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Amphiphilic Polyelectrolyte Graft Copolymers Enhance the Activity of Cyclic Dinucleotide STING Agonists
Author(s) -
Nguyen Dinh Chuong,
Shae Daniel,
Pagendarm Hayden M.,
Becker Kyle W.,
Wehbe Mohamed,
Kilchrist Kameron V.,
Pastora Lucinda E.,
Palmer Christian R.,
Seber Pedro,
Christov Plamen P.,
Duvall Craig L.,
Wilson John T.
Publication year - 2021
Publication title -
advanced healthcare materials
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.288
H-Index - 90
eISSN - 2192-2659
pISSN - 2192-2640
DOI - 10.1002/adhm.202001056
Subject(s) - intracellular , endosome , cytosol , copolymer , ethylene glycol , stimulator of interferon genes , sting , amphiphile , drug carrier , conjugate , in vivo , drug delivery , peg ratio , polyelectrolyte , biophysics , chemistry , polymer , materials science , nanotechnology , biochemistry , biology , organic chemistry , enzyme , mathematics , aerospace engineering , mathematical analysis , engineering , microbiology and biotechnology , finance , economics
Cyclic dinucleotide (CDN) agonists of stimulator of interferon genes (STING) hold great therapeutic potential, but their activity is hindered by poor drug‐like properties that restrict cytosolic bioavailability. Here, this challenge is addressed through the synthesis and evaluation of a novel series of PEGMA‐ co ‐DEAEMA‐ co ‐BMA copolymers with pH‐responsive, membrane‐destabilizing activity to enhance intracellular delivery of the CDN, cGAMP. Copolymers are synthesized with PEGMA of two different molecular weights (300 and 950 Da) and over a range of PEG mass fraction and polymer molecular weight, and relationships between copolymer structure, self‐assembly, endosomal escape, and cGAMP activity are elucidated. A subset of polymers that self‐assembled into 50–800 nm nanoparticles is identified, which can be loaded with cGAMP via a simple mixing strategy, resulting in significantly enhanced immunostimulatory activity. Increased cGAMP activity is found to be highly correlated with the capacity of carriers to enhance intracellular CDN uptake and to promote endosomal destabilization, findings that establish efficient cytosolic delivery as a criterion for CDN carriers. Additionally, it is demonstrated that a lead CDN carrier formulation can enhance STING activation in vivo in a model of intratumoral immunotherapy. Collectively, these investigations demonstrate the utility of PEGMA‐ co ‐DEAEMA‐ co ‐BMA copolymers as carriers for CDNs and potentially other cytosolically‐acting drug cargo.