Photodynamic eradication of intratumoral microbiota with bacteria-targeted micelles overcomes gemcitabine resistance of pancreatic cancer

Abstract

Increasing evidence suggests that intratumoral microbiota plays a pivotal role in tumor progression, immunosurveillance, metastasis, and chemosensitivity. Particularly, in pancreatic ductal adenocarcinoma, tumor-resident Gammaproteobacteria could transform the chemotherapeutic drug gemcitabine (Gem) into its inactive form, thus rendering chemotherapy ineffective. Herein, a strategy for selectively eradicating intratumoral bacteria was described for overcoming Gem resistance in a pancreatic cancer animal model. An antimicrobial peptide was linked with photosensitizer through a poly (ethylene glycol) chain, which can self-assemble into micelles with a diameter of ∼20 nm. The micelles could efficiently kill bacteria under light irradiation by inducing membrane depolarization, thereby inhibiting Gem metabolism. In a bacteria-resident pancreatic cancer animal model, the selective photodynamic eradication of intratumoral bacteria was demonstrated to efficiently reverse Gem resistance. This research highlights antibacterial photodynamic therapy as a promising adjuvant strategy for cancer therapy by modulating intratumoral microbiota.

Keywords

antimicrobial peptide / gemcitabine resistance / intratumoral microbiota / pancreatic ductal adenocarcinoma / photodynamic antibacterial therapy

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