Preparation And Pharmacodynamic Comparison In Vitro Of Paclitaxel-loaded Polylactide Polymers Microspheres

Paclitaxel(PTX) has been widely used as a potent anti-drug for the treatment of various types of tumors, but its poor water-solubility has been a huge challenge for clinical application. Cremephor EL as the solvents of paclitaxel in clinical setting has caused serious side effects such as hypersentivity, nephrotoxicity, neurotoxicity and so on. In order to avoid these problems and improve solubility, microspheres as the drug delivery systems has extremely attractive and broad prospects.In this paper, uniform-sized poly (DL-lactic acid) (PLA), poly(DL-lactic-co-glycolic acid) (PLGA) and poly(ethylene glycol-co-lactide acid) (PELA) microspheres containing PTX were prepared by premix membrane emulsification technique integrated with solvent evaporation method, and then the shape and surface morphology of PLA, PLGA and PELA microspheres were observed by scanning electron microscope. In order to choose the most suitbale carrier polymers of PTX, different precipitation rates of the polymers were throughly analyzed, and its corresponding effects on the distribution and crystallization ofPTX in microspheres, loading and encapsulation efficiency, the release profile and antitumor activity in vitro were systematically investigated. The PTX-loaded microspheres prepared by the most suitable polymers were modified on the surface and varied in size, the effects on the surface morphology, loading efficiency, encapsulation efficiency, release profile and antitumor activity in vitro were observed, the research results were as follows: PTX-loaded PLA, PLGA and PELA microspheres were prepared by premix membrane emulsification technique combined with solvent evaporation method. The result of size distribution suggested that the average diameters of three microspheres were about 900 nm, and the corresponding size distribution were narrow; PLA and PLGA microspheres were spherical with a smooth surface, while PELA microspheres was spherical with a porous and rough surface; In the process of microspheres formation, the precipitation rate of PTX and polymers PLA, PLGA and PELA during the evaporation of DCM resulted in the different distributions and crystallization of PTX in microspheres. It was found that PTX was uniformly distributed in PLA microspheres, and PTX aggregation existed in PLGA microspheres, while the flake of PTX was formed in PELA microspheres. The different hydrophobicity of polymers further led to different loading and encapsulation efficiency, release profile in vitro and cytotoxcity. The PLGA microspheres showed the highest loading and encapsulation efficiency of PTX (5.15%, 70.46%) and the fastest drug release in vitro.The antitumor activity in vitro of PTX-loaded PLA, PLGA and PELA microspheres was evaluated and the results suggested that PLA, PLGA and PELA polymers had no cytotoxicity and demonstrated excellent biocompatibility and safety; PTX-loaded PLA, PLGA and PELA microspheres showed excellent antitumor activity in vitro compared with Taxol?, and PTX-PLGA microspheres showed the most excellent antitumor activity compared with PLA and PELA microspheres; And the internalization amounts of PLGA microspheres were the highest, followed by PELA microspheres, and the amounts of PLA microspheres uptaken by cells were the lowest. Therefore, PLGA microspheres have great potential as delivery carriers for PTX.PTX-loaded PLGA microspheres and surface modified PTX-PLGA microspheres with HTCC were prepared by premix membrane emulsification technique combined with solvent evaporation method. Then the corresponding effects on surface morphology, loading efficiency and encapsulation efficiency, release profile and antitumor activity in vitro were systematically investigated. The results showed the mean diameter of PTX-loaded HTCC-PLGA microspheres was 882 nm, the loading and encapsulation efficiency were 5.15% and 70.46%, and the cumulative release rate in vitro for 22 days was 70.17%, which had little difference with PTX-loaded PLGA microspheres. However, PTX-loaded HTCC-PLGA microspheres showed positive surface charge at +36.7 mV while PLGA was ?14.8 mV. The intracellular PTX incubated with PTX-loaded PLGA and PLGA-HTCC microspheres was 5.6 and 9.7 times as much as that of Taxol?, and HTCC-PLGA microspheres showed lower cell viability than PLGA microspheres. Therefore, PTX-loaded HTCC-PLGA microspheres were identified as the potential delivery system for insoluble drug PTX.PTX-loaded PLGA microspheres of 198.2 nm and 864.9 nm were prepared by premix membrane emulsification technique combined with solvent diffusion method. In the process, the emulsion solution was pressured successively through different SPG membrane with different membrane aperture. The study result exhibited that these microspheres were spherical with a smooth surface and the corresponding size distribution were narrow; The loading efficiency and encapsulation efficiency of PTX-loaded PLGA microspheres of 198.2 nm were lower than those of 864.9 nm; However, PTX-loaded PLGA microspheres of 198.2 nm showed lower cell viability than those of 864.9 nm due to advantage of smaller sized microspheres in cellular uptake.