Journal
ACS APPLIED MATERIALS & INTERFACES
Volume 13, Issue 15, Pages 18033-18046Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsami.1c02567
Keywords
copper-free click chemistry; nanoparticle aggregation; tumor retention; immuno-chemotherapy; NK cells
Funding
- National Natural Science Foundation of China [81773658]
- Program Sichuan Veterinary Medicine and Drug Innovation Group of China Agricultural Research System [SCCXTD-2020-18]
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The study introduced a pH-responsive self-aggregated nanoparticle for the co-delivery of chemotherapy drugs and signaling pathway inhibitors, which could quickly aggregate in the tumor microenvironment and enhance tumor retention. The combination of chemotherapy and immunotherapy using this strategy showed significant efficacy in melanoma treatment.
Natural killer (NK) cell-based immunotherapy presents a promising antitumor strategy and holds potential for combination with chemotherapy. However, the suppressed NK cell activity and poor tumor retention of therapeutics hinder the efficacy. To activate NK cell-based immuno-chemotherapy and enhance the tumor retention, we proposed a pH-responsive self-aggregated nanoparticle for the codelivery of chemotherapeutic doxorubicin (DOX) and the transforming growth factor-beta (TGF-beta)/Smad3 signaling pathway inhibitor SIS3. Polycaprolactone-poly(ethylene glycol) (PCL-PEG(2000)) micelles modified with dibenzylcyclooctyne (DBCO) or azido (N-3) and coated with acid-cleavable PEG(5000) were established. This nanoplatform, namely, M-DN@DOX/SIS3, could remain well dispersed in the neutral systemic circulation, while quickly respond to the acidic tumor microenvironment and intracellular lysosomes, triggering copper-free click reaction-mediated aggregation, leading to the increased tumor accumulation and reduced cellular efflux. In addition, the combination of DOX with SIS3 facilitated by the aggregation strategy resulted in potent inhibition of melanoma tumor growth and significantly increased NK cells, NK cell cytokines, and antitumor T cells in the tumor. Taken together, our study offered a new concept of applying copper-free click chemistry to achieve nanoparticle aggregation and enhance tumor retention, as well as a promising new combined tumor treatment approach of chemotherapy and immunotherapy.
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