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Quercetin Remodels the Tumor Microenvironment To Improve the Permeation, Retention, and Antitumor Effects of Nanoparticles
Open accessAbstract
Our previous work demonstrated that Wnt16 expression in cisplatin-damaged tumor-associated fibroblasts is a key factor contributing to cisplatin resistance in malignancies. Natural antifibrotic compounds with low toxicities are promising candidates to downregulate Wnt16 expression, improving the antitumor effect of cisplatin nanoparticles. Upon screening several natural chemicals, we found that a dietary flavonoid, quercetin, significantly suppresses Wnt16 expression in activated fibroblasts. To facilitate drug delivery, we have prepared a targeted lipid/calcium/phosphate nanoparticle formulation consisting of a prodrug of quercetin, i.e., quercetin phosphate, with a high loading efficiency (26.6% w/w). This quercetin nanoparticle with a particle size of around 35 nm significantly improved the bioavailability and metabolic stability of the parent quercetin. Quercetin phosphate is released from the nanoparticles and converted back to the parent quercetin under physiological conditions. Following systemic administration of quercetin phosphate nanoparticles, a significant downregulation in Wnt16 expression was observed and further yielded a synergistic antitumor effect with cisplatin nanoparticles in a stroma-rich bladder carcinoma model. The α-SMA-positive fibroblast and collagen within the tumor decreased significantly after combination treatment. This suggests that the remodeling of the tumor microenvironment induced by quercetin plays a critical role in promoting the synergy. Indeed, our data further confirmed that quercetin phosphate alone significantly remodeled the tumor microenvironment and increased the penetration of second-wave nanoparticles into the tumor nests. Collectively, quercetin phosphate nanoparticles may be a safe and effective way to improve therapeutic treatment for desmoplastic tumors.
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Metadata
- Authors
- Hu, K., Miao, L., Goodwin, T. J., Li, J., Liu, Q., & Huang, L.
- Venue
- ACS Nano
- Publisher
- American Chemical Society (ACS)
- Published
- 2017-04-21
- Volume
- 11
- Issue
- 5
- Pages
- 4916-4925
- ISSN
- 1936-0851 (ISSN-L)
- 1936-086X
- OpenAlex
- W2607351395
- Cited by
- 292
- References
- 44
- FWCI
- 8.16
- Type
- journal article
- Language
- en
- Open access
- green
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