Journal
MOLECULAR PHARMACEUTICS
Volume 19, Issue 9, Pages 3439-3449Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.molpharmaceut.2c00611
Keywords
lipid/PLGA nanocomplexes; chemo-immunotherapy; L-peptide PD-L1 inhibitor; immunogenic cell death; cell-penetrating peptide
Funding
- National Natural Science Foundation of China [52073216, 51873121, 51773130]
- Natural Science Foundation of Zhejiang Province [LY20B040004]
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Lipid polymer nanocomplexes can serve as efficient drug carriers for chemo-immunotherapy of cancer. This study demonstrates their ability to efficiently internalize into cancer cells, induce immunogenic cell death, and block PD-L1, thus achieving antitumor effects.
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(WDP shows a diameter of 125 nm and a DOX and P-12 loading content of 5.0 and 6.2%, respectively. LPN-30-R82K(WDP 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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