Small molecules agonists of Toll-like receptors 7/8 (TLR7/8), such as imidazoquinlines, are potent activators of the innate immune system and hold promise as vaccine adjuvant and for anticancer immunotherapy. However, uncontrolled systemic inflammatory immune triggering hampers clinical translation of imidazoquinoline TLR7/8 agonists. To circumvent this issue, we conjugated an imidazolquinoline TLR7/8 agonist to amphiphilic lipid–polymer conjugates. These compounds bind to serum proteins and show a strong tendency to accumulate in lymphoid tissue upon local administration. Hence, systemic immune activation is dramatically suppressed, and innate immune activation is restricted to draining lymphoid tissue. We provide a rational base of the design of lipid–polymer amphiphiles, evaluating different kinds of lipid, polymer backbone and linker chemistry and correlate amphiphile design to cellular uptake in vitro and lymphatic translocation and innate activation in vivo.

Lymphatic translocation and spatial control over innate immune activation by polymer lipid amphiphile conjugates of small molecule immunomodulators

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.