Solubilization of Docetaxel in Poly(ethylene oxide)-<i>block</i>-poly(butylene/styrene oxide) Micelles

Complementary kinetic and equilibrium studies on the solubilization process of the sparingly water soluble tamoxifen (TAM) drug in polymeric aqueous solutions have been performed by using the spectrophotometric method. In particular, the amphiphilic copolymers obtained by derivatization of polymeric chain of poly(N-2-hydroxyethyl)-DLaspartamide, PHEA, with poly(ethylene glycol)s, PEG (2000 or 5000 Da), and/or hexadecylamine chain, C 16 , namely PHEA-PEG 2000 -C 16 , PHEA-PEG 5000 -C 16 , PHEA-C 16 , have been employed. Preliminary to the kinetic and equilibrium data quantitative treatment, the molar absorption coefficient of TAM in polymeric micelle aqueous solution has been determined. By these studies the solubization sites of TAM into the polymeric micelles have been determined and the solubilization mechanism has been elucidated through a nonconventional approach by considering the TAM partitioned between three pseudophases, i.e., the aqueous pseudophase, the hydrophilic corona, and the hydrophobic core. The simultaneous solution of the rate laws associated with each step of the proposed mechanism allowed the calculation of the rate constants associated with the involved processes, the values of which are independent of both the copolymer concentration and nature, with the exception of the rate of the TAM transfer from the corona to the core. This has been attributed to the steric barrier, represented by the corona, which hampers the solubilization into the core. The binding constant values of the TAM to the hydrophilic corona of the polymeric micelles, calculated through the quantitative analysis of the equilibrium data, depend on the thickness of the hydrophilic headgroup, while those of the hydrophobic core are almost independent of the copolymer type. Further confirmation to the proposed solubilization mechanism has been provided by performing the kinetic and equilibrium measurements in the presence of PHEA-PEG 2000 and PHEA-PEG 5000 copolymers.

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“…For these copolymers eq 9 reduces to = + Abs Abs Abs w p (12) Analogously to the treatment of the above absorbance data, we obtain…”

Section: Resultsmentioning

confidence: 97%

Peculiar Mechanism of Solubilization of a Sparingly Water Soluble Drug into Polymeric Micelles. Kinetic and Equilibrium Studies

et al. 2012

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“…[10][11][12][13][14][15] Given the hydrophobic property of DX, lipid-based NPs, especially liquid oil-filled NPs, serve as a viable alternative delivery system. Lipid-based NPs have the advantages of low toxicity, capability for controlled drug release, and the potential to penetrate the leaky vasculature of tumors.…”

Section: Introductionmentioning

confidence: 99%

Development and optimization of oil-filled lipid nanoparticles containing docetaxel conjugates designed to control the drug release rate in vitro and in vivo

Feng¹,

Wu²,

Ma³

et al. 2011

IJN

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Three docetaxel (DX) lipid conjugates: 2′-lauroyl-docetaxel (C12-DX), 2′-stearoyl-docetaxel (C18-DX), and 2′-behenoyl-docetaxel (C22-DX) were synthesized to enhance drug loading, entrapment, and retention in liquid oil-filled lipid nanoparticles (NPs). The three conjugates showed ten-fold higher solubility in the liquid oil phase Miglyol 808 than DX. To further increase the drug entrapment efficiency in NPs, orthogonal design was performed. The optimized formulation was composed of Miglyol 808, Brij 78, and Vitamin E tocopheryl polyethylene glycol succinate (TPGS). The conjugates were successfully entrapped in the reduced-surfactant NPs with entrapment efficiencies of about 50%–60% as measured by gel permeation chromatography (GPC) at a final concentration of 0.5 mg/mL. All three conjugates showed 45% initial burst release in 100% mouse plasma. Whereas C12-DX showed another 40% release over the next 8 hours, C18-DX and C22-DX in NPs showed no additional release after the initial burst of drug. All conjugates showed significantly lower cytotoxicity than DX in human DU-145 prostate cancer cells. The half maximal inhibitory concentration values (IC 50 ) of free conjugates and conjugate NPs were comparable except for C22-DX, which was nontoxic in the tested concentration range and showed only vehicle toxicity when entrapped in NPs. In vivo, the total area under the curve (AUC 0–∞ ) values of all DX conjugate NPs were significantly greater than that of Taxotere, demonstrating prolonged retention of drug in the blood. The AUC 0–∞ value of DX in Taxotere was 8.3-fold, 358.0-fold, and 454.5-fold lower than that of NP-formulated C12-DX, C18-DX, and C22-DX, respectively. The results of these studies strongly support the idea that the physical/chemical properties of DX conjugates may be fine-tuned to influence the affinity and retention of DX in oil-filled lipid NPs, which leads to very different pharmacokinetic profiles and blood exposure of an otherwise potent chemo-therapeutic agent. These studies and methodologies may allow for improved and more potent nanoparticle-based formulations.

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“…22 Elsabahy et al synthesized poly(ethylene oxide)-block-poly(styrene oxide) (PEO-b-PSO) and PEO-b-poly(butylene oxide) (PEO-b-PBO), which can selfassemble to form micelles in water with a highly viscous core at low CMC (,10 mg/L). 23 These polymers improved the solubility of DTX by 0.7%-4.2% and efficiently protected DTX from degradation. Mikhail and Allen coupled DTX to poly(ethylene glycol)-b-poly(ε-caprolactone) (PEG-b-PCL) copolymer, which formed the copolymer-drug conjugate PEG-b-PCL-DTX with a low CMC of 14 mg/L.…”

Section: Polymeric Micellesmentioning

confidence: 99%

How nanotechnology can enhance docetaxel therapy

Zhang¹,

Zhang²

2013

IJN

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Docetaxel has been recognized as one of the most efficient anticancer drugs over the past decade; however, its poor water solubility and systemic toxicity have greatly limited its clinical application. In recent decades, the emergence of nanotechnology has provided new drug delivery systems for docetaxel, which can improve its water solubility, minimize the side effects and increase the tumor-targeting distribution by passive or active targeting. This review focuses on the research progress in nanoformulations related to docetaxel delivery -such as polymer-based, lipid-based, and lipid-polymer hybrid nanocarriers, as well as inorganic nanoparticles -addressing their structures, characteristics, preparation, physicochemical properties, methods by which drugs are loaded into them, and their in vitro and in vivo efficacies. Further, the targeted ligands used in the docetaxel nanoformulations, such as monoclonal antibodies, peptides, folic acid, transferrin, aptamers and hyaluronic acid, are described. The issues to overcome before docetaxel nanoformulations can be used in clinical and commercial applications are also discussed.

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Solubilization of Docetaxel in Poly(ethylene oxide)-block-poly(butylene/styrene oxide) Micelles

Cited by 76 publications

References 41 publications

Peculiar Mechanism of Solubilization of a Sparingly Water Soluble Drug into Polymeric Micelles. Kinetic and Equilibrium Studies

Peculiar Mechanism of Solubilization of a Sparingly Water Soluble Drug into Polymeric Micelles. Kinetic and Equilibrium Studies

Development and optimization of oil-filled lipid nanoparticles containing docetaxel conjugates designed to control the drug release rate in vitro and in vivo

How nanotechnology can enhance docetaxel therapy

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