A high therapeutic efficacy of polymeric prodrug nano-assembly for a combination of photodynamic therapy and chemotherapy
In our paper published in Communications Biology, we describe a high therapeutic efficacy of polymeric prodrug nano-assembly for a combination of photodynamic therapy and chemotherapy
I am interest in the drug delivery system based on amphiphilic polymer micelles. A co-delivery system based on a reduction-sensitive polymeric prodrug was reported in 20161. The combination effects (antagonistic or synergistic) could be determined by controlling drug ratios of paclitaxel and DOX•HCl/DOX in the co-delivery system against HeLa and MCF-7/ADR cells. In 2017, I joined the team of Prof. Fan Xia and Prof. Xiaoding Lou in China University of Geosciences. Our lab has been developing a series of specific light-up aggregation-induced emission fluorogen (AIEgen) probes based on DNA and peptide2, 3, 4. Over the past two years, we have synthesized stimuli-responsive light-up AIEgen probe for controlled drug delivery, drug release tracking and inhibition of inflammatory cells5, 6. Based on previous research on AIEgen and polymeric prodrug, we aimed to construct a co-delivery system based on AIEgen photosensitizer and chemotherapy drug for a combination of PDT and chemotherapy. For this aim, we collaborated with Professor Zujin Zhao, whose research lab at the South China University of Technology has been working on the development and mechanism of AIEgen, to design this current project.
In the paper published in Communications Biology, a red emissive AIEgen photosensitizer (TPA-BDTO, TB) was synthesized and entrapped by reduction-sensitive polymeric prodrug PMP through hydrophobic effect to prepare TB@PMP micelles for combinational image-guided PDT/chemotherapy. Working with the co-delivery system TB@PMP micelles had several difficulties, the most impressive difficulty is the process for preparing TB@PMP micelles. In order to ensure the drug loading content and concentration of TB, a series of PMP polymer with different ration of hydrophobic ratio by changing the grafted ratio of paclitaxel on PMP. Fortunately, the TB@PMP micelles were successfully prepared, and the loading contents of paclitaxel and TB in TB@PMP micelles were 17.3% and 9.34% respectively.
Compared to traditional photosensitizer loaded micelles Ce6@PMP, the TB@PMP micelles had satisfactory photostability and in favor of image-guided PDT (Figure 1a). After TB@PMP micelles were uptake by the tumor cells, the released PTX binds to a specific site of tubulin to prevent its depolymerization, which eventually leads to cancer cell apoptosis (Figure 1b).
Meanwhile, the TB could keep track of the micelles and generate cytotoxic ROS to damage the tumor cell under light irradiation. The TB@PMP micelles exhibited synergistic effect on the suppression of HeLa cells and HeLa-bearing mouse animal mode (Figure 2).
1. Yi, X. Q. et al. A co-delivery system based on a reduction-sensitive polymeric prodrug capable of loading hydrophilic and hydrophobic drugs for combination chemotherapy. Polym. Chem. 7, 5966-5977 (2016).
2. Zhuang, Y., Shang, C., Lou, X. D., Xia, F. Construction of AlEgens-based bioprobe with two fluorescent signals for enhanced monitor of extracellular and intracellular telomerase activity. Anal. Chem. 89, 2073-2079 (2017).
3. Wang, X. D. et al. DNA-conjugated amphiphilic aggregation-induced emission probe for cancer tissue imaging and prognosis analysis. Anal. Chem. 90, 8162-8169 (2018).
4. Cheng, Y., Sun, C., Ou, X. W., Liu, B. F., Lou, X. D., Xia, F. Dual-targeted peptide-conjugated multifunctional fluorescent probe with AIEgen for efficient nucleus-specific imaging and long-term tracing of cancer cells. Chem. Sci. 8, 4571-4578 (2017).
5. Cheng, Y. et al. Protease-responsive prodrug with aggregation-induced emission probe for controlled drug delivery and drug release tracking in living cells. Anal. Chem. 88, 8913-8919 (2016).
6. Cheng, Y. et al. An intracellular H2O2-responsive AIEgen for the peroxidase-mediated selective imaging and inhibition of inflammatory cells. Angew. Chem. Int. Ed. 57, 3123-3127 (2018).