Internal cross-linked polymeric nanoparticles with dual sensitivity for combination therapy of muscle-invasive bladder cancer

Guanchen Zhu,Xiaozhi Zhao,Wenmin Cao,Haixiang Qin,Kaikai Wang,Hongqian Guo,Linfeng Xu,Wei Chen

doi:10.1186/s12951-020-00686-3

Guanchen Zhu, Xiaozhi Zhao + Show 6 more

Open Access

https://doi.org/10.1186/s12951-020-00686-3

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Abstract

BackgroundChemotherapy is a standard cancer treatment which uses anti-cancer drugs to destroy or slow the growth of cancer cells. However, chemotherapy has limited therapeutic effects in bladder cancer. One of the reasons of this resistance to chemotherapy is that higher levels of glutathione in invasive bladder cancer cells. We have fabricated nanoparticles that respond to high concentrations of glutathione and near-infrared laser irradiation in order to increase the drug accumulation at the tumor sites and combine chemotherapy with photothermal therapy to overcome the challenges of bladder cancer treatment.MethodsThe DOX&IR780@PEG-PCL-SS NPs were prepared by co-precipitation method. We investigated the tumor targeting capability of NPs in vitro and in vivo. The orthotopic bladder cancer model in C57BL/6 mice was established for in vivo study and the photothermal effects and therapeutic efficacy of NPs were evaluated.ResultsThe DOX&IR780@PEG-PCL-SS NPs were synthesized using internal cross-linking strategy to increase the stability of nanoparticles. Nanoparticles can be ingested by tumor cells in a short time. The DOX&IR780@PEG-PCL-SS NPs have dual sensitivity to high levels of glutathione in bladder cancer cells and near-infrared laser irradiation. Glutathione triggers chemical structural changes of nanoparticles and preliminarily releases drugs, Near-infrared laser irradiation can promote the complete release of the drugs from the nanoparticles and induce a photothermal effect, leading to destroying the tumor cells. Given the excellent tumor-targeting ability and negligible toxicity to normal tissue, DOX&IR780@PEG-PCL-SS NPs can greatly increase the concentration of the anti-cancer drugs in tumor cells. The mice treated with DOX&IR780@PEG-PCL-SS NPs have a significant reduction in tumor volume. The DOX&IR780@PEG-PCL-SS NPs can be tracked by in vivo imaging system and have good tumor targeting ability, to facilitate our assessment during the experiment.ConclusionA nanoparticle delivery system with dual sensitivity to glutathione and near-infrared laser irradiation was developed for delivering IR780 and DOX. Chemo-photothermal synergistic therapy of both primary bladder cancer and their metastases was achieved using this advanced delivery system.

Highlights

Bladder cancer, usually originates from the epithelial lining of a urinary bladder, is one of the most common malignancies of the urinary system [1,2,3]
Hydrophobizated doxorubicin, IR780 and polymer PCL-PEG-SS dissolved in DMSO, were added to Phosphate buffer solution (PBS) under ultrasonic conditions
Under DTT catalysis condition, the intramolecular disulfide bonds of PCL-PEG-SS will be broken, while intermolecular disulfide bonds may form inside the nanoparticles through the disulphide–sulfhydryl interchange reaction and stabilize the nanoparticles, which makes the spatial structure of nanoparticles more compact (Fig. 1b)

Summary

Introduction

Usually originates from the epithelial lining of a urinary bladder, is one of the most common malignancies of the urinary system [1,2,3]. NMIBC recurs at a rate of 50–80% and has a 14% chance of progression to muscle-invasive cancer after transurethral resection (TUR) alone [4]. Radical surgery combined with systemic chemotherapy is routinely used for muscle-invasive bladder cancer [6]. It is of great significance to overcome these limitations and improve the treatment effect of bladder cancer. Chemotherapy has limited therapeutic effects in bladder cancer. One of the reasons of this resistance to chemotherapy is that higher levels of glutathione in invasive bladder cancer cells. We have fabricated nanoparticles that respond to high concentrations of glutathione and near-infrared laser irradiation in order to increase the drug accumulation at the tumor sites and combine chemotherapy with photothermal therapy to overcome the challenges of bladder cancer treatment

Methods

Results

Conclusion