Accumulation of liposomes in metastatic tumor sites is not necessary for anti-cancer drug efficacy

• Published in: Journal of Translational Medicine
• Main Authors: Jessica Kalra, Jennifer Baker, XuXin Sun, Alastair Kyle, Andrew Minchinton, Marcel B. Bally
• Format: Article
• Language: English
• Published: BMC 2024-07-01
• Subjects: Liposomes; Enhanced permeability and retention effect; Metastases/metastasis; Tumor microenvironment; Inter- and intra-tumor heterogeneity; Pre-clinical models
• Online Access: https://doi.org/10.1186/s12967-024-05428-9

Abstract Background The tumor microenvironment is profoundly heterogeneous particularly when comparing sites of metastases. Establishing the extent of this heterogeneity may provide guidance on how best to design lipid-based drug delivery systems to treat metastatic disease. Building on our previous research, the current study employs a murine model of metastatic cancer to explore the distribution of ~ 100 nm liposomes. Methods Female NCr nude mice were inoculated with a fluorescently labeled, Her2/neu-positive, trastuzumab-resistant breast cancer cell line, JIMT-1mkate, either in the mammary fat pad to create an orthotopic tumor (OT), or via intracardiac injection (IC) to establish tumors throughout the body. Animals were dosed with fluorescent and radio-labeled liposomes. In vivo and ex vivo fluorescent imaging was used to track liposome distribution over a period of 48 h. Liposome distribution in orthotopic tumors was compared to sites of tumor growth that arose following IC injection. Results A significant amount of inter-vessel heterogeneity for DiR distribution was observed, with most tumor blood vessels showing little to no presence of the DiR-labelled liposomes. Further, there was limited extravascular distribution of DiR liposomes in the perivascular regions around DiR-positive vessels. While all OT tumors contained at least some DiR-positive vessels, many metastases had very little or none. Despite the apparent limited distribution of liposomes within metastases, two liposomal drug formulations, Irinophore C and Doxil, showed similar efficacy for both the OT and IC JIMT-1mkate models. Conclusion These findings suggest that liposomal formulations achieve therapeutic benefits through mechanisms that extend beyond the enhanced permeability and retention effect.