CollagenaseNanoparticles Enhance the Penetrationof Drugs into Pancreatic Tumors
2019
Overexpressed
extracellular matrix (ECM) in pancreatic ductal adenocarcinoma
(PDAC) limits drug penetration into the tumor and is associated with
poor prognosis. Here, we demonstrate that a pretreatment based on
a proteolytic-enzyme nanoparticle system disassembles the dense PDAC
collagen stroma and increases drug penetration into the pancreatic
tumor. More specifically, the collagozome, a 100 nm liposome encapsulating
collagenase, was rationally designed to protect the collagenase from
premature deactivation and prolonged its release rate at the target
site. Collagen is the main component of the PDAC stroma, reaching
12.8 ± 2.3% vol in diseased mice pancreases, compared to 1.4
± 0.4% in healthy mice. Upon intravenous injection of the collagozome,
∼1% of the injected dose reached the pancreas over 8 h, reducing
the level of fibrotic tissue to 5.6 ± 0.8%. The collagozome pretreatment
allowed increased drug penetration into the pancreas and improved
PDAC treatment. PDAC tumors, pretreated with the collagozome followed
by paclitaxel micelles, were 87% smaller than tumors pretreated with
empty liposomes followed by paclitaxel micelles. Interestingly, degrading
the ECM did not increase the number of circulating tumor cells or
metastasis. This strategy holds promise for degrading the extracellular
stroma in other diseases as well, such as liver fibrosis, enhancing
tissue permeability before drug administration.
Keywords:
- Correction
- Source
- Cite
- Save
- Machine Reading By IdeaReader
65
References
90
Citations
NaN
KQI