Brain targeting of self-assembled nanocarriers for treatment of Parkinson’s disease

Abstract

Parkinson’s disease (PD) is the second most relevant central nervous system (CNS) disease worldwide. Rotigotine HCl (Ro.HCl) is the most potent dopamine agonist for symptomatic treatment of PD. However, it suffers from poor water solubility, extensive first pass effect and great volume of distribution in vivo, limiting its brain bioavailability. Its available transdermal patch suffers from many drawbacks which limited its application worldwide. Polymeric micelles (PMs) are smart nanocarriers for brain delivery with lactoferrin (Lf) being a promising ligand for this purpose. In this study intravenous (IV) unmodified and Lf-modified Ro.HCl loaded PMs were prepared aiming at increasing the drug brain bioavailability.

First, three low molecular weight copolymers viz PEG2000-PLA2000, PEG2000-PLGA(75/25)2000 and PEG2000-PLGA(50/50)2000were used for PMs preparation. Optimization of different physicochemical properties of PMs was performed using Expert-design v.11 software, applying User-Defined response surface methodology (RSM) design. All the prepared PMs by thin film hydration method were neutral with zeta (ξ) potential range of -9.23 to -4.12 mV and owned particle size (P.S) range of 21.73-77.32 nm which is optimum for brain delivery. Further, the PMs showed high encapsulation efficiency (EE%) values of Ro.HCl with a range of 33.98-89.47%. A polymer amount of 30mg of the three studied copolymers and drug amount of 2mg were selected as they showed the highest EE% values giving rise to F10, F22 and F34 formulae, respectively. F34 was excluded due to its low serum stability. F10 was chosen as it showed higher serum stability, higher physical stability, no need for cryoprotection, more sustained release and optimum physicochemical properties.

Second, Lf-PEG2000-PLA2000 amide conjugate was successfully prepared applying amine-N-hydroxysuccinimide (NH2-NHS) coupling method as confirmed by Fourier transform infrared (FT-IR) spectroscopy, differential scanning calorimetry (DSC) and X-ray diffraction. The modification of PMs with Lf resulted in an increase in P.S, polydispersity index(PDI) and ξ potential proportionally to the amount of Lf. Moreover, it resulted in a decrease in EE% and drug loading (DL%). LP1 and LP2, composed ofPEG2000-PLA2000:Lf-PEG2000-PLA2000, 9:1 and 7:3 mg/mg, respectively, showed reasonable physicochemical properties, serum stability, physical stability and they could be efficiently freeze dried applying suitable cryoprotectants.