ACS Nano http://doi.org/pwn (2013)

Certain cancers, including pancreatic ductal adenocarcinoma (PDAC), are characterized by a dense stromal matrix that greatly reduces access of drugs to the tumour site. This is one factor that causes chemotherapeutic resistance in vivo. Now, Huan Meng et al. report a two-wave approach that targets stroma and enables more effective delivery of liposomal-encapsulated drugs to PDAC tumours. In the first stage, mesoporous silica nanoparticles with co-polymer coatings are used to deliver a small-molecule inhibitor to the tumour vasculature. The inhibitor blocks the TGF-β signalling pathway, preventing pericyte coverage of vascular fenestrations and thus improving access from the vascular system to the tumour. Two hours later, this enables gemcitabine-loaded liposomes to more effectively penetrate the tumour in the second phase of the treatment. Using fluorescently labelled liposomes, it was shown that the two-wave therapy improved the distribution of the liposomes within the tumour. In tumour xenograft models in mice, after 25 days, the two-wave nanocarrier treatment resulted in a greater reduction in tumour size compared with administration of gemcitabine-loaded liposomes only.