Co-Delivery of Doxorubicin and Anti-PD-L1 Peptide in Lipid/PLGA Nanocomplexes for the Chemo-Immunotherapy of Cancer

Abstract

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.

A lipid/PLGA nanocomplex to reshape tumor immune microenvironment for colon cancer therapy

“…RGD and DPPA were used to modify the nanoparticles to target tumor cells and block PD-L1, respectively. PLGA was synthesized by ring-opening polymerization [ 36 ], DSPE-PEG-RGD and DSPE-PEG-DPPA were synthesized by click reaction of maleimide in DSPE-PEG-Mal with sulfhydryl in RGD or DPPA according to our previous study [ 32 ]. The MMP-2 cleavage activity of DSPE-PEG-DPPA was shown in Supplementary Figure S1 .…”

“…1,2-Distearoyl-snglycero-3-phosphoethanolamine-N-methoxy (poly (ethylene glycol)-2000) (DSPE-PEG) and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-maleimide (poly (ethylene glycol)-2000) (DSPE-PEG-Mal) were purchased from Laysan Bio, Inc (AL 35016, Arab). Poly (DL-lactic-co-glycolic acid) (PLGA), DSPE-PEG-RGD and DSPE-PEG-DPPA were synthesized according to our previous study [ 32 , 36 ]. 1-Methyl-D-tryptophan (1MT) was obtained from Selleck (Shanghai, China).…”

“…And 1MT concentration was performed through high performance liquid chromatography (HPLC) [ 38 , 39 ]. The drug loading content (DLC) was analyzed according our previously reports [ 32 ].…”

“…Nano-drug delivery systems are designed to prolong the circulation time of drugs in vivo , enable targeted delivery of multiple therapeutics to tumor sites and tumor-specific payload release [ 26–31 ]. Lipid/polymer nanocomplex is a promising nano-drug delivery system that combines the advantages of liposomes and polymer nanoparticles such as high drug loading, good biocompatibility, and easy manufacturing process [ 32–35 ].…”

Nano-Delivery of Immunogenic Cell Death Inducers and Immune Checkpoint Blockade Agents: Single-Nanostructure Strategies for Enhancing Immunotherapy

“…Zhang et al developed lipid/PLGA nanocomplexes (LPNs) for combination therapy using DOX and PD-L1 blockade [ 55 ]. They encapsulated DOX and the anti-PD-L1 peptide P-12 within PLGA and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-(polyethylene glycol) (DSPE-PEG) nanocomplexes, which were further surface-modified with a cell-penetrating peptide, octaarginine (LPN-30-R8 2k @DP) ( Figure 2 A).…”