Boston University, Departments of Chemistry and Biomedical Engineering, Boston, Massachusetts 02215, United States.
Division of Thoracic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts 02114, United States.
Bioconjug Chem. 2024 Sep 18;35(9):1429-1440. doi: 10.1021/acs.bioconjchem.4c00325. Epub 2024 Aug 19.
Drug delivery to the esophagus through systemic administration remains challenging, as minimal drug reaches the desired target. Local delivery offers the potential for improved efficacy while minimizing off-target toxicities but necessitates bioadhesive properties for mucosal delivery. Herein, we describe the synthesis of two new mucoadhesive amphiphilic copolymers prepared by sequential ring-opening copolymerization or postpolymerization click conjugation. Both strategies yield block copolymers containing a hydrophilic amine-functionalized poly-amido-saccharide and either a hydrophobic alkyl derivatized poly-amido-saccharide or poly(lactic acid), respectively. The latter resulting copolymers readily self-assemble into spherical, ≈200 nm diameter, positively charged mucoadhesive nanoparticles. The NPs entrap ultrahigh levels of paclitaxel via encapsulation of free paclitaxel and paclitaxel conjugated to a biodegradable, biocompatible poly(1,2-glycerol carbonate). Paclitaxel-loaded NPs rapidly enter cells, release paclitaxel, are cytotoxic to esophageal OE33 and OE19 tumor cells in vitro, and, importantly, demonstrate improved mucoadhesion compared to conventional poly(ethylene glycol)-poly(lactic acid) nanoparticles to ex vivo esophageal tissue.
通过全身给药将药物递送到食管仍然具有挑战性，因为只有很少的药物能到达所需的靶标。局部给药具有提高疗效的潜力，同时最大限度地减少非靶毒性，但需要生物粘附特性来进行粘膜给药。本文描述了两种新的粘膜粘附两亲性嵌段共聚物的合成，这些共聚物是通过顺序开环共聚或聚合后点击接枝制备的。这两种策略分别得到含有亲水性胺官能化聚酰胺-多糖和疏水性烷基化聚酰胺-多糖或聚（乳酸）的嵌段共聚物。后者得到的共聚物容易自组装成直径约 200nm 的球形、带正电的粘膜粘附纳米颗粒。NP 通过包裹游离紫杉醇和连接到可生物降解、生物相容的聚（1,2-甘油碳酸酯）的紫杉醇来有效负载紫杉醇。载紫杉醇的 NP 迅速进入细胞，释放紫杉醇，对体外食管 OE33 和 OE19 肿瘤细胞具有细胞毒性，重要的是，与传统的聚（乙二醇）-聚（乳酸）纳米颗粒相比，它们在离体食管组织中表现出更好的粘膜粘附性。
