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

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 15months 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.

Materials

Methotrexate was gifted by Cipla Ltd., Diethylene glycol monoethyl ether (Transcutol-P) was obtained as a kind gift from Gattefosse India Pvt. Ltd, Mumbai. Solutol HS15 was a gift from BASF, India. All other chemicals that were used in the experimentations were analytical grade, the same were obtained from local suppliers.

Prashant Upadhaya, Puja Panwar Hazari, Anil Kumar Mishra, Bijaideep Dutta, Puthusserickal Hassan, Vandana Patravale, Nose to brain delivery of radiolabeled chemotherapeutic micelles: Meeting the unmet needs of brain tumors,
Journal of Drug Delivery Science and Technology, 2023, 104700, ISSN 1773-2247, https://doi.org/10.1016/j.jddst.2023.104700.

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