Phosphatidylcholine-derived carriers facilitate brain tumor delivery and enhance glioblastoma therapy.

Glioblastoma (GBM) is the most common primary brain cancer without effective treatment. The ineffective treatment of GBM can be partially attributed to the existence of the blood-brain barrier (BBB). Lipids, which constitute over half the weight of the brain and play a vital role in brain tumor biology, can be transported to the brain in the form of lysophosphatidylcholines (LPCs) via specific LPC transporters at the BBB. We hypothesize that LPC analogs could be used as carriers for drug delivery to tumors in the brain. To test this hypothesis, we synthesized and screened a collection of LPC analogs, among which LPC analog 3 (A3), featuring a glycerophosphorylcholine (GPC) headgroup and a 15‑carbon tail, exhibited a marked ability to penetrate brain tumors. We characterized A3 as a carrier for drug delivery to brain tumors by using Doxorubicin (Dox) as the therapeutic payload and found that the A3-Dox conjugate with a cathepsin B-cleavable linker has a great ability to accumulate in brain tumors, leading to effective treatment of GBM without inducing significant cytotoxicity. Our study suggests a novel approach to improving the treatment of GBM by enhancing the delivery of therapeutic agents to the brain using A3 as a carrier.