Transarterial chemoembolization is the standard of care for patients with intermediate stage hepatocellular carcinoma, with delivery of chemotherapeutics and vessel blocker sequentially into the liver tissues through a catheter1. In addition to deprivation of oxygen and nutrient, embolism also confines the chemotherapeutics in the tumour region, thus enhancing therapeutic efficacy and reducing adverse effects. Based on these unique advantages and our previous studies2,3, in the present work, we developed a facile nanosystem to co-deliver Dox and thrombin into tumour tissues for simultaneously and synergistically killing tumours, with the purpose to advance the chemoembolization strategy.
Harnessing the economical, biodegradable and biocompatible properties, the polymeric chitosan nanoparticles integrating both thrombin and Dox were developed. A tumour-homing pentapeptide with the sequence of Cys-Arg-Glu-Lys-Ala (CREKA) was functionalized onto the surfaces of the particles. Fibrin-fibronectin complexes, the targets of CREKA peptide, distribute uniquely on tumour vessel walls and in stroma due to the tumour-associated hypercoagulability4,5. The targeting signals can even be amplified when therapeutic thrombus was formed, thereby attracting more nanoparticles to accumulate in the tumour tissues. Intravenously administration of nanoparticles more efficiently killed tumour cells —even those located in the tumour rim than single vascular infarction or chemotherapeutic therapy.
In contrast to the existed chemoembolization therapy, the use of nanoparticles avoids physical injury for patients caused by the catheter during the therapeutic process. Systemic administration can be performed without the aid of specialized interventional radiologists, with easily controlled dosage. In addition, nanoparticle-based chemoembolization is not only proper for treating hepatocellular carcinoma but also fits for treating breast cancer and melanoma tumours as demonstrated in our current work. More importantly, nanoparticles have a better ability to distinguish normal vessels and tumour vessels than surgical techniques owing to the specific recognition for tumour biomarker. This proof-of-concept study opens a door to further develop nanosystem with various properties to deliver both chemotherapeutics or antibody drugs and clotting inducer for synergistic tumour therapy.
- Sieghart, W., Hucke, F. & Peck-Radosavljevic, M. Transarterial chemoembolization: modalities, indication, and patient selection. J. Hepatol. 62, 1187-1195 (2015).
- Li, S. et al. Nanoparticle-mediated local depletion of tumour-associated platelets disrupts vascular barriers and augments drug accumulation in tumours. Nat Biomed Eng 1, 667-679 (2017).
- Li, S. et al. A DNA nanorobot functions as a cancer therapeutic in response to a molecular trigger in vivo. Nat. Biotechnol. 36, 258-264 (2018).
- Simberg, D. et al. Biomimetic amplification of nanoparticle homing to tumors. Proc. Natl. Acad. Sci. U. S. A. 104, 932-936 (2007).
- Liu, S. et al. Tumor-Specific Silencing of Tissue Factor Suppresses Metastasis and Prevents Cancer-Associated Hypercoagulability. Nano Lett. 19, 4721-4730 (2019).
Written by Suping Li, Zefang Lu and Guangjun Nie.