Preparation And Evaluation Of Docetaxel-phospholipid Complex-and Its Self-assembled Nano-drug Delivery Systems

Docetaxel(DTX)is a kind of effective anticancer drug with a wide anti-cancer spectrum extenisively utilized in clinic.However,DTX is subject to limitations associated with extremely low water solubility,poor stability,short blood half-life,low bioavailability,and rapid metabolism,and serious side effects,thus the plasma DTX concentration at the tumor site is rather low after intravenous administration.Therefore,how to maximize the improvement of drug amphiphicity and the enhancement of drug stability and efficacy for killing tumor cells is undoubtedly an important issue of DTX in cancer therapy.In this study,on the basis of drug-phospholipid complex technique and self-assembly technique,we designed and developed DTX-phospholipid complex and DTX-phospholipid complex-based self-assembled nano-drug delivery systems.The self-assemble behaviors,quality,drug release behavior,as well as in vitro and in vivo drug efficacy of those drug delivery systems were systemically investigated.The full work includes the following contents:We prepared DTX-phospholipid complex and optimized its preparation process.We demonstrated the effective complexation(complexation rate was high as 92%)between DTX and phospholipid using various characterization methods.We further certified that electrostatic interaction acted an important role in weak interactions between DTX and phospholipid.Besides,the DTX-phospholipid complex remarkably improved the amphiphilicity of drug and increased both the lipophilicity and hydrophilicity of drug.We self-assmebled and fabricated DTX-phospholipid complex-based nanscaled drug delivery systems.Based on DTX-phospholipid complex,DTX-soybean phosphatidylcholine(SPC)complex-self-assembled nanoparticles functionalized with poloxamer were controlledly constructed using a anti-solvent method method by hydrophilic-hydrophobic interaction-induced self-assembly.Besides,the optimal DTX-SPC complex-self-assembled nanoparticles functionalized with poloxamer were prepared by single-factor and orthogonal experiments.The morphology,size distribution,dispersion,and physical and chemical properties were characterized.These results exhibited that DTX-SPC complex-self-assembled nanoparticles functionalized with poloxamer had an intact structure,a nearly spherical shape,a hydrodynamic particle size of 128 nm,a zeta potential of-19 mV,and drug-loading content of 18.2%.In addition,we exploited mannitol and dextran as composite protective agents and prepared the lyophilization of DTX-SPC complex-self-assembled nanoparticles.The result indicated lyophilization products possessed excellent long-term storage stability.We evaluated the in vitro and in vivo performance of DTX-phospholipid-based nanoscaled drug delivery sytems.DTX-SPC complex-self-assembled nanoparticles functionalized with poloxamer and DTX-SPC complex-self-assembled nanoparticles demonstrated a bi-phase drug release manner including an initial burst drug release and a subsequent sustained drug release.The advantage of these two kind of drug delivery systems was that they could reduce the premature drug leakage and burst release(reduce the non-specific drug release)and increase the sustained drug release(prolong the action time of drug).Qualitative result by lasing confocal scanning microscopy(LCSM)proved that DTX-SPC complex-self-assembled nanoparticles functionalized with poloxamer and DTX-SPC complex-self-assembled nanoparticles obviously enhanced the cellular uptake against HeLa cells compared to free DTX.More importantly,the result of standard MTT experiment demonstrated that DTX-SPC complex-self-assembled nanoparticles functionalized with poloxamer and DTX-SPC complex-self-assembled nanoparticles possess signifcant concentration-dependent inhibition effect against HeLa cells,and significantly enhanced the anticancer activity compared to free DTX.The result of in vivo imaging experiment showed that DTX-SPC complex-self-assembled nanoparticles functionalized with poloxamer more easily accumulated in the tumor tissue compared to DTX-SPC complex-self-assembled nanoparticles and DTX.Furthermore,the result of in vivo anti-cancer effect showed that DTX-SPC complex-self-assembled nanoparticles functionalized with poloxamer were more remarkable for inhibition of tumor growth.These results demonstrated that DTX-SPC complex-self-assembled nanoparticles functionalized with poloxamer could greatly improved treatment effect and reduce the side effects.Therefore,DTX-SPC complex-self-assembled nanoparticles functionalized with poloxamer had high potential as simple,effective,flexible,and safe delivery systems for cancer chemotherapy.