目的 合成透明質(zhì)酸（HA）接枝單油酸甘油酯（GMO）兩親性聚合物HGO，并研究其所制備載阿霉素（DOX）納米粒的理化性質(zhì)及體外抗腫瘤效果。方法 HA與GMO通過(guò)酯化反應(yīng)制得載體聚合物HGO，通過(guò)核磁共振波譜法及紅外光譜法對(duì)其進(jìn)行結(jié)構(gòu)表征；采用芘熒光探針?lè)y(cè)定聚合物臨界聚集濃度（CAC）。采用透析法制備聚合物HGO載阿霉素（DOX@HGO）納米粒，并對(duì)其進(jìn)行粒徑分布、Zeta電位及微觀形態(tài)的表征；通過(guò)檢測(cè)其在不同離子強(qiáng)度、不同pH條件下的粒徑變化考察納米粒的體外穩(wěn)定性；考察DOX@HGO納米粒在不同pH條件下的體外釋放行為；CCK-8法考察DOX@HGO納米粒對(duì)MDA-MB-231細(xì)胞的體外抑瘤效果；并通過(guò)熒光顯微鏡研究MDA-MB-231細(xì)胞對(duì)DOX溶液、DOX@HGO納米粒的攝取能力，以及HA預(yù)處理對(duì)DOX@HGO納米粒攝取的影響。結(jié)果 成功制得兩親性聚合物HGO，聚合物HGO中GMO的取代度為15.8%，CAC為0.023 mg·mL^-1。DOX@HGO納米粒呈規(guī)則的球形，平均粒徑為（130.800±1.709）nm，平均電位為（-32.600±0.153）mV，包封率和載藥量分別為（98.65±0.74）%和（33.03±0.17）%，在不同離子強(qiáng)度下、模擬胃腸液中表現(xiàn)出良好的穩(wěn)定性；DOX@HGO納米粒的體外釋放表現(xiàn)出pH依賴(lài)性。體外抗腫瘤活性實(shí)驗(yàn)表明，DOX@HGO納米粒對(duì)MDA-MB-231細(xì)胞的生長(zhǎng)具有較好的抑制作用；與DOX溶液比較，DOX@HGO納米粒顯著增加腫瘤細(xì)胞對(duì)于DOX的攝?。?i>P＜0.05） ，HA預(yù)處理顯著減少腫瘤細(xì)胞對(duì)DOX@HGO的攝?。?i>P＜0.05）。結(jié)論 所構(gòu)建的DOX@HGO納米粒具有良好的理化性質(zhì)，并且具有一定的pH敏感性及靶向抗腫瘤細(xì)胞的能力，是具有應(yīng)用潛力的藥物載體。

Objective To prepare an amphiphilic polymer HGO of hyaluronic acid (HA) grafted glyceryl monooleate (GMO), study the physicochemical properties of doxorubicin (DOX) loaded nanoparticles and determine the physicochemical properties as well as in vitro antitumor effect. Methods HA and GMO were esterified to prepare the carrier polymer HGO, and the structure of the polymer was characterized by ¹H-NMR and FT-IR. The critical aggregate concentration (CAC) was determined by pyrene fluorescence method. The hyaluronic acid grafted glyceryl monooleate loaded DOX nanoparticles (DOX@HGO) were prepared by dialysis method, and their particle size distribution, Zeta potential and micromorphology were characterized. The in vitro stability of the nanoparticles was investigated by the particle size changes under different ionic strengths and pH conditions. The drug release behaviors of the nanoparticles were examined under different pH. The in vitro antitumor effect of drug loaded nanoparticles were evaluated by CCK-8 method. The cellular uptake of DOX and DOX@HGO and effect of HA pre-treatment on DOX@HGO nanoparticle uptake was investigated under fluorescence microscope. Results The amphiphilic polymer HGO was successfully prepared, and the substitution degree of GMO in polymer HGO was 15.8%, the CAC was 0.023 mg·mL^-1. DOX@HGO nanoparticles showed a regular spherical shape, with an average particle size of (130.800 ±1.709) nm, an average potential of (-32.600 ±0.153) mV, an encapsulation efficiency of (98.65 ±0.74)% and a drug loading capacity of (33.03 ±0.17)%, respectively. The polymeric nanoparticles showed good stability under different ionic strengths and simulated gastrointestinal fluid dilution. Moreover, the in vitro release of DOX@HGO nanoparticles indicated pH dependent behavior. In vitro antitumor activity experiments showed that DOX@HGO nanoparticles had a good inhibitory effect on the growth of MDA-MB-231 cells and could significantly improve the cellular uptake of DOX by tumor cells. Compared with DOX solution, DOX@HGO nanoparticle significantly increased the uptake of DOX by tumor cells (P < 0.05), and HA pretreatment significantly reduced the uptake of DOX@HGO by tumor cells (P < 0.05). Conclusion The DOX@HGO nanoparticles prepared in this study have good physicochemical properties, excellent pH sensitivity and great anti-tumor targeting effects, which exhibited great application potential in drug delivery systems.

國(guó)家自然科學(xué)基金面上項(xiàng)目（82074030）；國(guó)家自然科學(xué)基金青年項(xiàng)目（82104568）；天津市教委科研計(jì)劃項(xiàng)目（2020KJ195）