Evaluation of cell membrane-derived nanoparticles as therapeutic carriers for pancreatic ductal adenocarcinoma using an in vitro tumour stroma model

• Published in: Journal of controlled release 2023-10, Vol.362, p.225-242
• Main Authors: Tapeinos, Christos, Torrieri, Giulia, Wang, Shiqi, Martins, João P., Santos, Hélder A.
• Format: Article
• Language: English
• Subjects: actin; adenocarcinoma; Cell membrane nanoparticles; Chemotherapy; collagen; colony-stimulating factors; drug therapy; drugs; endocytosis; humans; Immunotherapy; In vitro desmoplasia model; macrophages; muscles; nanoparticles; paclitaxel; pancreatic neoplasms; PDAC; viability
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2023.08.045

Here, we fabricated nanoparticles made solely from the membrane of cells found in the pancreatic tumour's microenvironment (TME), like the human MiaPaCa-2 cells and M2-polarized macrophages. The cell membrane-derived nanoparticles (CMNPs) deriving from the MiaPaCa-2 cells (MPC2-CMNPs) were loaded with the chemotherapeutic drug paclitaxel (PTX), and the CMNPs deriving from M2-polarized macrophages (M2-CMNPs) were loaded with the colony-stimulating factor 1 receptor inhibitor, pexidartinib (PXDB). The CMNPs' thorough morphological and physicochemical characterisation was followed by an in-depth study of their targeting ability and the endocytosis pathway involved during their internalisation. An in vitro model of the desmoplastic stroma comprising cancer-associated fibroblast-mimicking cells and M2-polarized macrophages was also developed. The model was characterised by collagen and α-smooth muscle actin (α-SMA) expression (overexpressed in desmoplasia) and was used to assess the CMNPs' ability to cross the stroma and target the tumour cells. Moreover, we assessed the effect of PXDB-loaded M2-CMNPs on the expression of M1 (CD80/CD86) and M2 (CD206/CD209) polarisation markers on activated macrophages. Finally, we evaluated the PTX and PXDB-loaded CMNPs' effect on the viability of all the used TME cell lines alone or in combination. Overall, this pilot study showed the potential of the CMNPs to cross an in vitro stroma model and act synergistically to treat PDAC. [Display omitted] •Comparative studies of MiaPaCa-2 and M2-polarized cell membrane-derived nanoparticles (CMNPs).•Internalisation and endocytosis depend on the type of CMNPs used.•CMNPs achieve crossing of an in vitro desmoplastic stroma model developed in the lab.•Pexidartinib-loaded CMNPs inhibit activation towards the M2 phenotype.•Paclitaxel/Pexidartinib-loaded CMNPs significantly reduce the viability of MiaPaCa-2 cells.