Journal
ADVANCED MATERIALS
Volume 34, Issue 49, Pages -Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/adma.202206765
Keywords
bacteria-mediated drug inactivation; dual-cascade responsive nanoparticles; pancreatic cancer; precise drug delivery; tumor-resident intracellular bacteria
Categories
Funding
- National Natural Science Foundation [21574008, 52003161]
- National Mega-project for Innovative Drugs [2019ZX09721001-007-002]
- Fundamental Research Funds for the Central Universities of China [BHYC1705B]
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This study presents a dual-cascade responsive nanoparticle that can sequentially trigger deep tumor penetration, killing of intratumor bacteria, and controlled release of chemo-drug in pancreatic cancer. The nanoparticle effectively addresses the limited drug penetration and robust bacteria-mediated drug inactivation issues. Additionally, it activates the immune response and enhances anticancer capacity.
The limited drug penetration and robust bacteria-mediated drug inactivation in pancreatic cancer result in the failure of chemotherapy. To fight against these issues, a dual-cascade responsive nanoparticle (sNP@G/IR) that can sequentially trigger deep penetration, killing of intratumor bacteria, and controlled release of chemo-drug, is reported. sNP@G/IR consists of a hyaluronic acid (HA) shell and glutathione (GSH)-responsive polymer-core (NP@G/IR), that encapsulates gemcitabine (Gem) and photothermal agent (IR1048). The polymer core, as an antibiotic alternative, is tailored to exert optimal antibacterial activity and selectivity. sNP@G/IR actively homes in on the tumor due to the CD44 targeting of the HA shell, which is subsequently degraded by the hyaluronidase in the extracellular matrix. The resultant NP@G/IR in decreased size and reversed charge facilitates deep tumor penetration. After cellular endocytosis, the exposed guanidine on NP@G/IR kills intracellular bacteria through disrupting cell membranes. Intracellular GSH further triggers the controlled release of the cargo. Thus, the protected Gem eventually induces cell apoptosis. Under laser irradiation, the hyperthermia of IR1048 helps further elimination of tumors and bacteria. Moreover, sNP@G/IR activates immune response, thereby reinforcing anticancer capacity. Therefore, this dual-cascade responsive sNP@G/IR eliminates tumor-resident intracellular bacteria and augments drug delivery efficacy, providing a new avenue for improving cancer therapy.
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