Michael D. Bentley

Photoimmobilization of organophosphorus hydrolase within a PEG-based hydrogel

Organophosphorous hydrolase (OPH) was physically and covalently immobilized within photosensitive polyethylene glycol (PEG)-based hydrogels. The hydroxyl ends of branched polyethylene glycol (b-PEG, four arms, MW = 20,000) were modified with cinnamylidene acetate groups to give water-soluble, photosensitive PEG macromers (b-PEG-CA). The b-PEG-CA macromers underwent photocrosslinking reaction and formed gels upon UV irradiation (>300 nm) in the presence of erythrosin B. Native OPH was pegylated with cinnamylidene-terminated PEG chains (MW = 3400) to be covalently linked with the b-PEG-CA macromers during photogelation. The effect of pegylation on the stability of the enzyme was determined. Furthermore, the effect of enzyme concentration, wavelength of irradiation, and photosensitizer on the stability of the entrapped enzyme was also investigated. The pegylated OPH was more stable than the native enzyme, and the OPH-containing gels exhibited superior stability than the soluble enzyme preparations.

Rotigotine Polyoxazoline Conjugate SER-214 Provides Robust and Sustained Antiparkinsonian Benefit

Currently available dopaminergic drugs such as levodopa and dopamine (DA) receptor agonists impart considerable improvement in Parkinsons disease (PD) motor symptoms but often lead to significant motor complications including “wearing‐off” and dyskinesia. Such complications are believed to stem from the pulsatile nature of dopaminergic stimulation with these agents. Continuous dopaminergic drug delivery using polyoxazoline (POZ) polymer conjugation may improve motor symptoms, while avoiding development of side effects. The purposes of the current study are to characterize the in vitro and in vivo pharmacokinetics of POZ conjugation of a U.S. Food and Drug Administration (FDA)‐approved DA agonist, rotigotine, and to evaluate their effects in an established rat model of PD. After determination of release profiles of several POZ‐conjugated constructs (“fast”: SER‐212; “moderate”: SER‐213; and “slow”: SER‐214) using in vitro hydrolysis, normal male Sprague‐Dawley rats were used for determination of the pharmacokinetic profile of both acute and chronic exposure. Finally, a separate group of rats was rendered hemiparkinsonian using intracranial 6‐hydroxydopamine (6‐OHDA) infusions, treated acutely with POZ‐rotigotine, and assessed for rotational behavior and antiparkinsonian benefit using the cylinder test. POZ‐rotigotine formulations SER‐213 and SER‐214 led to substantial pharmacokinetic improvement compared to unconjugated rotigotine. In addition, SER‐214 led to antiparkinsonian effects in DA‐lesioned rats that persisted up to 5 days posttreatment. Repeated weekly dose administration of SER‐214 to normal rats for up to 12 weeks demonstrated highly reproducible pharmacokinetic profiles. The continuous dopaminergic stimulation profile afforded by SER‐214 could represent a significant advance in the treatment of PD, with potential to be a viable, once‐per‐week therapy for PD patients.

Synthesis of unsaturated poly(ether amide)s based on amine‐terminated poly(ethylene glycol)

Novel water-soluble unsaturated poly(ether amide)s (PEAs) were synthesized by low-temperature polycondensation of fumaryl chloride and amine-terminated poly(ethylene glycol) (Jeffamine®). The unsaturated copolymers were further chemically modified with thiols to provide reactive pendant functional groups. Hydrogels based on these copolymers were prepared by copolymerization of the PEA with N-vinyl pyrrolidone exposure to ultraviolet (UV) irradiation. The resulting hydrogels exhibited a high swelling ratio, and the magnitude of swelling depended on the molecular weight of Jeffamine®. The swelling ratio and equilibrium water content tended to increase with increasing chain length of the Jeffamine® used in copolymer synthesis.