Enhanced oral bioavailability and antitumor therapeutic efficacy of sorafenib administered in core-shell protein nanoparticle.

Autor: Gopakumar L; Centre for Nanosciences and Molecular Medicine, Amrita University, Ponekkara PO, Edappally, Kochi, 41, Kerala, India., Sreeranganathan M; Centre for Nanosciences and Molecular Medicine, Amrita University, Ponekkara PO, Edappally, Kochi, 41, Kerala, India., Chappan S; Centre for Nanosciences and Molecular Medicine, Amrita University, Ponekkara PO, Edappally, Kochi, 41, Kerala, India., James S; Centre for Nanosciences and Molecular Medicine, Amrita University, Ponekkara PO, Edappally, Kochi, 41, Kerala, India., Gowd GS; Centre for Nanosciences and Molecular Medicine, Amrita University, Ponekkara PO, Edappally, Kochi, 41, Kerala, India., Manohar M; Centre for Nanosciences and Molecular Medicine, Amrita University, Ponekkara PO, Edappally, Kochi, 41, Kerala, India., Sukumaran A; Centre for Nanosciences and Molecular Medicine, Amrita University, Ponekkara PO, Edappally, Kochi, 41, Kerala, India., Unni AKK; Central Lab Animal Facility, Amrita Institute of Medical Sciences and Research Centre, Amrita University, Ponekkara PO, Edappally, Kochi, 41, Kerala, India., Nair SV; Centre for Nanosciences and Molecular Medicine, Amrita University, Ponekkara PO, Edappally, Kochi, 41, Kerala, India., Koyakutty M; Centre for Nanosciences and Molecular Medicine, Amrita University, Ponekkara PO, Edappally, Kochi, 41, Kerala, India. manzoork@aims.amrita.edu.
Jazyk: angličtina
Zdroj: Drug delivery and translational research [Drug Deliv Transl Res] 2022 Nov; Vol. 12 (11), pp. 2824-2837. Date of Electronic Publication: 2022 Jun 09.
DOI: 10.1007/s13346-022-01142-5
Abstrakt: Orally delivered molecularly targeted small-molecule drugs play a significant role in managing cancer as a chronic disease. However, due to the poor oral bioavailability of some of these molecules, high-dose administration is required leading to dose-limiting toxicity especially when delivered daily for a long duration. Here, we report an oral nanoformulation for small-molecule multi-kinase inhibitor, sorafenib tosylate, showing nearly two fold enhancement in the oral bioavailability and enhanced therapeutic efficacy with a better safety profile compared to the current clinical formulation. Using a scalable process involving high-pressure homogenization, sorafenib was loaded into an albumin nanocarrier at ~ 50 w/w%. Repeated preparation of gram-scale batches (n = 7) showed an average particle size of 180 ± 9 nm, encapsulation efficiency of 95 [Formula: see text] 2%, and drug-loading efficiency of 48 [Formula: see text] 0.7%. Further, surface engineering with a mucoadhesive layer on nanoparticles (referred to as ABSORF) resulted in the final size of 299 ± 38 nm and surface charge of -54 ± 8 mV. Single-dose and multidose pharmacokinetic studies showed two fold enhancement in the plasma concentration of sorafenib compared to current clinically used tablets. Antitumor efficacy studies in the orthotopic rat liver tumor model showed significant tumor regression (p value = 0.0037) even at half dose (eqv. to 200 mg of human equivalent dose) of ABSORF compared to clinical control (eqv. to 400 mg). The biodistribution of sorafenib from ABSORF was higher in the liver; however, liver and kidney function test parameters were comparable with that of the 2 × dose of clinical control. No abnormalities and signs of toxicity were seen in the histopathological analysis for ABSORF-treated animals. In summary, we demonstrate a scalable preparation of small-molecule drug-loaded nanoformulation with approximately two fold enhancement in oral bioavailability, improved antitumor efficacy, and acceptable toxicity profile.
(© 2022. Controlled Release Society.)
Databáze: MEDLINE
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