TY - JOUR
T1 - Synthesis and Application of Injectable Bioorthogonal Dendrimer Hydrogels for Local Drug Delivery
AU - Xu, Leyuan
AU - Cooper, Remy C.
AU - Wang, Juan
AU - Yeudall, William Andrew
AU - Yang, Hu
N1 - Funding Information:
This work was supported, in part, by the National Science Foundation (CAREER award CBET0954957) and the National Institutes of Health (R01EY024072 and R01DE024381).
Publisher Copyright:
© 2017 American Chemical Society.
PY - 2017/8/14
Y1 - 2017/8/14
N2 - We developed novel dendrimer hydrogels (DHs) on the basis of bioorthogonal chemistry, in which polyamidoamine (PAMAM) dendrimer generation 4.0 (G4) functionalized with strained alkyne, i.e., dibenzocyclooctyne (DBCO), via a PEG spacer (Mn = 2000 g/mol) underwent strain-promoted azide-alkyne cycloaddition (SPAAC) with polyethylene glycol bisazide (PEG-BA) (Mn= 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 the chemical and physical properties of bioorthogonal DHs. We used this platform to prepare an injectable liquid DH. This bioorthogonal DH exhibited high cytocompatibility and enabled the sustained release of the physically loaded anticancer drug 5-fluorouracil (5-FU). Following intratumoral injection, the DH/5-FU formulation significantly suppressed tumor growth and improved the survival of HN12 tumor-bearing mice by promoting tumor cell death as well as by reducing tumor cell proliferation and angiogenesis.
AB - We developed novel dendrimer hydrogels (DHs) on the basis of bioorthogonal chemistry, in which polyamidoamine (PAMAM) dendrimer generation 4.0 (G4) functionalized with strained alkyne, i.e., dibenzocyclooctyne (DBCO), via a PEG spacer (Mn = 2000 g/mol) underwent strain-promoted azide-alkyne cycloaddition (SPAAC) with polyethylene glycol bisazide (PEG-BA) (Mn= 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 the chemical and physical properties of bioorthogonal DHs. We used this platform to prepare an injectable liquid DH. This bioorthogonal DH exhibited high cytocompatibility and enabled the sustained release of the physically loaded anticancer drug 5-fluorouracil (5-FU). Following intratumoral injection, the DH/5-FU formulation significantly suppressed tumor growth and improved the survival of HN12 tumor-bearing mice by promoting tumor cell death as well as by reducing tumor cell proliferation and angiogenesis.
KW - chemotherapy
KW - copper-free click chemistry
KW - hydrogel
KW - local drug delivery
KW - nanomedicine
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U2 - 10.1021/acsbiomaterials.7b00166
DO - 10.1021/acsbiomaterials.7b00166
M3 - Article
AN - SCOPUS:85027244722
SN - 2373-9878
VL - 3
SP - 1641
EP - 1653
JO - ACS Biomaterials Science and Engineering
JF - ACS Biomaterials Science and Engineering
IS - 8
ER -