Abstract
Biocompatible, environmentally responsive, and scalable nanocarriers are needed for targeted and triggered delivery of therapeutic proteins. Suitable polymers, preparation methods, and crosslinking chemistries must be considered for nanogel formation. Biocompatible dendritic polyglycerol (dPG) is used in the mild, surfactant-free inverse nanoprecipitation method for nanogel preparation. The biocompatible, fast, and bioorthogonal inverse electron demand Diels-Alder (iEDDA) crosslinking chemistry is used. In this work, the synthesis of pH-degradable nanogels, based on tetrazine, norbonene, and bicyclo[6.1.0]nonyne (BCN) functionalized macromonomers, is reported. The macromonomers are non-toxic up to 2.5 mg mL−1 in three different cell lines. Nanogels are obtained in the size range of 47 to 200 nm and can be degraded within 48 h at pH 4.5 (BA-gels), and pH 3 (THP-gels), respectively. Encapsulation of asparaginase (32 kDa) yield encapsulation efficiencies of up to 93% at 5 wt.% feed. Overall, iEDDA-crosslinked pH-degradable dPG-nanogels from inverse nanoprecipitation are promising candidates for biomedical applications.Graphical Schematic overview of formed ph-degradable Nanogels through inverse nanoprecipitation. Inverse electron demand Diels-Alder reaction was used as crosslinking method, using a pH-degradable Norbonene-/BCN- and Tetrazine-dPG as macromonomer basis
Highlights
Modern medicine has a high demand for new and smart nanocarrier systems for drug delivery, that improve pharmacokinetics, permit the use of less overall drug, reduce side effects, and lead to prolonged drug circulation time, and can deliver their cargo to diseased tissue and not to healthy tissue [1]
We present the synthesis of new pH-cleavable macromonomers based on the biocompatible and easy to functionalize dendritic polyglycerol (dPG) [12, 50,51,52] with methyl-tetrazine and the dienophiles norbonene and bicyclo[6.1.0]non-4-yne (BCN) as inverse electron demand Diels-Alder (iEDDA) reactive functional groups. pH degradability is introduced by incorporation of benzacetal (BA) and tetrahydropyran (THP)–based acetals into the macromonomers which cleave at pH values of 5 and 3, respectively
The synthetic focus of this work lies on the synthetic description of the pH-cleavable THP linker that was used, to our knowledge, for the first time and the different macromonomers that were obtained from the dPG-benzacetal- and dPG-THP-amine cores
Summary
Modern medicine has a high demand for new and smart nanocarrier systems for drug delivery, that improve pharmacokinetics, permit the use of less overall drug, reduce side effects, and lead to prolonged drug circulation time, and can deliver their cargo to diseased tissue and not to healthy tissue [1]. These carrier systems must be biocompatible and either biodegradable or be excreted by the body after delivering their cargo [2, 3]. Alternatives that provide the same advantages as PEG, but allow for a targeted delivery and release of the protein are needed
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