Synergistic Encapsulation of Paclitaxel and Sorafenib by Methoxy Poly(Ethylene Glycol)-b-Poly(Caprolactone) Polymeric Micelles for Ovarian Cancer Therapy
Ovarian cancer has a high mortality rate due to difficult detection at an early stage. It is necessary to develop a novel anticancer treatment that demonstrates improved efficacy while reducing toxicity. Here, using the freeze-drying method, micelles encapsulating paclitaxel (PTX) and sorafenib (SRF) with various polymers were prepared, and the optimal polymer (mPEG-b-PCL) was selected by measuring drug loading (%), encapsulation efficiency (%), particle size, polydispersity index, and zeta potential. The final formulation was selected based on a molar ratio (PTX:SRF = 1:2.3) with synergistic effects on two ovarian cancer cell lines (SKOV3-red-fluc, HeyA8). In the in vitro release assay, PTX/SRF micelles showed a slower release than PTX and SRF single micelles.
In pharmacokinetic evaluation, PTX/SRF micelles showed improved bioavailability compared to PTX/SRF solution. In in vivo toxicity assays, no significant differences were observed in body weight between the micellar formulation and the control group. The anticancer effect of PTX/SRF combination therapy was improved compared to the use of a single drug. In the xenografted BALB/c mouse model, the tumor growth inhibition rate of PTX/SRF micelles was 90.44%. Accordingly, PTX/SRF micelles showed improved anticancer effects compared to single-drug therapy in ovarian cancer (SKOV3-red-fluc).
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Materials
Soluplus (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer; PCL-PVAc-PEG) was donated by BASF (Ludwigshafen, Rhineland-Palatinate, Germany). Methoxy poly (ethylene glycol)-b-poly (D, L-lactide) (mPEG[4000]-b-PLA[2200]) was purchased from Advanced Polymer Materials Inc. (Montreal, QC, Canada). Poly (ethylene oxide-b-ε-caprolactone) (PEO[2000]-b-PCL was from Polyscitech (West Lafayette, IN, USA), and Pluronic F-127 was purchased from Sigma-Aldrich Corp. (St. Louis, MO, USA). Buffered saline (DPBS), trypsin, Cremophor EL, Matrigel, D–luciferin potassium salt (GoldBio, St. Louis, MO, USA), and Roswell Park Memorial Institute medium (RPMI 1640) were purchased from Corning Inc. (New York, NY, USA). PTX, SRF, and genistein were purchased from LC Laboratories (Woburn, MA, USA). Methanol was purchased from Honeywell Burdick & Jackson (Ulsan, Republic of Korea), and ethanol and acetonitrile (ACN) were purchased from Fisher Scientific Ltd (Waltham, MA, USA). Distilled water was purchased from Tedia (Fairfield, OH, USA) and Tert-Butanol was from Sigma-Aldrich Corp. (St. Louis, MO, USA). All solvents for high-performance liquid chromatography (HPLC) were HPLC grade or higher.
Jin, C.E.; Yoon, M.S.; Jo, M.J.; Kim, S.Y.; Lee, J.M.; Kang, S.J.; Park, C.-W.; Kim, J.-S.; Shin, D.H. Synergistic Encapsulation of Paclitaxel and Sorafenib by Methoxy Poly(Ethylene Glycol)-b-Poly(Caprolactone) Polymeric Micelles for Ovarian Cancer Therapy. Pharmaceutics 2023, 15, 1206. https://doi.org/10.3390/pharmaceutics15041206
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