Synthesis and characterization of poly(2-ethyl 2-oxazoline)-conjugates with proteins and drugs: Suitable alternatives to PEG-conjugates?

Mero, Anna; Pasut, Gianfranco; Via, Lisa Dalla; Fijten, Martin W. M.; Schubert, Ulrich S.; Hoogenboom, Richard; Veronese, Francesco M.

doi:10.1016/j.jconrel.2007.10.010

Cited by 202 publications

(160 citation statements)

References 27 publications

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“…21,22,24 Additionally, it can be conjugated in a "dose-loading" manner, allowing for control over the speed and amount of drug released from the polymer backbone. 23,24 Release of drug from POZ occurs via simple hydrolysis and POZ FIG. 6.…”

Section: Discussionmentioning

confidence: 99%

“…20 Polyoxazolines (POZs) are one of the bioconjugate polymers that show early promise in drug delivery. [21][22][23] In preclinical settings we have shown that POZ-insulin conjugates lower blood glucose levels for up to 8 hours, compared to 2 hours with insulin treatment alone. 24 Here, we describe the development of a POZ-rotigotine conjugate.…”

Section: Introductionmentioning

confidence: 99%

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Rotigotine polyoxazoline conjugate SER‐214 provides robust and sustained antiparkinsonian benefit

et al. 2013

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Currently available dopaminergic drugs such as levodopa and dopamine (DA) receptor agonists impart considerable improvement in Parkinson's 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.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Rotigotine polyoxazoline conjugate SER‐214 provides robust and sustained antiparkinsonian benefit

et al. 2013

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“…This novel type of lipopolymers did not exhibit rheological transitions, and Jordan et al correspondingly claimed jammed surface micelles to be responsible for the gelation. Hoogenboom, Veronese et al compared pEtOx conjugates with low molar mass biomolecules such as trypsin with their poly(ethylene glycol) analogues, in order to prove if pEtOx is a suitable alternative polymer for poly(ethylene glycol) [57]. They converted the OH end-group of semitelechelic pEtOx to a carboxylic acid end-group (reaction with potassium tert-butoxide, addition of tert-butyl bromoacetate, and deprotection of the acid), subsequent activation with N-hydroxysuccinimide, and the reaction with amino groups of proteins, yielding their covalent linkage by amide bonds.…”

Section: Functionalization Of Poly(2-oxazoline)s With Non-olefinic Rementioning

confidence: 99%

Design Strategies for Functionalized Poly(2-oxazoline)s and Derived Materials

2013

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Abstract:The polymer class of poly(2-oxazoline)s currently is under intensive investigation due to the versatile properties that can be tailor-made by the variation and manipulation of the functional groups they bear. In particular their utilization in the biomedic(in)al field is the subject of numerous studies. Given the mechanism of the cationic ring-opening polymerization, a plethora of synthetic strategies exists for the preparation of poly(2-oxazoline)s with dedicated functionality patterns, comprising among others the functionalization by telechelic end-groups, the incorporation of substituted monomers into (co)poly(2-oxazoline)s, and polymeranalogous reactions. This review summarizes the current state-of-the-art of poly(2-oxazoline) preparation and showcases prominent examples of poly(2-oxazoline)-based materials, which are retraced to the desktop-planned synthetic strategy and the variability of their properties for dedicated applications.

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“…Poly(2-ethyl 2-oxazoline) (PEOZ) (Figure 6) is a linear synthetic polymer that is considered to be a promising substitute for PEG in view of its stealth properties [89][90][91]. PEOZ is soluble in water and in many organic solvents [92].…”

Section: Poly(2-ethyl 2-oxazoline) (Peoz)mentioning

confidence: 99%

“…Studies in mice using radiolabelled poly(2-alkyl-oxazoline) showed that these polymers do not accumulate in the body and are mainly cleared by the kidneys and only to a small extent by the liver [99]. It was relatively easy to transfer the chemistry expertise and know-how behind polymer activation and coupling to PEOZ in view of its similarity to PEG [91,100]. PEOZ can be produced with a terminal hydroxyl group that can be activated and, in turn, reacted with spacers bearing common functional groups and yielding carboxyl, amino, maleimide or aldehyde PEOZs.…”

Section: Poly(2-ethyl 2-oxazoline) (Peoz)mentioning

confidence: 99%

Polymers for Protein Conjugation

Pasut

2014

Polymers

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Polyethylene glycol (PEG) at the moment is considered the leading polymer for protein conjugation in view of its unique properties, as well as to its low toxicity in humans, qualities which have been confirmed by its extensive use in clinical practice. Other polymers that are safe, biodegradable and custom-designed have, nevertheless, also been investigated as potential candidates for protein conjugation. This review will focus on natural polymers and synthetic linear polymers that have been used for protein delivery and the results associated with their use. Genetic fusion approaches for the preparation of protein-polypeptide conjugates will be also reviewed and compared with the best known chemical conjugation ones.

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Synthesis and characterization of poly(2-ethyl 2-oxazoline)-conjugates with proteins and drugs: Suitable alternatives to PEG-conjugates?

Cited by 202 publications

References 27 publications

Rotigotine polyoxazoline conjugate SER‐214 provides robust and sustained antiparkinsonian benefit

Rotigotine polyoxazoline conjugate SER‐214 provides robust and sustained antiparkinsonian benefit

Design Strategies for Functionalized Poly(2-oxazoline)s and Derived Materials

Polymers for Protein Conjugation

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