Paclitaxel Modified By Chemical Materials

Paclitaxel (trade name:Taxol) is a naturally diterpenoid found in the stem bark ofthe Western Yew,Taxus brevifolia , which has great potential as an anti-cancer drugs,It has been found effective against a wide spectrum of cancers including ovarian cancer, breast cancer, small and non small cell lung cancer and many other malignant tumors. The biological activity of taxol is releated to its effect on cell division.Taxol promotes formaton of microtubules that form the mitotic spindle during cell division.Taxol prevents depolymerization of the tubulin forming the microtubules of the mitotic spindle ,which is essential for cell division and proliferation .Like many other anticancer drugs, taxol has difficulties in clinical administration due to its poor solubility in water and most pharmaceutical reagents. Taxol has short life time. In its current clinical application, an adjuvant called Cremophor EL has to be employed, which has been found to be responsible for many serious side effects.Microspheres/microencapsules of two kinds of materials, poly(lactic-co-glycolic acid) and alginate, are proposed in the present work for clinical administration of an antineoplastic drug paclitaxel with hypothesis that microparticals might prolonged the half life of paclitaxel in the serum. Characterization of the microparticle was then followed to examine the particle size, the drug loading efficiency, the surface chemistry, the surface morphology, the drug physical state and its in vitro release behavior. The partical size were measured by light microscopy and scanning electron microscopy.The drug encapsulation efficiency and the drug release kinetics under in vitro conditions were measured by high performance liquid chromatography (HPLC) and the IC50 were calculated by MTT method.Two kinds of paclitaxel derivatives modified by hydrophilic Polyethylene glycol (PEG) and lactose were synthesized. The structure of mPEG-paclitaxel and TS1 and TS2were illustrated with lH nuclear magnetic resonance (NMR) and infrared spectrum. The physicochemical characteristics of mPEG-paclitaxel and TSl and TS2 (i.e. melting point, water-solubility) were studied. The in vitro and in vivo cytotoxic activity of mPEG-paclitaxel and TSl and TS2 was evaluated compared to paclitaxel alone.The effect on tumor cell cycle and atoposis by TSl and TS2 was also detected. The cytotoxic activity of mPEG -paclitaxel and TSl and TS2 microspheres in vivo were evaluated by tumor-graft nude mice also.The mean particle size of the fresh Alginate—paclitaxel microspheres/ microencapsules was 256 microm and were spherical in shape.The shape crimpled and changd to irregular spheres after lyophilized. The loading efficiency of paclitaxel in microcapsules and microspheres were about 25% and less than 10% respectively. The in vivro release of paclitaxel from microspheres and microcapsules were relative fast initially followed by more controlled release. The 85 percent drug in Alginate-paclitaxel microspheres was released on the 30th day. The HeLa tumor cell line experiment showed that after 72 hours of incubation, the cell mortality caused by the drug administered by such microspheres could be higher than that caused by the free drug under similar conditions.The cytotoxic activity of Alginate-paclitaxel microcapsules/microspheres were stronger compared to paclitaxel alone.The mean size of PLGA-Paclitaxel micropartical were 7~37um which were in spherical shape.The encapsulation efficiency of Paclitaxel were more than 90%.and the loading efficiency of Paclitaxel were about 40%.The in vivo release of paclitaxel from microspheres show initially burst release and then sustained release. The cytotoxic activity of PLGA-Paclitaxel microspheres were stronger compared to paclitaxel alone.Paclitaxel was attached to mPEG via a succinic spacer arm by a two step. (1) synthesis of 2'- succinylpaclitaxel; (2) synthesis of mPEG-2'- succinylpaclitaxel.The macromolecular conjugate was characterized by 'H NMR analysis. Paclitaxel was linked to lactose via a succinic spacer arm by three step.(l) synthesis of two kinds of lactose derivates S1,S2. (2) synthesis of 2'- succinylpaclitaxel. (3) synthesis of SI-2'-...