Indocarbocyanine nanoparticles extravasate and distribute better than liposomes in brain tumors

Glioblastoma (GBM) is the most devastating and aggressive brain tumor in adults. Hidden behind the blood-brain and blood-tumor barriers (BBTB), this invasive type of brain tumor is not readily accessible to nano-sized par-ticles. Here we demonstrate that fluorescent indocarbocyanine lipids (ICLs: DiD, DiI) formulated in PEGylated lipid nanoparticle (PLN) exhibit highly efficient penetration and accumulation in GBM. PLN-formulated ICLs demonstrated more efficient penetration in GBM spheroids and organoids in vitro than liposomal ICLs. Over 82% of the tumor's extravascular area was positive for ICL fluorescence in the PLN group versus 13% in the liposomal group just one hour post-systemic injection in the intracranial GBM model. Forty-eight hours post-injection, PLN-formulated ICLs accumulated in 95% of tumor myeloid-derived suppressor cells and macrophages, 70% of tumor regulatory T cells, 50% of tumor-associated microglia, and 65% of non-immune cells. PLN-formulated ICLs extravasated better than PEGylated liposomal doxorubicin and fluorescent dextran and efficiently accumulated in invasive tumor margins and brain-invading cells. While liposomes were stable in serum in vitro and in vivo, PLNs disassembled before entering tumors, which could explain the differences in their extravasation efficiency. These findings offer an opportunity to improve therapeutic cargo delivery to invasive GBM.

Automated summary

The study demonstrates that fluorescent indocarbocyanine lipids (ICLs) formulated in PEGylated lipid nanoparticles (PLN) show highly efficient penetration and accumulation in glioblastoma (GBM). PLN-formulated ICLs exhibit better penetration than liposomal ICLs in vitro and in an intracranial GBM model. They accumulate in different immune and non-immune cells within the tumor, including myeloid-derived suppressor cells, macrophages, regulatory T cells, and tumor-associated microglia. PLN-formulated ICLs also extravasate better than PEGylated liposomal doxorubicin and fluorescent dextran, and accumulate in invasive tumor margins and brain-invading cells.