He Haiwei, Huang Nian, Qiu Zhiwen, He Lei, Guo Jiahao, Xu Mingjuan, Li Wei
Department of Obstetrics and Gynecology, Changhai Hospital, Naval Medical University, Shanghai, China.
Department of Integrative Medicine, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China.
J Gastrointest Oncol. 2023 Aug 31;14(4):1659-1668. doi: 10.21037/jgo-23-206. Epub 2023 Jul 11.
Paclitaxel (PTX) is widely used in the treatment of advanced esophageal and gastric cancer. Polymeric micelles can improve the drug-loading efficiency of PTX. However, the end groups on the amphiphilic blocks affect the drug-loading efficiency and the release kinetics of polymeric micelles. Therefore, there is an urgent need to disclose the tailoring of the core-/shell-forming terminal groups.
Different from the conventional block copolymer synthesis in the reversible addition-fragmentation chain-transfer polymerization, which has a hydrophilic end group on the core-forming blocks, an alternative monomer addition method was applied to tune and obtain two block copolymers with symmetrical and similar block length PBMA--PNAM [PNAM, poly(-acryloylmorpholine); PBMA, poly(-butyl methacrylate)] but distinct end groups on the hydrophobic core-forming blocks, that is, HOOC-PBMA-PNAM-Phen and HOOC-PNAM-PBMA-Phen. The chemical structure of the resulting copolymers was elucidated by proton nuclear magnetic resonance spectroscopy and differential scanning calorimetry. The spherical morphology revealed by transmission electron microscopy and the uniform particle size revealed by dynamic light scattering analysis clearly confirmed the successful preparation of a PTX-polymeric micelle complex.
The particle sizes of HOOC-PBMA-PNAM-Phen and HOOC-PNAM-PBMA-Phen were about 40 and 235 nm respectively. The PTX loading efficiency of HOOC-PBMA-PNAM-Phen was much lower than that of HOOC-PNAM-PBMA-Phen. The PTX release from HOOC-PBMA-PNAM-Phen was much slower than that of HOOC-PNAM-PBMA-Phen. The polymers had glass transition temperature () values of 70.24 and 74.22 ℃, which was from the HOOC-PBMA-PNAM-Phen and HOOC-PNAM-PBMA-Phen micelles, respectively. The systematic study on the PTX loading and releasing profile disclosed that, compared with the HOOC-PBMA-PNAM-Phen, the micelles with Phen group on the hydrophobic block (HOOC-PNAM-PBMA-Phen) enhanced drug loading and prolonged drug release but with a larger particle size.
The results indicated that the hydrophobic end group Phen on the core-forming blocks can promote hydrophobic drug loading and suppress burst release.
紫杉醇（PTX）广泛用于治疗晚期食管癌和胃癌。聚合物胶束可提高PTX的载药效率。然而，两亲性嵌段上的端基会影响聚合物胶束的载药效率和释放动力学。因此，迫切需要揭示形成核/壳的端基的剪裁方法。
与可逆加成-断裂链转移聚合中传统的嵌段共聚物合成不同，传统方法在形成核的嵌段上有一个亲水端基，本研究采用另一种单体添加方法来调节并获得两种具有对称且相似嵌段长度的PBMA-PNAM嵌段共聚物[PNAM，聚（丙烯酰基吗啉）；PBMA，聚（甲基丙烯酸丁酯）]，但在疏水的形成核的嵌段上有不同的端基，即HOOC-PBMA-PNAM-Phen和HOOC-PNAM-PBMA-Phen。通过质子核磁共振光谱和差示扫描量热法阐明所得共聚物的化学结构。透射电子显微镜显示的球形形态和动态光散射分析显示的均匀粒径清楚地证实了PTX-聚合物胶束复合物的成功制备。
HOOC-PBMA-PNAM-Phen和HOOC-PNAM-PBMA-Phen的粒径分别约为40和235 nm。HOOC-PBMA-PNAM-Phen的PTX载药效率远低于HOOC-PNAM-PBMA-Phen。HOOC-PBMA-PNAM-Phen的PTX释放比HOOC-PNAM-PBMA-Phen慢得多。聚合物的玻璃化转变温度（）值分别为70.24和74.22℃，分别来自HOOC-PBMA-PNAM-Phen和HOOC-PNAM-PBMA-Phen胶束。对PTX载药和释放曲线的系统研究表明，与HOOC-PBMA-PNAM-Phen相比，疏水嵌段上带有Phen基团的胶束（HOOC-PNAM-PBMA-Phen）提高了载药量并延长了药物释放，但粒径较大。
结果表明，形成核的嵌段上的疏水端基Phen可促进疏水性药物载药并抑制突释。
