期刊
INTERNATIONAL JOURNAL OF PHARMACEUTICS
卷 624, 期 -, 页码 -出版社
ELSEVIER
DOI: 10.1016/j.ijpharm.2022.122018
关键词
Photodynamic therapy; Bufalin; HIF-1?; SRC-3; Colorectal cancer; Nanoparticles
资金
- National Nature Science Foundation of China [81973700, 32030065, 31722033, 92049304]
- Development Program of China [2019YFA0904800]
- Science and Technology Commission of Shanghai Municipality [10DZ2220500]
- Shanghai Committee of Science and Technology [11DZ2260600]
- Science and Technology Innovation Project of Shanghai Putuo District Health Comission [ptkwws202004]
- Fifth batch of Xinglin Scholar of Shanghai University of Traditional Chinese Medicine
- Reserve Outstanding Chinese Medicine Talent of Shanghai University of Traditional Chinese Medicine
This study designed iRGD-modified nanoparticles to co-deliver mTHPC and BU, aiming to enhance the efficacy of photodynamic therapy (PDT) in colorectal cancer (CRC). The nanoparticles passively accumulated in tumor cells, with mTHPC inducing apoptosis and death under laser irradiation, while the sustained release of BU inhibited hypoxia and angiogenesis by targeting the SRC-3/HIF-1α pathway.
Photodynamic therapy (PDT) induces tumour cell death by producing reactive oxygen species (ROS), and hypoxia is one of the main factors that limits its efficiency. In our previous study, bufalin (BU) enhanced photosensitizer mTHPC-mediated PDT therapy in colorectal cancer (CRC) cells, but its mechanism was not elucidated. To explore a strategy for improving the efficacy of PDT, we designed iRGD-modified nanoparticles to co-capsuled mTHPC and BU for simultaneous delivery to the tumour site and explored the underlying mechanism of the synergistic anti-CRC effect. In our study, mTHPC&BU@VES-CSO/TPGS-RGD nanoparticles (T-B@NP) had a particle size of 148.3 +/- 2.5 nm and a zeta potential of 22.8 +/- 2.0 mV. Specifically, these nanoparticles passively accumulated in tumour cells, and under laser irradiation, mTHPC induced cell apoptosis and death. In addition, the sustained release of BU inhibited HIF-1 alpha and reduced VEGF-mediated angiogenesis by targeting the SRC-3/HIF-1 alpha pathway, which induced a strong PDT effect against CRC. In vivo studies demonstrated that codelivery of the nanoparticles under laser irradiation exhibited a superior antitumour effect (84.2%) and significantly prolonged survival time of mice, with the mechanisms of alleviating hypoxia and inhibiting angiogenesis. In summary, mTHPC and BU codelivery via nanoparticles efficiently enhances the therapeutic effects of PDT by inhibiting the SRC-3/HIF-1 alpha pathway in CRC. This work provides an effective strategy to combat hypoxia-induced tumour resistance and overcome the barriers of PDT treatment.
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