Poly -paclitaxel

Poly(ADP-ribose)polyrmerase (PARP) inhibitors, 42 (2004) 125 P2 Purinoreceptor ligands, 38 (2001) 115 p38 MAP kinase inhibitors, 38 (2001) 1 Paclitaxel, anticancer agent, 32 (1995) 289... 

Liggins RT, Burt HM (2001) Paclitaxel loaded poly(L-lactic acid) microspheres properties of microspheres made with low molecular weight polymers. Int J Pharm 222 19-33... 

Since the discovery of vesicular structures, termed liposomes, by Alec Bangham, a tremendous amount of work on applications of liposomes has emerged. The use of small unilamellar liposomes as carriers of drugs for therapeutic applications has become one of the major fields in liposome research. The majority of these applications are based on the encapsulation of water-soluble molecules within the trapped volume of the liposomes. Long circulating poly(ethylene glycol) (PEG) modified liposomes with cytotoxic drugs doxorubicin, paclitaxel, vincristine, and lurtotecan are examples of clinically applied chemotherapeutic liposome formulations (1,2). 

The taxanes are practically insoluble in water and solubility is limited to mixtures of ethanol with poly-ethoxylated castor oil. They are generally administered in 3-24 hour infusions. The taxanes are for 90-95% plasma protein bound and primarily metabolized by P450 enzymes in the liver. Less than 10% is excreted in the urine as parent compounds. The elimination half-life of docetaxel is approximately 10 hours while that of paclitaxel has been vary-ingly reported between 5 and 50 hours. Inhibitors of the cytochrome P450 isoenzyme Cyp3A4, like keto-conazole and erythromycine, are contraindicated. 

The effect ofthe medium composition orthe loaded drug on the CMC may be difLcuitto predict. Zhang, Jackson, and Burt (1996a) found that the incorporation of 10% paclitaxel into MePEO-b PDLLA micelles did not cause the CMC to change signiLcantly. Those authors also showed that the CMC of methoxy (Me) PECb-PDLLA (poly(DL-lactic acid)) micelles remained the same in water,... 

Polymeric micelles formed by Pluronics, PEG phospholipid conjugates, PEG-b-polyesters, or PEG-b-poly-L-amino acids were proposed for drug delivery of poorly water-soluble compounds, such as amphotericin B, propofol, paclitaxel, and photosensitizers [77,86,87]. It was also emphasized that using polymeric micelles can significantly increase the drug transport into the brain. 

Poly-lactic acid/poly caprolocatone Paclitaxel Rabbit iliac (81,82)... 

See color plate) Atomic force microscopy images and drug release kinetics of the paclitaxel-poly(styrene-i>isobutylene-i>styrene) polymer combination. Abbreviations PTx, paclitaxel SIBS, poly(styrene-b-isobutylene-b-slyrene). 

Biostable polymers have been chosen for use in the majority of DES that are marketed or in clinical development. The main attractiveness of biostable polymers is their physical stability, inertness toward the drug, and predictable drug kinetics. In Cypher, a blend of poly(ethylene-co-butyl methacrylate) (PEVAc/PBMA) is used as the drug carrier. This hydrophobic polymer, along with additional polymer process steps, effectively controls the release of sirolimus, eluting 80% of the drug over 30 days after implantation. In the case of Taxus, atri-block copolymer of styrene-isobutylene-styrene (SIBS) is used as the hydrophobic polymer matrix that releases 10% of incorporated paclitaxel in the first 30 days (20). 

The Taxus stent by Boston Scientific uses a tri-block copolymer [poly(styrene-b-isobutylene-b-styrene)] for sustained delivery of paclitaxel. This new polymer is specifically designed for this use and has a trade name of Translute , Paclitaxel can be released at a fast or a slow rate by varying the drug loading in the polymer matrix as shown in Figure 4. 

Another study of stent-based paclitaxel delivery, which also used a degradable polymer [poly(lactide-co-Scaprolactone)] to control the drug-release kinetics, demonstrated sustained reduction in neointimal hyperplasia in the rabbit iliac model (Fg. I I) (56). 

Poly(lactide-co-X-caprolactone)-coated stent —Poly(lactide-co- -caprolactone)-coated paclitaxel-releasing stent... 

