Immune checkpoint blockade (ICB) strategy based on suppressing programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway has been proved to be promising and effective in cancer immunotherapy. However, its potential risk of immune-related adverse events (irAEs) places stringent requirements on the precise loading of anti-PD-L1 agent in nanomedicine. Precise control of the loading content of anti-PD-L1 antibody is a difficult task since physical encapsulation has inevitable drawbacks like batch-to-bath variation and chemical modification is limited by the low stability of the antibody. Herein, we proposed a molecular engineering strategy to develop the nanomedicine with precise control of anti-PD-L1 agent content by using anti-PD-L1 peptide (APP) as the substitute to anti-PD-L1 antibody. The APP was chemically bonded with a photosensitizer IR780 to obtain IR780-M-APP, a molecule able to self-assemble into nanoparticles (NPs) with a precise APP loading (48.4 wt%) determined by the molecular structure. Specifically, the IR780 moiety in IR780-M-APP NPs endows the nanoparticles with photodynamic therapeutic effect as well as the ability to trigger immunogenic cell death (ICD), while the APP moiety can block the PD-1/PD-L1 pathway for promoting immunotherapy. The proposed photodynamic-immunotherapy nanoplatform not only killed primary tumors directly but also eradicated the metastatic and invasive tumors effectively. The present molecular engineering strategy combined with anti-PD-L1 peptide might provide more opportunities for the design of advanced nanoplatforms for cancer therapy.
Nan Zhang,Jing Li,Wenxia Gao,Wangwei Zhu,Jianqin Yan,Ziyun He,Li Li,Fang Wu,Yuji Pu,Bin He
The combined delivery of chemotherapeutics with checkpoint inhibitors of the PD-1/PD-L1 pathway provides a new approach for cancer treatment. Small-molecule peptide inhibitors possess short production cycle, low immunogenicity, and fewer side effects; however, their potential in cancer therapy is hampered by the rapid biodegradation and a nanocarrier is needed for efficient drug delivery. Herein, anticancer drug doxorubicin (DOX) and PD-L1 inhibitor peptide P-12 are co-loaded by a lipid polymer nanocomplex based on poly(lactic-co-glycolic acid) (PLGA) and DSPE-PEG. Octaarginine (R8)-conjugated DSPE-PEG renders the LPN efficient internalization by cancer cells. The optimal nanomedicine LPN-30-R82K@DP shows a diameter of 125 nm and a DOX and P-12 loading content of 5.0 and 6.2%, respectively. LPN-30-R82K@DP exhibits good physiological stability and enhanced cellular uptake by cancer cells. It successfully induces immunogenic cell death and PD-L1 blockade in CT26 cancer cells. The in vivo antitumor study further suggests that co-loaded nanomedicine efficiently suppresses CT26 tumor growth and elicits antitumor immune response. This study manifests that lipid polymer nanocomplexes are promising drug carriers for the efficient chemo-immunotherapy of cancer.
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