The effect of core composition in biodegradable oligomeric micelles as taxane formulations.
ABSTRACT Docetaxel (DCTX) and paclitaxel (PTX) are very potent anti-cancer drugs, but the currently marketed formulations, Taxotere and Taxol, respectively, are associated with vehicle-related toxicity. An attractive alternative to formulate these hydrophobic cytotoxic agents are polymeric micelles. In this study, the loading of taxanes into oligomeric micelles composed of mPEG750-b-oligo(epsilon-caprolactone)5 (mPEG750-b-OCL5) with a hydroxyl (OH), benzoyl (Bz) or naphthoyl (Np) end group was investigated. Next, the release characteristics and cytotoxicity of the loaded micelles were studied. MPEG750-b-OCL5 -OH micelles loaded with taxanes formed unstable particles with rapid leakage of the drug. In contrast, the presence of an aromatic end group (Bz or Np) resulted in the formation of small (10nm), almost monodisperse micelles with stable encapsulation of 10% (w/w) of PTX or DCTX. This was ascribed to a better compatibility between the micellar core and the drug as compared to the oligomers with the hydroxyl end group. 1H NMR studies showed that the micellar core was liquid, and that PTX was molecularly dissolved in the core. The in vitro stability was studied in PBS at 37 degrees C, which showed that leakage of PTX from 10% and 5% (w/w) loaded mPEG750-b-OCL5-Bz micelles started after 8 and 24h, respectively. The presence of albumin did not affect the stability, suggesting that the micelles are not destabilised and the drug was not extracted from the micellar core by this protein. The in vitro cytotoxic effect of the taxane-loaded micelles on C26 carcinoma cells was comparable to that of the commercial formulations, but the empty micelles were far less toxic than the Cremophor EL vehicle. The results show that mPEG-b-oligo(epsilon-caprolactone) micelles hold good promise for the formulation of taxanes.
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ABSTRACT: The preparation, release and in vitro cytotoxicity of a novel polymeric micellar formulation of paclitaxel (PTX) were investigated. The micelles consisted of an AB block copolymer of poly(N-(2-hydroxypropyl) methacrylamide lactate) and poly(ethylene glycol) (pHPMAmDL-b-PEG). Taking advantage of the thermosensitivity of pHPMAmDL-b-PEG, the loading was done by simply mixing of a small volume of a concentrated PTX solution in ethanol and an aqueous polymer solution and subsequent heating of the resulting solution above the critical micelle temperature of the polymer. PTX could be almost quantitatively loaded in the micelles up to 2 mg/mL. By dynamic light scattering and cryo-transmission electron microscopy, it was shown that PTX-loaded micelles have a mean size around 60 nm with narrow size distribution. At pH 8.8 and 37 degrees C, PTX-loaded micelles destabilized within 10 h due to the hydrolysis of the lactic acid side group of the pHPMAmDL. Because the hydrolysis of the lactic acid side groups is first order in hydroxyl ion concentration, the micelles were stable for about 200 h at physiological conditions. The presence of serum proteins did not have an adverse effect on the stability of the micelles during at least 15 h. Interestingly, the dissolution kinetics of pHPMAmDL-b-PEG micelles was retarded by incorporation of PTX, indicating a strong interaction between PTX and the pHPMAmDL block. The PTX-loaded micelles showed a release of the incorporated 70% of PTX during 20 h at 37 degrees C and at pH 7.4. PTX-loaded pHPMAmDL-b-PEG micelles showed comparable in vitro cytotoxicity against B16F10 cells compared to the Taxol standard formulation containing Cremophor EL, while pHPMAmDL-b-PEG micelles without PTX were far less toxic than the Cremophor EL vehicle. Confocal laser-scanning microscopy (CLSM) and fluorescence activated cell sorting (FACS) analysis of fluorescently labelled micelles showed that pHPMAmDL-b-PEG micelles were internalized by the B16F10 cells. The present results suggest that pHPMAmDL-b-PEG block copolymer micelles are a promising delivery system for the parenteral administration of PTX.Journal of Controlled Release 04/2005; 103(2):341-53. · 7.63 Impact Factor
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ABSTRACT: A new micelle system formed from methoxy (polyethylene glycol)-b-poly (5-benzyloxy-trimethylene carbonate; MePEG-b-PBTMC 5000-b-4800) was investigated as a delivery system for the hydrophobic anti-cancer agent, ellipticine. The ellipticine was loaded into the MePEG-b-PBTMC micelles with a loading efficiency of 95% using a high-pressure extrusion technique. The ellipticine-loaded micelles have a spherical morphology and an average diameter of 96 nm. The anti-cancer activity of ellipticine was confirmed to be retained following formulation in the MePEG-b-PBTMC micelles. The extent of protein adsorption to the MePEG-b-PBTMC micelles was investigated by transmission electron microscopy, dynamic light scattering and gel filtration chromatography. Overall, the amount of protein both loosely and tightly associated with the micelles was found to be minimal and insignificant. The partitioning properties of ellipticine between an aqueous medium containing protein and the MePEG-b-PBTMC micelles were examined over a range of protein concentrations. Under physiologically relevant conditions, it was found that 61% of the drug remained within the micelle fraction while 39% was in the protein-containing aqueous phase. In addition, the in vitro drug release profile of ellipticine from the micelles was fit using a modified Higuchi model and found to be accelerated in the presence of protein. These studies demonstrate that although there are no significant interactions between micelle and protein, the properties of the micelle as a delivery vehicle may be strongly influenced by protein-drug interactions.Journal of Controlled Release 04/2005; 103(2):481-97. · 7.63 Impact Factor
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ABSTRACT: The majority of novel anticancer drugs developed to date are intended for parenteral administration. Paradoxically, most of these drugs are water-insoluble, delaying their clinical development. A common approach to confering water solubility to drugs is to use amphiphilic, solubilizing agents, such as polyethoxylated castor oil (e.g., Cremophor EL, CrmEL). However, these vehicles are themselves associated with a number of pharmacokinetic and pharmaceutical concerns. The present work is aimed at evaluating a novel polymeric solubilizer for anticancer drugs, i.e., poly(N-vinylpyrrolidone)-block-poly(D,L-lactide) (PVP-b-PDLLA). This copolymer self-assembles in water to yield polymeric micelles (PM) that efficiently solubilize anticancer drugs, such as paclitaxel (PTX), docetaxel (DCTX), teniposide (TEN) and etoposide (ETO). A PM-PTX formulation was evaluated, both, in vitro on three different cancer cell lines and in vivo for its safety, pharmacokinetics, biodistribution and antitumor activity. In vitro, cytotoxicity studies revealed that the drug-loaded PM formulation was equipotent to the commercial PTX formulation (Taxol). In the absence of drug, PVP-b-PDLLA with 37% DLLA content was less cytotoxic than CrmEL. In vivo, acute toxicity was assessed in mice after a single injection of escalating dose levels of formulated PTX. PM-PTX was well tolerated and the maximum tolerated dose (MTD) was not reached even at 100 mg/kg, whereas the MTD of Taxol was established at 20 mg/kg. At 60 mg/kg, PM-PTX demonstrated greater in vivo antitumor activity than Taxol injected at its MTD. Finally, it was shown in mice and rabbits that the areas under the plasma concentration-time curves were inversely related to PM drug loading.Journal of Controlled Release 10/2004; 99(1):83-101. · 7.63 Impact Factor