Polyoxazoline: Chemistry, Properties, and Applications in Drug Delivery

Abstract

Polyoxazoline polymers with methyl (PMOZ), ethyl (PEOZ), and propyl (PPOZ) side chains were prepared by the living cationic polymerization method and purified by ion-exchange chromatography. The following properties of polyoxazoline (POZ) were measured: apparent hydrodynamic radius by aqueous size-exclusion chromatography, relative lipophilicity by reverse-phase chromatography, and viscosity by cone-plate viscometry. The PEOZ polymers of different molecular weights were first functionalized and then conjugated to model biomolecules such as bovine serum albumin, catalase, ribonuclease, uricase, and insulin. The conjugates of catalase, uricase, and ribonuclease were tested for in vitro activity using substrate-specific reaction methods. The conjugates of insulin were tested for glucose lowering activity by injection to naïve Sprague-Dawley rats. The conjugates of BSA were injected into New Zealand white rabbits and serum samples were collected periodically and tested for antibodies to BSA. The safety of POZ was also determined by acute and chronic dosing to rats. The results showed that linear polymers of POZ with molecular weights of 1 to 40 kDa can easily be made with polydispersity values below 1.10. Chromatography results showed that PMOZ and PEOZ have a hydrodynamic volume slightly lower than PEG; PEOZ is more lipophilic than PMOZ and PEG; and PEOZ is significantly less viscous than PEG especially at the higher molecular weights. When PEOZ was attached to the enzymes catalase, ribonuclease, and uricase, the in vitro activity of the resultant bioconjugates depended on the extent of protein modification. POZ conjugates of insulin lowered blood glucose levels for a period of 8 h when compared to 2 h for insulin alone. PEOZ, like PEG, was also able to successfully attenuate the immunogenic properties of BSA. The POZ polymers (10 and 20 kDa) are safe when administered intravenously to rats, and the maximum tolerated dose (MTD) was greater than 2 g/kg. Blood counts, serum chemistry, organ weights, and the histopathology of key organs were normal. These results conclude that POZ has the desired drug delivery properties for a new biopolymer.

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

“…3) and demonstrated similar extension in pharmacokinetics compared to other POZ-conjugated drugs. 24 When conjugates were administered subcutaneously, SER-214 had a much slower t1 =2 release rate ( 40-50 hours) and did not show an initially high rate of release when compared to SER-212 (Fig. 3).…”

“…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.…”

“…[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. We have examined its pharmacokinetic profile, and determined the pharmacodynamic effects of POZ-rotigotine treatment in a rat model of PD.…”

Polymers for Protein Conjugation

“…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.…”

“…These derivatives offer a wide selection of protein coupling chemistries, and it is also possible to perform enzymatic mediated protein conjugation with PEOZ [98]. As demonstrated by the preserved enzymatic activity of PEOZylated uricase, catalase and ribonuclease and the preserved secondary structure of coupled proteins [98], PEOZ does not interact with the protein surface [100]. Its stealth properties have been confirmed, as the PEOZ-bovive serum albumin (BSA) conjugate is significantly less immunogenic with respect to BSA or PEG-BSA [100].…”