Abstract
The therapeutic effect of chemotherapeutics such as gemcitabine against pancreatic cancer is considerably attenuated by immune-suppressive tumor microenvironment. Improvement of chemotherapeutic efficacy by targeting tumor-associated macrophage and reprograming tumor microenvironment to enhance their efficacy may become a promising strategy. To this end, we developed a biomimetic dual-targeting nanomedicine (PG@KMCM) where gemcitabine-loaded poly (lactic-co-glycolic acid) (PLGA) nanoparticles are coated with a layer of bioengineered cancer cell membrane that stably expresses peptides targeting M2-like macrophages (M2pep) while reserving tumor-associated antigens (TAAs). The PG@KMCM nanomedicine enables the simultaneous targeted delivery of gemcitabine to pancreatic tumor sites and TAMs to potentiate its therapeutic effects. Furthermore, the combination of an immune checkpoint inhibitor (PD-L1 antibody) with PG@KMCM synergistically enhanced the anti-tumoral effect by reprogramming the immune-suppressive tumor microenvironment, including the elimination of PD-L1-positive macrophages and the downregulation of PD-L1 expression. Our study proved dual-targeting PG@KMCM nanomedicine in combination with PD-L1 immune checkpoint inhibitor therapy is able to effectively reprogram the tumor microenvironment and kill pancreatic cancer cells to enhance overall therapeutic potential.Graphical
Highlights
The close crosstalk between pancreatic cancer and its tumor microenvironment complicates carcinogenesis and tumor progression [1,2,3], which significantly compromise the therapeutic potential of both conventional chemotherapies and other new therapies
Successful fabrication of gemcitabine nanomedicine with exogenously bioengineered cancer cell membrane Biomimetic nano-system assembled from the cell membrane and the core nanoparticle inherits key features from both components [18, 19]
To acquire the membrane expressing the M2pep peptide verified with high affinity to Tumor-associated macrophages (TAMs) (Additional file 1: Fig. S1), we developed an efficient exogenous bioengineering strategy, by obtaining cell membrane from the lysed KPC cells which were stably transfected with M2pep-encoding lentivirus (Scheme 1)
Summary
The close crosstalk between pancreatic cancer and its tumor microenvironment complicates carcinogenesis and tumor progression [1,2,3], which significantly compromise the therapeutic potential of both conventional chemotherapies and other new therapies. Realtime in vivo fluorescent distribution studies showed that the biomimetic PG@KMCM and PG@KCM both accumulated in pancreatic xenograft tumors even after 24 h post tail-vein administration, while the non-biomimetic PG treatment only resulted in liver distribution (Fig. 3a), benefiting from the homing nature of the cancer cell membrane [20].
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