Paclitaxel-Loaded Colloidal Silica and TPGS-Based Solid Self-Emulsifying System Interferes Akt/mTOR Pathway in MDA-MB-231 and Demonstrates Anti-tumor Effect in Syngeneic Mammary Tumors

• Published in: AAPS PharmSciTech Vol. 21; no. 8; p. 313
• Main Authors: Meher, Jaya Gopal, Dixit, Shivani, Singh, Yuvraj, Pawar, Vivek K., Konwar, Rituraj, Saklani, Ravi, Chourasia, Manish K.
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 09.11.2020
• Subjects: Animals; Antineoplastic Agents, Phytogenic - administration & dosage; Antineoplastic Agents, Phytogenic - chemistry; Apoptosis - drug effects; Biochemistry; Biological Availability; Biomedical and Life Sciences; Biomedicine; Biotechnology; Cell Line, Tumor; Colloids - chemistry; Drug Delivery Systems; Emulsions - pharmacology; Humans; Mammary Neoplasms, Animal - drug therapy; Paclitaxel - administration & dosage; Paclitaxel - chemistry; Pharmacology/Toxicology; Pharmacy; Proto-Oncogene Proteins c-akt - metabolism; Rats; Rats, Sprague-Dawley; Research Article; Research Design; Silicon Dioxide - chemistry; TOR Serine-Threonine Kinases - metabolism; Vitamin E - chemistry; Akt/mTOR pathway; paclitaxel; breast cancer; apoptosis; solid SEDDS
• ISSN: 1530-9932; 1530-9932
• DOI: 10.1208/s12249-020-01855-1

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 μM 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 IC 50 of 0.19 ± 0.03 μM 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.