Collagenase-Functionalized Liposomes Overcome Stromal Barriers in Pancreatic Cancer.

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Oncology

Background:

• Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense, collagen-rich stroma that impedes drug delivery and limits treatment efficacy.
• The fibrotic extracellular matrix (ECM) in PDAC creates a physical barrier, reducing vascular perfusion and penetration of chemotherapeutics like gemcitabine.

Purpose of the Study:

• To develop and evaluate gemcitabine-loaded collagenase-conjugated liposomes (GLCLs) for enhanced drug delivery in PDAC.
• To investigate the ability of GLCLs to enzymatically remodel the collagenous ECM and improve intratumoral drug penetration.

Main Methods:

• Synthesis and characterization of GLCLs, assessing enzymatic activity, stability, and pharmacokinetic profiles.
• Evaluation of GLCLs in PDAC-bearing mouse models using in vivo imaging, ex vivo fluorescence, and quantitative desorption electrospray ionization mass spectrometry imaging (DESI-MSI).
• Comparison of tumor growth inhibition by GLCLs versus non-functionalized liposomes (GLL) and free gemcitabine.

Main Results:

• GLCLs demonstrated retained collagenase activity, prolonged circulation, and superior tumor accumulation compared to GLL.
• GLCLs achieved deeper and more homogeneous intratumoral gemcitabine penetration.
• GLCLs exhibited a 6-fold higher tumor growth inhibition (69.8%) than GLL (10.9%) at equivalent doses.

Conclusions:

• GLCLs effectively overcome the fibrotic collagen barrier in PDAC through enzymatic ECM remodeling.
• This nanocarrier-mediated drug delivery strategy enables deep intratumoral drug penetration, offering a promising and clinically translatable approach for PDAC treatment.
• The study provides molecular-level validation of nanocarrier-mediated drug penetration in PDAC using a multiscale imaging approach.