and a 45.83-fold higher cellular uptake in comparison to free PTX. Molecular mechanistic studies showed mitochondria-mediated intrinsic pathway of apoptosis following Akt/mTOR pathway, which is accompanied by survivin downregulation. Rhodamine 123 assay and chylomicron flow blocking studies revealed P-gp inhibition potential and lymphatic uptake of Si-PTX-S-SEDDS, responsible for over 4-fold increment in oral bioavailability compared to PTX administered as Taxol. In vivo anti-tumor studies in syngeneic mammary tumor model in SD rats revealed higher efficacy of Si-PTX-S-SEDDS as evident from significant reduction in tumor burden. In total, the developed Si-PTX-S-SEDDS formulation was found as an appropriate option for oral delivery of PTX.
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