posted on 2021-04-23, 17:35authored byZhaopei Guo, Yingying Hu, Mengyao Zhao, Kai Hao, Pan He, Huayu Tian, Xuesi Chen, Meiwan Chen
Chemo-immunotherapy combination effect
remains to be a great challenge
due to the poor tumor penetration of therapeutic agents that resulted
from condensed extracellular matrix (ECM), T cell-related immune escape,
and thus the potential recurrence. Herein, a helix self-assembly camptothecin
(CPT) prodrug with simultaneous physical and physiological tumor penetration
was constructed to realize effective chemo-immunotherapy. Specifically,
CPT was modified with arginine to self-assemble into nanofibers to
physically improve tumor penetration. Two plasmids, pshPD-L1 and pSpam1 for expressing small hairpin
RNA PD-L1 and hyaluronidase, respectively, were loaded to down-regulate
tumor surface PD-L1 expression for converting anergic state of T cells
into the tumor-reactive T cells and produce hyaluronidase to physiologically
degrade ECM for further enhanced tumor penetration. Moreover, the
degraded ECM could also increase immune cells’ infiltration
into tumor sites, which may exert a synergistic antitumor immunity
combined with immune checkpoint inhibition. Such a nanomedicine could
cause significant inhibition of primary, distant tumors, and effective
prevention of tumor recurrence.