posted on 2024-01-16, 22:34authored bySoonbum Kwon, Fanfei Meng, Hassan Tamam, Hytham H. Gadalla, Jianping Wang, Boyang Dong, Amber S. Hopf Jannasch, Timothy L. Ratliff, Yoon Yeo
Local delivery of immune-activating agents has shown
promise in
overcoming an immunosuppressive tumor microenvironment (TME) and stimulating
antitumor immune responses in tumors. However, systemic therapy is
ultimately needed to treat tumors that are not readily locatable or
accessible. To enable systemic delivery of immune-activating agents,
we employ poly(lactic-co-glycolide) (PLGA) nanoparticles
(NPs) with a track record in systemic application. The surface of
PLGA NPs is decorated with adenosine triphosphate (ATP), a damage-associated
molecular pattern to recruit antigen-presenting cells (APCs). The
ATP-conjugated PLGA NPs (NPpD-ATP) are loaded with paclitaxel
(PTX), a chemotherapeutic agent inducing immunogenic cell death to
generate tumor antigens in situ. We show that the
NPpD-ATP retains ATP activity in hostile TME and provides
a stable “find-me” signal to recruit APCs. Therefore,
the PTX-loaded NPpD-ATP helps populate antitumor immune
cells in TME and attenuate the growth of CT26 and B16F10 tumors better
than a mixture of PTX-loaded NPpD and ATP. Combined with
anti-PD-1 antibody, PTX-loaded NPpD-ATP achieves complete
regression of CT26 tumors followed by antitumor immune memory. This
study demonstrates the feasibility of systemic immunotherapy using
a PLGA NP formulation that delivers ICD-inducing chemotherapy and
an immunostimulatory signal.