| Popis: |
The delivery of biomacromolecular drugs to cytosolic targets has been a long-standing engineering challenge due to the presence of multiple biological barriers including cellular and endosomal membranes. Although many promising carriers designed to facilitate endosomal escape have been developed, the clinical translation of these carriers is often limited by complex production processes that are not amenable to scaled-up manufacturing. In this study, we employed flash nanoprecipitation (FNP) for the rapid, scalable, and reproducible assembly of nanocarriers composed of the pH-responsive, endosomolytic diblock copolymer poly[(ethylene glycol)x-block-[((2-diethylamino) ethyl methacrylate)0.6-co-(butyl methacrylate)0.4]y (PEG-b-DEAEMA-co-BMA). We found that varying the second block molecular weight, while holding the first block molecular weight constant, significantly influenced nanoparticle self-assembly and hence nanocarrier properties and function – including drug encapsulation, endosomolytic capacity, cytotoxicity, and in vitro activity of a cytosolically-active drug cargo, a cyclic dinucleotide (CDN) stimulator of interferon genes (STING) agonist. We found that while increasing second block molecular weight enhanced the capacity of nanocarriers to induce endosomal destabilization, larger second block molecular weights also lead to increased cytotoxicity, increased particle size and heterogeneity, increased the encapsulation efficiency of small ( |
