Local Anti-tumor With Paclitaxel Pcl/f68 Contained Microspheres And Nanoparticles

In drug delivery system, poorly water-soluble drugs have presented a challenge to the development of a safe and effective formulation. Some active substances through high-throughput screening for new drugs are abandoned owing to the poor water solubility. Conventional formulations of poorly water-soluble drugs in the clinic are frequently plagued with problems such as sub-optimal dosing and poor performance. Paclitaxel is a microtubule stabilizing agent with a wide spectrum of anticancer activity against human cancers such as ovarian cancer, breast cancer, non-small-cell lung carcinoma, colon cancer. Due to paclitaxel's poor solubility in water, an adjuvant called Cremophor EL has to be used in current paclitaxel formulation for clinical administration. The Cremophor EL was found to cause serious side effects including hypersensititivity reaction, nephrotoxicity, neurotoxicity and cardiotoxicity. Pre- medication with corticosteroids and antihistamine is used with paclitaxel to increase safety and to reduce the intensity of serious hypersensitivity reactions associated with paclitaxel administration in cremophor EL. As a result, there is a need for the development of more biocompatible formulations for the delivery of paclitaxel by eliminating cremophor EL.Local administration of chemotherapeutics at the tumor site is thought to enhance chemoresponsiveness by exposing tumors and adjacent metastases to high local concentration of antitumor agents while reducing systemic exposure, therefore alleviating the systemic toxicity. Paclitaxel is a prime candidate for localized delivery by offering excellent pharmacokinetic profile and following therapeutic advantages: 1) Since paclitaxel displays a dose-dependent cytotoxicity, the higher local concentration of drug in rumor site will help to kill the tumor cells with the highly concentrated cytotoxicity. 2) Paclitaxel has potent antiangiogenic activity. Studies have shown that the antiangiogenic response with local administration is more efficient than with systemic administraion. 3) The antimetastatic, antiangiogenic and apoptotic effects are also dose-dependent. 4) The high local concentrations of paclitaxel will reduce systemic toxic effect such as bone marrow suppression and cardiac rhythm.Due to paclitaxel's excellent pharmacokinetic profile and therapeutic advantages as a prime candidate for localized delivery, in this study paclitaxel loaded polymeric microspheres and nanoparticles for localized delivery was investigated. Poly(ε- caprolactone) (PCL) / Poloxamer 188 (Pluronic F68, F68) blend matrix was used as drug delivery materials. F68 was incorporated into PCL matrices as both a pore- forming agent and a drug releasing enhancer to accelerate the release of paclitaxel. The local antitumor activity of paclitaxel loaded PCL/F68 blend microspheres and PCL/F68 blend nanoparticles was also evaluated in this study.The major contents of this paper are shown as follows: 1. The preparation of PCL/F68 blend microspheres and the elementary evaluation of its local antitumor activityTo prepare paclitaxel loaded PCL/F68 blend microspheres and evaluate its local antitumor activity against sarcoma 180 cells solid tumor and hepatoma H22 cells ascites tumor in mice. Paclitaxel loaded PCL/F68 microspheres showed certain antitumor activity against sarcoma 180 cells solid tumor, however, which was no more effective than conventional paclitaxel injection. Paclitaxel loaded PCL/F68 microspheres showed the potent antitumor activity against hepatoma H22 cells in ascites tumor model and more lasting antitumor activity compared with paclitaxel injection. To improve the antitumor activity of paclitaxel loaded delivery system against solid tumor, two means were taken as follows: 1) One means was to enhance paclitaxel releas from PCL/F68 blend microspheres, discussing the effect of the blend amount of F68 and the molecular weight of PCL on the release of paclitaxel from PCL/F68 blend microspheres. 2) The other means was to develop paclitaxel loaded PCL/F68 blend nanoparticles.2. The influences of F68 with different blend amount on PCL/F68 blend microspheresThe influences of F68 with different blend amount on microsphere morphology, paclitaxel release and in vitro degradation of PCL/F68 blend microsphere were discussed. The results showed that F68 can form the porous structure in the surface of PCL/F68 blend microsphere. The porosity of the surface of PCL/F68 blend microspheres and the release rate of paclitaxel from the PCL/F68 blend microspheres increased as the initial amount of blended F68 increased. In vitro degradation studies showed that the degradation of PCL also increased as the initial amount of blended F68 increased. The degradation process of PCL was very slow. The PCL/F68 blend microsphere with various amount of F68 were not observed with deformation. The drug diffusion process is the key factor to determine the drug release from the PCL/F68 blend microspheres.3. The influences of the molecular weight of PCL on PCL/F68 blend microspheresInfluences of molecular weight of PCL on the release of paclitaxel from PCL/F68 blend microsphere were discussed. The results showed that the decrease of molecular weight of PCL enhanced the release of paclitaxel from PCL/F68 blend microspheres. But the decrease of molecular weight of PCL reduced the encapsulation of paclitaxel with the microspheres. The difference between immediate release method and dialysis release method for the in vitro drug release study was studied. The results showed that the drug release rate determined by dialysis method was less than by immediate method. This may be due to the little concentration difference between the inside and outside of dialysis bag, which resulted in the slow drug diffusion and low release rate.4. Paclitaxel loaded PCL/F68 blend microspheresThe interracial deposition method was used in the preparation of paclitaxel loaded PCL/F68 blend nanoparticles, which involves only one step for dispersion of the water-miscible organic phase in the aqueous phase. The process of the interfacial deposition method can be easily industrialized. The preparation parameters were optimized. The in vitro drug release study showed that paclitaxel loaded PCL/F68 nanoparticles has a good property of controlled release. The effect of paclitaxel loaded PCL/F68 blend nanoparticles on tumour growth of TA2 inbred mice bearing with lung metastasis models of breast cancer was studied, and the results showed that paclitaxel loaded PCL/F68 nanoparticles after local administration at tumor site can potently inhibit the growth and metastasis of tumor.In PCL/F68 blends for the drug delivery of paclitaxel, PCL controlled the release of paclitaxel from PCL/F68 delivery system to keep effective the drug concentration in the tumor site. F68 as a pore-forming agent can be leached out in the aqueous solution to enhance the release of paclitaxel. Paclitaxel loaded PCL/F68 microspheres showed the potent antitumor activity in ascites tumor model. Paclitaxel loaded PCL/F68 nanoparticles after local administration at tumor site can potently inhibit the growth and metastasis of solid tumor. Through this study, the developed PCL/F68 blend microspheres and nanoparticles could be used as an effective formulation for the local delivery of paclitaxel and would make paclitaxel to be applied more widely in clinic.