目的 新型樹狀大分子（PAMAM-co-0.25OEG，PGD）作穩(wěn)定劑制備多烯紫杉醇（Docetaxel，DTX）納米粒，以提高多烯紫杉醇的溶解度和生物利用度。方法 將多烯紫杉醇（DTX）、PGD按藥載比8：1，采用超聲沉淀聯(lián)合高壓均質(zhì)法制備DTX-PGD納米粒，動(dòng)態(tài)光散射測定載藥納米粒粒徑及電位；考察37℃條件下，DTX-PGD納米粒在生理鹽水、5%葡萄糖、PBS及血漿中的穩(wěn)定性及DTX-PGD納米粒的溶血性。X射線粉末衍射法測定DTX在納米粒中的晶型形式。透析法測定DTX-PGD納米粒的體外釋放度，MTT法檢測DTX-PGD納米粒對(duì)4T1細(xì)胞的殺傷作用。結(jié)果 多烯紫杉醇在水中的溶解度提高到1.6 mg/mL（原藥在水中幾乎不溶），納米粒載藥量達(dá)65.7%。DTX-PGD納米粒粒徑270.7 nm，PDI值為0.112，電位28.6 mV。DTX-PGD納米粒在5%葡萄糖及血漿中穩(wěn)定存在。掃描電鏡觀察納米粒為片狀，XRD圖譜顯示，多烯紫杉醇在納米粒中以晶體形式存在。DTX-PGD納米粒在PBS緩沖液中釋放緩慢，有較好的緩釋效果。溶血實(shí)驗(yàn)得知，DTX-PGD納米粒無溶血現(xiàn)象，可采用靜脈注射法給藥。MTT結(jié)果表明，DTX-PGD納米粒對(duì)4T1細(xì)胞較多烯紫杉醇溶液具有更強(qiáng)的殺傷作用。結(jié)論 PGD樹狀大分子可以作為一種有效的穩(wěn)定劑應(yīng)用到多烯紫杉醇納米粒的制備中，DTX-PGD納米粒有望作為一種新型的藥物輸送系統(tǒng)應(yīng)用到癌癥的臨床治療中。

Objective To prepare docetaxel (DTX) nanoparticles with the codendrimer PGD as a stabilizer in order to enhance the solubility and bioavailability of DTX. Methods The DTX-PGD nanoparticles were prepared via the method of ultrasound precipitation combined high-pressure homogenization using codendrimer PAMAM-co-0.25OEG (PGD) as a stabilizer. The particle size and Zeta potential of DTX-PGD nanoparticles were measured by dynamic light scattering; The stability of DTX-PGD nanoparticles in normal saline solution, 5% glucose, PBS, and plasma were investigated at 37℃, along with the hemolysis rate of the nanoparticles. X-ray powder diffraction was used to detect the state of DTX in DTX-PGD nanoparticles. The in vitro release behavior of DTX-PGD nanoparticles was measured via dialysis method. MTT assay was employed to investigate the cytotoxicity of DTX-PGD nanoparticles towards 4T1 cells. Results The drug loading capacity (DL%) of DTX-PGD nanoparticles was 65.7%, the solubility of DTX was increased to 1.6 mg/mL. The mean diameter of nanoparticles was 270.4 nm, the PDI was 0.128, and the Zeta potential was 28.6 mV. The DTX-PGD nanoparticles were stable in glucose and plasma. The nanoparticles exhibited schistose morphology in SEM. The XRD spectra of DTX-PGD nanoparticles showed that DTX was present as crystal morphology in the nanoparticles. The release of DTX from nanoparticles was detected in PBS+0.5% SDS release medium and presented obvious controlled release behavior.There was no hemolytic phenomenon which means they were suitable for iv administration. MTT results showed that the nanoparticles exhibited higher cytoxicity for 4T1 cells compared with DTX solution. Conclusion In summary, PGD may be an effective stabilizer for the preparation of DTX-PGD nanoparticles and DTX-PGD nanoparticle is a promising drug delivery system for DTX application in clinic.

國家自然科學(xué)基金（NO. 21444003）；北京協(xié)和醫(yī)學(xué)院青年基金（NO. 33320140184）資助項(xiàng)目