pH-Responsive Liposomes for Targeted Detection of Pancreatic Adenocarcinoma Using MSOT

Area of Science:

• Nanomedicine
• Biomedical Imaging
• Oncology

Background:

• Pancreatic ductal adenocarcinoma (PDAC) diagnosis and treatment are hindered by a lack of sensitive and specific contrast agents.
• Nanocontrast agents offer potential for targeted tumor detection, especially within acidic tumor microenvironments.
• Multispectral optoacoustic tomography (MSOT) is an advanced imaging modality suitable for intraoperative tumor visualization.

Purpose of the Study:

• To develop and evaluate pH-low insertion peptide (pHLIP) V7-targeted, IR780 dye-encapsulated liposomes (V7-lipo-780) as a nanocontrast agent for pancreatic cancer.
• To assess the tumor-specific uptake and biodistribution of V7-lipo-780 in vitro and in vivo.
• To explore the potential of V7-lipo-780 for enhanced intraoperative imaging using MSOT.

Main Methods:

• Liposomes encapsulating IR780 dye (Lipo-780) were synthesized and characterized (size, PDI).
• V7 peptide conjugation to Lipo-780 was achieved using a SMCC linker, confirmed by zeta potential.
• In vitro uptake studies were performed in pancreatic cancer cell lines (S2VP10, S2013) at varying pH. Liposome internalization was validated using propidium iodide-encapsulated liposomes (Lipo-PI).
• In vivo studies involved an orthotopic human pancreatic cancer xenograft murine model, with biodistribution analysis 6 hours post-intravenous administration.
• Histological analysis of major organs (kidney, liver, spleen) assessed liposome toxicity.

Main Results:

• V7-lipo-780 demonstrated significantly higher cellular uptake compared to non-targeted Lipo-780 in both S2013 (3.5-fold) and S2VP10 (2.4-fold at pH 6.6) cells.
• Liposome internalization was confirmed, with V7-lipo-PI showing substantially greater uptake than Lipo-PI in S2VP10 cells at pH 6.6 (mean red fluorescence 5535 vs. 334 counts).
• Biodistribution revealed a 40-fold higher accumulation of V7-lipo-780 in tumors compared to the liver and 4-fold higher than the kidney.
• Histological examination confirmed the non-toxic nature of the liposomes in major organs.

Conclusions:

• V7-lipo-780 effectively targets the acidic tumor microenvironment of pancreatic cancer, leading to enhanced tumor-specific accumulation.
• This targeted approach minimizes off-target toxicity and maximizes contrast signal at the tumor site.
• The developed nanocontrast agent holds significant promise for improving intraoperative detection of pancreatic cancer using MSOT.