Nose to brain delivery of radiolabeled chemotherapeutic micelles: Meeting the unmet needs of brain tumors

Abstract

The blood brain barrier postures colossal challenges to the CNS delivery of drugs administered via the oral/parenteral route. In conditions like glioblastoma where mean patient survival rate is mere 15 months from diagnosis, outwitting the blood brain barrier pathway could be a boon to the patient treatment with added compliance. The presented work aims at formulating a chemotherapeutic aid for CNS tumors to be delivered through the non-invasive nose-to-brain pathway. We also propose intranasal delivery of a chemotherapeutic agent amalgamated with radiotherapy nuclide to be used against CNS tumors owing to the synergistic anti-cancer potential of the both. For demonstration purposes, methotrexate was conjugated with a bifunctional chelating agent, radiolabeled with a model radionuclide 99mTc and delivered to the CNS upon intranasal administration. The invented micelles were found to be safe for nasal administration when subjected to in vivo nasal toxicity studies in rats. The fabricated micelles due to their mucoadhesivity, dimension, geometry and improved permeation were found to have an increased nose-to-brain uptake when evaluated for in vivo organ biodistribution studies in mice. The in-vitro cytotoxicity analysis in U87-MG glioblastoma cell lines showed a threefold enhanced activity of the drug-conjugate loaded micelles when compared to the drug solution. Upon SPECT imaging of rabbits administered intranasally with radiolabeled micelles, it was observed that the micellar formulation presented an improved uptake in the animal brain. The authors are of the view that the presented formulation could potentially conglomerate the chemotherapy with radiotherapy towards a synergistic anti-cancer conclusion resulting in an effective GBM treatment.