Immuno-modulation of tumor and tumor draining lymph nodes through enhanced immunogenic chemotherapy by nano-complexed hyaluronic acid/polyvinyl alcohol microneedle

Abstract

Certain chemo-drugs could induce immunogenic cell death (ICD) activating T cell antitumor immunity while trigger indoleamine-2,3-dioxygenase (IDO) upregulation suppressing immune responses. Moreover, to achieve therapeutic efficacies on both primary tumors and tumor draining lymph nodes (TDLNs) in the meantime is still a big challenge. In this study, transfersomes functionalized with a tumor targeting, cell penetrating peptide tLyp1 (CGNKRTR) was developed to co-encapsulate doxorubicin (DOX, ICD inducer) and 1MT (IDO inhibitor). The functionalized transfersomes were complexed with microneedles (MNs) to realize co-delivery towards primary tumors and TDLNs via transdermal administration. The transfersomes were concentrated in the needles of MNs and released with needle dissolution after insertion into skin. After being internalized by cells, DOX induced tumor ICD effect to promote DCs maturation and dramatically activated cytotoxic T lymphocytes (CD8+ T), while 1MT inhibited IDO activity in DCs and reduced the immunosuppressive Tregs, thus mitigating tumor suppressive microenvironment. The nano-complexed microneedles exhibited 2.2-fold suppression in tumor growth compared with the I.V. group, which significantly enhanced anti-tumor effect.