Journal
NANO LETTERS
Volume 21, Issue 9, Pages 3721-3730Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.nanolett.0c04772
Keywords
Camptothecin prodrug; nanofiber; chemo-immunotherapy; gene therapy
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Funding
- National Natural Science Foundation of China [51922111, 51803014]
- Science and Technology Development Fund, Macau SAR [083/2017/A2]
- National Science and Technology Major Projects for Major New Drugs Innovation and Development [2018ZX09711003-012]
- University of Macau [MYRG2017-00182-ICMS]
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The combination of chemo-immunotherapy is challenging due to poor tumor penetration of therapeutic agents. A new strategy using a helix self-assembly camptothecin prodrug combined with plasmids to down-regulate tumor surface PD-L1 expression and degrade ECM showed significant inhibition of tumor growth and prevention of recurrence.
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.
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