The Preliminary Preclinical Drug Evaluation Of Water-soluble Paclitaxel Lyophilized Powder

Paclitaxel (Taxol (?)) has been established as a standard drug for cancer chemotherapy, especially against ovarian, breast and lung cancers after approval by the Federal Drug Administration (FDA), USA,1992. One of the major drawbacks of paclitaxel is poor solubility in water. Therefore, paclitaxel is usually administered by injection using Cremophor EL(?) and ethanol as solvent, and this formulation is associated with significant side effects, which are considered to be related to the pharmaceutical vehicle, causing hypersensitivity reactions and peripheral neuropathy, etc. In recent years, many countries continue to develop the new formulations of paclitaxel in order to improve its aqueous solubility and decrease the side effects. For this reason, we produced a new nano-paclitaxel by paclitaxel granule wrapped with mannitol and Human Serum Albumin (HSA), which had better water solubility and lower systemic toxicity. In order to prove the anti-tumor effects of nano-paclitaexl, we have done some experiments via the following ways:1) Using some human tumor cells detect the activity of nano-paclitaxel in vitro;2) Using intraperitoneal injection to the S180mice model and SKOV-3nude mouse model to study the activity of nano-paclitaxel in vivo.3) Studing mice’s acute toxicity of nano-paclitaxel by tail vein injection, and observing the mice behavior after long time administration.4) Using the Caco-2cells model to simulate the absorption of nano-paclitaxel in vivo, it was interesting to us whether the nano-paclitaxel could be developed into oral medicine.1. Using paclitaxel as a positive control, the anti-tumor effect of nano-paclitaxel to some common tumor was studied by the way of MTT chromatometry. The experimental results showed that nano-paclitaxel had better inhibitory effect on cancer cells (MCF-7, SKOV-3, and PC-3). The values of cancer cells (MCF-7, SKOV-3, and PC-3) were0.886μM,0.913μM,0.687μM, respectively.2. Established the department of mice sarcoma S180mice xenograft model, the mice were divided randomly into six groups treated with intraperitoneal injection. The six groups were injected three concentrations of nano paclitaxel (high-dose, medium-dose, low-dose), paclitaxel, ABI-007, saline respectively. After7days injection, the inhibition rates of each group were52.8%,54.9%,81.3%,71.9%,81.6%. The data suggested that the nano-paclitaxel had significant inhibitory effect on S-180mice xenograft model.3. SKOV-3cells were injected subcutaneously into nude mice to establish the xenograft model. The nude mice were divided randomly into five groups. The five groups were injected saline, paclitaxel, ABI-007, nano-paclitaxel in middle dose, nano-paclitaxel in high dose respectively via intraperitoneal injection. The inhibitory effect of nano-paclitaxel on the xenograft model in nude mice was observed and the volume and weight of tumor were measured. The inhibition rates of each group were54.9%,65.7%,57.7%,58.1%. The data showed that the nano-paclitaxel had a good inhibitory effect on SKOV-3nude mice xenograft model.4. In order to study the nano-paclitaxel on mice acute toxicity, a maximum dose method was used in this article. At the premise of the reasonable maximum drug concentration, the mouse was given the maximum dose of20mg/kg through the tail vein injection. After the administration, we observed the growth status of each group. The data suggested that the nano-paclitaxel had low toxicity and high safety factor in the dose range.5. It was interesting to us whether the nano-paclitaxel could be developed into oral medicine. In this paper, using a well-established model of human intestinal absorption, human colonic cell line Caco-2cell to investigate the transepithelial flux of nano-paclitaxel. The flux of nano-paclitaxel (at a concentration range of0.5-20μM) across the Caco-2cell layer was linear with time for up to3hours. The apparent permeability coefficient (Papp) for the apical to basolateral transport of nano-paclitaxel (20.9±2.1×10-6cm/s; N=3). The Papp of drugs with good absorption were more than1.0R10-6cm/s, the data indicated that nano-paclitaxel had the possibility to develop an oral dosage form.In summary, a new nano-paclitaxel by paclitaxel granule wrapped with mannitol and Human Serum Albumin (HSA), overcoming the shortcoming of the paclitaxel, which had better water solubility and lower systemic toxicity. The data showed that the nano-paclitaxel had better anti-tumor effects in vitro and in vivo. Therefore, the nano-paclitaxel has great research value and market prospects.