Drug release kinetics and blood-brain barrier crossing efficacy of polymer encapsulated magnetic nanocarriers

Spinal cord injury (SCI) causes neuronal death and leads to permanent loss of motor and sensory functions. Treatment of SCI is challenging as axon regeneration from damaged neurons is limited by their intrinsic inability to regenerate as well as by the presence of extrinsic growth inhibitory molecules at the injury site. Moreover, targeting therapeutics to damaged CNS neurons is difficult due to the presence of the blood brain or blood spinal cord barrier (BBB/BSCB). This increases the demand for developing new treatment strategies for SCI. Unique properties of nanomaterials make them promising for targeted drug delivery to CNS neurons. We have developed a polymer encapsulated magnetic nanocarrier (PE-MNC) system for targeted and controlled drug delivery across the BBB. PE-MNCs were synthesized by precipitation polymerization method and tested for their biocompatibility in neurons. Drug loaded nanocarriers were tested for their release kinetics and targeted drug delivery to neurons in culture. We have also tested their size dependent BBB crossing efficacy in the presence and absence of an external magnetic field as well as induced hypoxia.
We found that the physicochemical properties of PE-MNCs are ideal for their in vivo applications. Specifically, PE-MNCs possess superparamagnetic behavior in the presence of an external magnetic field and a higher LCST value. Increasing doses of PE-MNC treatment for up to 96 h did not detrimentally affect the neuron morphology. These nanocarriers exhibited a 50-70 nm volumetric reduction at physiological temperatures and released 80% of the imbibed drugs in a controlled manner. Moreover, they could induce neurite outgrowth on inhibitory substratum by delivering outgrowth promoting drugs to cortical neurons. We have used two different sizes of PE-MNCs for transport studies across bovine brain microvascular endothelial cell in vitro BBB model. In the presence of an external magnetic field, irrespective of their size, PE-MNCs were transported across a hypoxic in vitro BBB model. We conclude that PE-MNCs have the potential to deliver therapeutics to severed neurons across BBB following SCI.