Abstract
Metastatic cancer is a persistent clinical enigma, which requires combination of several treatment modules. Here, we developed an all-in-one nanomedicine strategy to systemically co-deliver photosensitive, chemotherapeutic, and immunomodulating agents for effective immunochemo-photothermal therapy (PTT) to inhibit both primary tumor and distal metastatic tumor. Two types of polydopamine (dp)-coated nanoparticles (NPs) (N/PGEM/dp-5 and N/PGEM/dp-16) co-loaded with gemcitabine (GEM) and NLG919, a potent indoleamine-2, 3-dioxygenase (IDO) inhibitor, were prepared. N/PGEM/dp-16 NPs with a thicker dp coating layer showed higher photothermal conversion ability, more favorable biodistribution profile and better tumor inhibition effect compared to N/PGEM/dp-5 NPs with a thinner coating layer. Combination with laser irradiation further enhanced the tumor inhibition effect of N/PGEM/dp-16 NPs. In an "early metastatic" pancreatic cancer PANC02 model with small distal tumors, introduction of NLG and dp coating improved the inhibition effect on both primary and distal tumors. Compared to N/PGEM/dp-16, N/PGEM/dp-16 plus laser irradiation further enhanced the inhibition effect on primary tumor, but didn't improve the abscopal antitumor effect. When the initial volume of distal tumor was sufficiently large in a "late metastasis" model, a more dramatic abscopal antitumor effect was achieved, resulting in a significant growth inhibition of both primary tumor and the unirradiated distal tumor. Furthermore, laser irradiation can amplify the immunochemo-NPs-mediated innate and adaptive immune responses in both tumors. This work demonstrated a distal tumor-size dependent abscopal effect, and provided a perspective for future design of more effective immunochemo-PTT nano-formulations for early- and late-stage metastatic tumors.