Stimuli‐responsive nanoparticles for the codelivery of chemotherapeutic agents doxorubicin and siPD‐L1 to enhance the antitumor effect

Abstract

Cancer cells have been reported to exhibit high resistance against immune system recognition through various cell intrinsic and extrinsic mechanisms. Considerable challenges have been encountered in monotherapy with chemotherapeutics to attain the desired antitumor efficacy. In this study, a nanodelivery system was designed to incorporate doxorubicin (DOX) and programmed death‐ligand 1 (PD‐L1) small interfering RNA (siRNA), that is, siPD‐L1. DOX and siPD‐L1 were formed from a stimuli‐responsive polymer with a poly‐L‐lysine–lipoic acid reduction‐sensitive core and a tumor extracellular pH‐stimulated shedding polyethylene glycol layer. The codelivery system was stable under physiological pH conditions and demonstrated enhanced cellular uptake at the tumor site. Moreover, the combined treatment of DOX and siPD‐L1 exhibited improved antitumor effect in vitro and in vivo compared with either modality alone. The combination of chemotherapy and immunotherapy presented in this work through the codelivery of a chemotherapeutic agent and a gene‐silencing agent (siRNA) may provide a new strategy for cancer treatment.

PD-L1 siRNA Theranostics With a Dextran Nanoparticle Highlights the Importance of Nanoparticle Delivery for Effective Tumor PD-L1 Downregulation

“…In another study, PLGA NPs simultaneously delivered PD-1 and PD-L1 siRNA, silencing these genes in cytotoxic T lymphocytes and tumor cells in a colon murine model ( 43 ). A polymer containing a poly-L-lysine-lipoic acid reduction-sensitive core and a tumor extracellular pH-stimulated shedding polyethylene glycol layer was used to co-deliver PD-L1 siRNA and doxorubicin in a melanoma model with promising results ( 44 ). Silencing the expression of PD-L1 in dendritic cells (DCs) and of PD-1 in T cells by siRNA-loaded chitosan-dextran sulfate nanoparticles was recently described ( 45 ).…”

Targeting the PD-1/PD-L1 axis for cancer treatment: a review on nanotechnology

“…In another work, doxorubicin and PD-L1 siRNA were loaded into a stimuli-responsive polymer with a poly-L-lysine–lipoic acid reduction-sensitive core and a tumour extracellular pH-stimulated shedding polyethylene glycol layer. This NP accumulated selectively to tumour site, downregulated the PD-L1 expression, increased the CD8 + T cells population in the tumour and reduced the tumour size ( figure 3 a ) [ 32 ]. Toward the treatment using chemo-immunotherapy, Wan et al co-delivered siRNA-PD-L1 and doxorubicin in a reactive oxygen species responsive NP, modified with the HAIYPRH peptide that targets to transferrin receptor.…”

Nucleic Acid-Based Approaches for Tumor Therapy

“…Systemic toxicity can be reduced by targeted delivery of checkpoint inhibitors using NPs and by nucleic acid-based approaches [ 442 ]. Concerning the latter, mRNA encoding for an anti-CTLA-4 antibody [ 445 ], pDNA encoding for PD-L1 traps [ 386 , 446 , 447 ], siRNA specific for PD-L1 [ 448 , 449 , 450 , 451 , 452 ], and CRISPR/Cas9-mediated knock-out of the PD-1 gene in CAR-T cells [ 453 , 454 ] have been tested so far ( Figure 3 ).…”

“…A further combination approach was conducted by Zhou et al by combined administration of doxorubicin and of PD-L1-specific siRNA delivered by stimuli-responsive NPs in a B16 melanoma tumor model [ 452 ]. These NPs were dually sensitive towards the extracellular slightly acidic pH of tumor cells (pH-triggered detachment of the PEG layer) and their elevated intracellular redox potential (reduction-sensitive polymer core of poly-L-lysine–lipoic acid).…”