| In cancer chemotherapy, the conventional approaches for drug delivery lack the property of targeting, leading to indiscriminate drug uptake by the normal and tumor cells. Hence, drugs can do harm to the normal cells inevitably when killing the tumor cells, resulting to toxicity and decreased quality of patients' life. The treatment effectiveness is greatly affected, thus hindering the further development and application of chemotherapy. Consequently, cancer targeting therapy emerged and became a research focus quickly.Drug loaded nanoparticles prepared with human albumin can improve the solubility of water-insoluble drugs significantly. Besides the biocompatibility, biodegradability, bioavailability as well as passive targeting of nanoparticles in the tumor region, the albumin nanoparticles can achieve active targeting via binding with receptors highly expressed on the vascular endothelial cells and tumor cells. The passive and active targeting can both decrease the side effects from diffuse distribution of anticancer drugs. Now, anticancer drug delivery system prepared with human albumin has been utilized in clinic. Paclitaxel, which has been widely used in breast cancer, prostate cancer, ovarian cancer, head and neck tumors, non-small cell cancer and so on, is one of the most effective broad-spectrum anticancer drugs. The solubility of paclitaxel in water is extremely low, whereas the traditional formulation Taxol has obvious toxicity. Researches exploring a novel formulation of paclitaxel with reduced toxicity and improved targeting are popular in tumor therapy.In the present study, we prepared paclitaxel loaded human serum albumin nanoparticles (PTX-HSA NPs) employing the simple method of our lab's patents. The mean diameter of nanoparticles with a 15% addition dosage is around 120nm, and particles were relatively uniform. It was demonstrated through TEM, SEM and AFM that the nanoparticles were spherical and the distribution of diameters was from 100nm to 200nm. With HPLC, it was proved the highest drug loading of the nanoparticles prepared by us is over 20%. Further, we found that the diameter, encapsulation efficiency, and drug loading are associated with the amount of paclitaxel added and the pH of the solution. The X-ray diffraction showed that paclitaxel in nanoparticles existed as non-crystalline. Through CD, it was proved the second structures of albumin were nearly unchanged after the preparation. Nanoparticles in our research had great stability. In room temperature, the particles could keep for over 48 hours without alternation of diameter in isotonic solution, and they can also kept for over 24 hours in 37℃serum.In the pharmacological experiments in vitro, there was no significant difference in the growth inhibition rate of MCF-7 cells between our nanoparticles and Taxol, but the repression of our nanoparticles on A549 cell was obviously better than Taxol. Thus, our nanoparticles could keep or even improve the antitumor efficiency of paclitaxel. It was discovered with LSCM that nanoparticles distributed in the cytoplasm once entering the cell. Cellular uptake of the nanoparticles could be inhibited by natural human albumin and inhibitors of endocytic pits, and the conclusion above was proved quantitatively by FCM, illustrating that our nanoparticles could be taken by tumor cells through the same way as albumin. That was, albumin nanoparticles could bind receptors on tumor cells, and then they would enter the cells via the formation of endocytic vesicles. The active targeting could be realized finally in this way.In monkey models, we investigated the pharmacokinetics of PTX-HSA NPs. The results displayed that the formulation in this study had a similar plasma PTX concentration-time curve with Abraxane. In addition, there were no significant difference between their Cmax, Tmax, AUC, CL and MRT. All these proved that PTX-HSA NPs had a good bioequiavailability with Abraxane. |
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