Tailoring polymeric hybrid micelles with lymph node targeting ability to improve the potency of cancer vaccines

It has been widely accepted that lymph nodes (LNs) are critical targets of cancer vaccines and particles sized between 10 and 100 nm with a neutral or negative surface charge are preferred for lymphatic transfer after subcutaneous or intradermal injection. However their limited uptake by antigen presenting cells (APCs) and inadequate retention within LNs undoubtedly restrains their strength on activating T cell immunity. Here, we address this issue by tailoring the physicochemical properties of polymeric hybrid micelles (HMs), which are self-assembled from two amphiphilic diblock copolymers, poly-(ethylene glycol) phosphorethanolamine (PEG-PE) and polyethylenimine-stearic acid conjugate (PSA) via hydrophobic and electrostatic interactions. We successfully encapsulate melanoma antigen peptide Trp2 and Toll-like receptor-9 (TLR-9) agonist CpG ODN into HMs with a size of sub-30 nm. Their surface characteristics which are found closely related to their in vivo kinetics can be modulated by simply adjusting the molar ratio of PEG-PE and PSA. Our results demonstrated the optimized HMs with an equal mol of PEG-PE and PSA can potently target proximal LNs where their cargos are efficiently internalized by DCs. Furthermore, HMs mediated Trp2/CpG delivery system greatly expands antigen specific cytotoxic T lymphocytes (CTLs) and offers a strong anti-tumor effect in a lung metastatic melanoma model.