Xu Leyuan, Cooper Remy C, Wang Juan, Yeudall W Andrew, Yang Hu
Department of Chemical and Life Science Engineering, Virginia Commonwealth University, 737 North 5 Street, Richmond, Virginia 23219, United States.
Department of Biomedical Engineering, 601 West Main Street, Virginia Commonwealth University, Richmond, Virginia 23284, United States.
ACS Biomater Sci Eng. 2017 Aug 14;3(8):1641-1653. doi: 10.1021/acsbiomaterials.7b00166. Epub 2017 Jun 21.
We developed novel dendrimer hydrogels (DH)s on the basis of bioorthogonal chemistry, in which polyamidoamine (PAMAM) dendrimer generation 4.0 (G4) functionalized with strained alkyne dibenzocyclooctyne (DBCO) via PEG spacer (M = 2,000 g/mol) underwent strain-promoted azide-alkyne cycloaddition (SPAAC) with polyethylene glycol bisazide (PEG-BA) (M= 20,000 g/mol) to generate a dendrimer-PEG cross-linked network. This platform offers a high degree of functionality and modularity. A wide range of structural parameters including dendrimer generation, degree of PEGylation, loading density of clickable DBCO groups, PEG-BA chain length as well as the ratio of clickable dendrimer to PEG-BA and their concentrations can be readily manipulated to tune chemical and physical properties of DHs. We used this platform to prepare an injectable liquid DH. This bioorthogonal DH exhibited high cytocompatibility and enabled sustained release of the anticancer drug 5-fluorouracil (5-FU). Following intratumoral injection, the DH/5-FU formulation significantly suppressed tumor growth and improved survival of HN12 tumor-bearing mice by promoting tumor cell death as well as by reducing tumor cell proliferation and angiogenesis.
我们基于生物正交化学开发了新型树枝状大分子水凝胶（DH），其中通过聚乙二醇间隔基（M = 2000 g/mol）用应变炔基二苯并环辛炔（DBCO）功能化的第4.0代聚酰胺-胺（PAMAM）树枝状大分子（G4）与聚乙二醇双叠氮化物（PEG-BA）（M = 20000 g/mol）进行应变促进的叠氮化物-炔烃环加成反应（SPAAC），以生成树枝状大分子-聚乙二醇交联网络。该平台具有高度的功能性和模块化。包括树枝状大分子代数、聚乙二醇化程度、可点击DBCO基团的负载密度、PEG-BA链长以及可点击树枝状大分子与PEG-BA的比例及其浓度在内的广泛结构参数可以很容易地进行调控，以调节DH的化学和物理性质。我们使用该平台制备了一种可注射的液体DH。这种生物正交DH表现出高细胞相容性，并能够实现抗癌药物5-氟尿嘧啶（5-FU）的持续释放。瘤内注射后，DH/5-FU制剂通过促进肿瘤细胞死亡以及减少肿瘤细胞增殖和血管生成，显著抑制了肿瘤生长并提高了荷HN12肿瘤小鼠的存活率。
