Pulmonary Delivery of Nanoparticle-Bound Toll-Like Receptor 9 Agonist for the Treatment of Metastatic Lung Cancer.

CpG oligodeoxynucleotides (ODNs) are potent toll-like receptor (TLR) 9 agonists and have shown promise as anti-cancer agents in preclinical studies and clinical trials. Binding of CpG to TLR9 initiates a cascade of innate and adaptive immune responses, beginning with activation of dendritic cells, and resulting in a range of secondary effects that include the secretion of pro-inflammatory cytokines, activation of natural killer (NK) cells, and expansion of T cell populations. Recent literature suggests that local delivery of CpG in tumors results in superior antitumor effects as compared to systemic delivery. In this study, we utilized PRINT (particle replication in non-wetting templates) nanoparticles as a vehicle to deliver CpG into murine lungs through orotracheal instillations. In two orthotopic metastasis models of non-small cell lung cancer (NSCLC) - 344SQ (lung adenocarcinoma) and KAL-LN2E1 (lung squamous carcinoma), local delivery of PRINT-CpG into the lungs effectively promoted substantial tumor regression and also limited systemic toxicities associated with soluble CpG. Furthermore, cured mice were completely resistant to tumor re-challenge. Additionally, nano-delivery showed extended retention of CpG within the lungs as well as elevated anti-tumor cytokines. These results demonstrate that PRINT-CpG is a potent nanoplatform for local treatment of lung cancer that has collateral therapeutic effects on systemic disease, an encouraging toxicity profile, and may have the potential to treat lung metastasis of other cancer types.