Employment of polymeric nanomaterials in cancer therapeutics is actively pursued since they often enable drug administration with increased efficacy along with reduced toxic side effects. In this study, drug conjugated micellar constructs are fabricated using triblock dendron-linear polymer conjugates where a hydrophilic linear polyethylene glycol (PEG) chain is flanked by well-defined hydrophobic biodegradable polyester dendrons bearing an antiangiogenic drug, combretastatin-A4 (CA4). Variation in dendron generation is utilized to obtain a library of micellar constructs with varying sizes and drug loadings. In particular, a family of drug appended dendron-polymer conjugates based on polyester dendrons of generations ranging from G1 to G3 and 10 kDa linear PEG were obtained using [3 + 2] Huisgen type "click" chemistry. The final constructs benefit from PEG's hydrophilicity and antibiofouling character, as well as biodegradable nature of the hydrophobic polyester dendrons. The hydrophobic-hydrophilic-hydrophobic character of these constructs leads to the formation of flower-like micelles in aqueous media. In addition to generation-dependent subnanomolar range critical micelle concentrations, the resulting micelles possess hydrodynamic diameters suitable for passive tumor targeting through enhanced permeability and retention (EPR) effect; thereby they are suitable candidates as controlled drug delivery agents. For all constructs, in vitro cytotoxicities were investigated and inhibitory effect of Comb-G3-PEG on tube formation was shown on human umbilical vein endothelial cells (HUVECs).
Clickable" hydrogels were fabricated using dendron− polymer conjugate based triblock copolymers containing orthogonally functionalizable dendrons. Because of their well-defined chemical composition, the dendron-based hydrogels provide control over the number of reactive groups in the hydrogel so that the desired (bio)molecules can be immobilized with tailored density within the hydrogel matrix. Well-defined hydrogel precursors were obtained using the copper-catalyzed azide−alkyne "click" cycloaddition between second and third polyester dendrons bearing an alkyne group at their focal point and linear poly(ethylene glycol) (PEG) diazides PEG2kDa, PEG4kDa, and PEG6kDa. The surfaces of the outer dendron-based blocks were decorated with methacrylate and alkyne groups, the former necessary for photo-cross-linking, while the latter "clickable" alkyne groups would enable efficient postfunctionalization of hydrogels. The degree of cross-linking and the amount of reactive alkyne units available for postgelation functionalization of the hydrogels were tuned by adjusting the stoichiometry of the orthogonally reactive groups on the dendrons. Hydrogels containing alkyne groups were synthesized via photopolymerization with gelation efficiencies between 91 and 99%. Water uptake of these hydrogels in aqueous media could be tuned between 500 and 3010% by varying the length of PEG as well as generation and substitution of the dendrons. Successful covalent modification of these hydrogels via the azide−alkyne "click" reaction was demonstrated by attachment of the fluorescent dye bodipy and immobilization of the protein streptavidin onto biotinylated hydrogels. Importantly, it was demonstrated that the amount of protein immobilization can be tuned varying the amount of ligand incorporated in the hydrogel using the "clickable" alkyne-based reactive handles. Three-dimensional hydrogel micropatterns on silicon oxide surfaces were fabricated using either micromolding in capillaries or via photo-cross-linking using a photomask. These reactive micropatterns were amenable to efficient functionalization in a tailored manner by using the Huisgen-type "click" cycloaddition reaction.
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