Potineni, A., Lynn, D. M., Langer, R., and Amiji, M. M. (2003), Poly(ethylene oxide)-modified poly(beta-amino ester) nanoparticles as a pH-sensitive biodegradable system for paclitaxel delivery, / Controlled Release, 86(2-3), 223-234. 

Dong, Y., and Feng,S.S. (2006),Nanoparticles of poly(D,L-lactide)/methoxypoly(ethylene glycol)-poly(D,L-lactide) blends for controlled release of paclitaxel, J. Biomed. Mater. Res. A, 78(1), 12-19. 

Amphiphilic block copolymers consisting of polyethylene glycol and poly-lactide, (I), were prepared by Seo [1] and used as drug delivery agents for Paclitaxel . 

Seo [4] prepared poly(d,l-lactide-b-E-caprolactone), (III), and poly(d,l-lactide-b-ethylene glycol) using stannous octanate. Both polymers were used as Paclitaxel delivery agents. 

Li, C. Yu, D.-R Newman, R. A. Cabral, P. Stephens, L. C. Milas, L. Wallace, S. Complete regression of well-established tumors using a novel water-soluble poly(L-glutamic acid)-paclitaxel conjugate. Cancer Res., 1998, 58 2404—2409. 

Rendri, A. Conover, C. D. Greenwald, R. B. Antitumor activity of paclitaxel-2 -glycinate conjugated to poly(ethylene glycol) a water-soluble prodrug. Anti-Cancer Drug Des., 1998, 13 387-395. 

By these reactions, optically active 1,2-diol units can be positioned efficiently on the desired carbon skeletons. Recently, the above methodologies have been successfully utilized for the stereoselective syntheses of natural and unnatural poly-oxy compounds such as monosaccharides, leinamycin, paclitaxel (Taxol ), and a part of rapamycin. ... 

Being the first poly(glutamic acid) conjugate tested in clinical trials, paclitaxel conjugate of poly(glutamic acid) (CT-2103) was observed to have superior antitumor activity to free paclitaxel. In preclinical studies, it was evidenced that the whole conjugate extravasated to the tumor site and the drug was released extracellularly in... 

Poly(glutamic acid) Paclitaxel Ester A variety of tumor models in mice Phase... 

Ruan, G. Feng, S.-S. Preparation and characterization of poly(lactic acid)-poly(ethylene glycol)-poly(lactic acid) (PLA-PEG-PLA) microspheres for controlled release of paclitaxel. Biomaterials 2003, 24, 5037-5044. 

Fig. 1 Fluorescence microscopy of the binding of Rh-PE-labeled paclitaxel-loaded poly(ethylene glycol)-phosphatidyl ethanolamine (PEG-PE)-based micelles to murine EL4 and large luteal cells (LLC) and human BT-20 and MCF-7 cells. (With permission from Ref. l)...

The solid dispersion method (Fig. 2B) was used for solubilization of paclitaxel into PEG-poly(D,L-lactide) diblock copolymer micelles. Paclitaxel and the polymer were dissolved in acetonitrile followed by evaporation of the solvent under a stream of nitrogen at 60°C to obtain a gel-like polymer-drug matrix. Dissolution of the solid matrix in water at about 60° C with stirring led to formation of drug-loaded micelles. Because a heating is needed to completely dissolve the polymer-drug matrix, this method may not be not desirable for thermally unstable drugs. 

While the structure of the hydrotropic moiety of the polymer is the most important factor in hydrotropy, other factors can also contribute to the overall hydrotropic property of the polymers. The spacer between the polymer backbone and the hydrotropic moiety is one key factor affecting the overall hydrotropy. Two different hydrotropic polymers based on V-PNA have different hydrotropic properties depending on the nature of the spacer. The paclitaxel solubility in P(6-VBOPNA) increased to a larger extent than in poly(6-allyloxy-V-PNA) (P(6-APNA)), where the aromatic spacer was replaced with a linear chain. 

Phospholipid polymers having a 2-methacryloylox-yethyl phosphorylcholine (MPC) were investigated as a solubilizer for paclitaxel. The paclitaxel solubility was observed to increase up to 5.0mg/ml in the presence of a copolymer of MPC and Ai-butyl methacrylate (BMA), poly(MPC-co-BMA), with 70mol% of the BMA unit. The MPC polymer forms a polymer aggregate with the diameter of 23 nm, called a polymeric lipid nanosphere, in aqueous media by hydrophobic interaction, which may solubilize hydrophobic drugs. 

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