Intrathecal magnetic drug targeting to the central nervous system with superparamagnetic nanoparticles
For a family of diseases of the central nervous system (CNS), especially brain tumors and spinal metastases, few effective treatment options exist. Existing treatments have serious side effects including acute pain, nausea and even paralysis, due to lack of a targeted drug delivery strategy. In order to localize drug molecules in specific diseased target sites within the CNS, the investigator proposes a novel nanoparticle drug delivery technique termed Intrathecal Magnetic Drug Targeting (IT-MDT). It combines traditional intrathecal drug administration with magnetic drug targeting for highly localized treatment of neurological disorders. In this technique, magnetic nanoparticles (MNPs) conjugated to therapeutic agents are directly infused into the cerebrospinal fluid (CSF) and collected at the desired target site via an external magnetic field. The drug then desorbs from the MNPs to begin its therapeutic mechanism of action. The most notable benefit of MDT resides in highly confined local drug action in the desired region such as the tumor site. At the same time, systemic side effects are minimal because of the limited drug spread. The project will advance the fundamental understanding of magnetically targeted nanoparticle transport within the CNS and develop fundamental insights about biotransport phenomena within the intrathecal space. This study will also create intellectual advancements necessary to elevate MNP based carriers from a research subject to a clinically useful technology.
The Blood Brain Barrier (BBB) regulates molecular transport and protects the CNS against harmful compounds, but also hinders therapeutic interventions by preventing drugs from reaching the brain or spinal cord. Therefore, there is a critical need for developing drug delivery techniques for guiding and localizing therapeutic agents at specific target cells in the CNS. The proposed IT-MDT delivery technique uses magnetic forces to guide and confine intrathecally delivered, superparamagnetic drug functionalized MNPs to any desired target location within the CNS. This mode of drug administration offers the following advantages: it (i) bypasses the BBB, (ii) reduces toxicity while enhancing treatment efficiency in the target site, and (iii) enables active external control over the spatial and temporal distribution of the drug inside the CNS. To establish this novel mechanism, it is planned to (1)design and synthesize magnetic nanoparticle based drug delivery vehicles, (2) conduct IT-MDT experiments in a physiologically relevant 3D live cell spine model,(3) perform IT-MDT treatment of in vitro spinal cord tumors using doxorubicin loaded magnetic nanoparticles. This study will establish a novel technique for effectively conjugating tumor drug molecules to MNPs, build and validate a 3D live tumor cell spine model to demonstrate cellular uptake and tumor cell death from the drug functionalized nanoparticles. The experiments will study cellular uptake of MNPs at the cerebrospinal fluid (CSF)-pia interface in the presence of pulsatile CSF motion and eddies caused by the spinal micro-anatomy. The results will enable to select critical parameters such as MNP infusate concentration, flow rate and duration to achieve desired therapeutic concentrations of MNPs at specific target locations along the CNS. Optimal magnetic field parameters for steering nanoparticles to desired locations in the CNS will be established both by experiments and by computational fluid dynamic methods and magnetostatics.
This award by the Biotechnology, Biochemical, and Biomass Engineering Program of the CBET Division is co-funded by the Instrument Development for Biological Research Program of the Division of Biological Infrastructure.
