Site‐Specific Zwitterionic Polymer Conjugates of a Protein Have Long Plasma Circulation. Issue 17 (20th October 2015)

• Record Type: Journal Article
• Authors: Bhattacharjee, Somnath; Liu, Wenge; Wang, Wei‐Han; Weitzhandler, Isaac; Li, Xinghai; Qi, Yizhi; Liu, Jinyao; Pang, Yan; Hunt, Donald F.; Chilkoti, Ashutosh
• Is Part Of: Chembiochem. Volume 16:Issue 17(2015)
• Page Start: 2451
• Page End: 2455
• Publication Date: 2015-10-20
• Subjects: atom-transfer radical polymerization -- pharmacokinetics -- protein–polymer conjugates -- site-specific modifications -- zwitterions; Biochemistry -- Periodicals; Molecular biology -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1002/cbic.201500439
• Languages: English
• ISSNs: 1439-4227

Abstract

Abstract: Many proteins suffer from suboptimal pharmacokinetics (PK) that limit their utility as drugs. The efficient synthesis of polymer conjugates of protein drugs with tunable PK to optimize their in vivo efficacy is hence critical. We report here the first study of the in vivo behavior of a site‐specific conjugate of a zwitterionic polymer and a protein. To synthesize the conjugate, we first installed an initiator for atom‐transfer radical polymerization (ATRP) at the N terminus of myoglobin (Mb‐N‐Br). Subsequently, in situ ATRP was carried out in aqueous buffer to grow an amine‐functionalized polymer from Mb‐N‐Br. The cationic polymer was further derivatized to two zwitterionic polymers by treating the amine groups of the cationic polymer with iodoacetic acid to obtain poly(carboxybetaine methacrylate) with a one‐carbon spacer (PCBMA; C1 ), and sequentially with 3‐iodopropionic acid and iodoacetic acid to obtain PCBMA(mix) with a mixture of C1 and C2 spacers. The Mb‐N‐PCBMA polymer conjugates had a longer in vivo plasma half‐life than a PEG‐like comb polymer conjugate of similar molecular weights (MW). The structure of the zwitterion plays a role in controlling the in vivo behavior of the conjugate, as the PCBMA conjugate with a C1 spacer had significantly longer plasma circulation than the conjugate with a mixture of C1 and C2 spacers. Abstract : Live action : Mb‐N‐PCBMA, the site‐specific conjugate of a zwitterionic polymer—poly(carboxybetaine methacrylate)—and a model protein, myoglobin shows a longer in vivo plasma half‐life than a PEG‐like comb polymer conjugate of similar molecular weight. The spacer between the cation and anion plays an important role in controlling the plasma residence time of the conjugate.