Nanoparticle-mediated local depletion of tumour-associated platelets disrupts vascular barriers and augments drug accumulation in tumours

• Published in: Nature biomedical engineering Vol. 1; no. 8; pp. 667 - 679
• Main Authors: Li, Suping, Zhang, Yinlong, Wang, Jing, Zhao, Ying, Ji, Tianjiao, Zhao, Xiao, Ding, Yanping, Zhao, Xiaozheng, Zhao, Ruifang, Li, Feng, Yang, Xiao, Liu, Shaoli, Liu, Zhaofei, Lai, Jianhao, Whittaker, Andrew K., Anderson, Gregory J., Wei, Jingyan, Nie, Guangjun
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-08-2017; Nature Publishing Group
• Subjects: 631/154/1438; 639/61/350/2093; 639/67/1059/602; 639/925/350/2093; 639/925/352/152; Accumulation; Antibodies; Biomedical and Life Sciences; Biomedical Engineering/Biotechnology; Biomedicine; Chemotherapy; Depletion; Doxorubicin; Lipids; Matrix metalloproteinase; Metalloproteinase; Metastases; Nanoparticles; Peptides; Perfusion; Permeability; Platelets; Polymers; Stroma; Tumors
• ISSN: 2157-846X; 2157-846X
• DOI: 10.1038/s41551-017-0115-8

Limited intratumoural perfusion and nanoparticle retention remain major bottlenecks for the delivery of nanoparticle therapeutics into tumours. Here, we show that polymer–lipid–peptide nanoparticles delivering the antiplatelet antibody R300 and the chemotherapeutic agent doxorubicin can locally deplete tumour-associated platelets, thereby enhancing vascular permeability and augmenting the accumulation of the nanoparticles in tumours. R300 is specifically released in the tumour on cleavage of the lipid–peptide shell of the nanoparticles by matrix metalloprotease 2, which is commonly overexpressed in tumour vascular endothelia and stroma, thus facilitating vascular breaches that enhance tumour permeability. We also show that this strategy leads to substantial tumour regression and metastasis inhibition in mice.
Polymer–lipid–peptide nanoparticles carrying an antiplatelet antibody and a chemotherapy drug deplete tumour-associated platelets to increase vascular permeability and augment the accumulation of the drug in tumours.