Abstract
Sustained release is being explored to increase plasma and tissue residence times of polymer-protein therapeutics for improved efficacy. Recently, poly(oligo(ethylene glycol) methyl ether methacrylate) (PEGMA) polymers have been established as potential PEG alternatives to further decrease immunogenicity and introduce responsive or sieving properties. We developed a drug delivery system that locally depresses the lower critical solution temperature (LCST) of PEGMA-protein conjugates within zwitterionic hydrogels for controlled release. Inside the hydrogel the conjugates partially aggregate through PEGMA-PEGMA chain interactions to limit their release rates, whereas conjugates outside of the hydrogel are completely solubilized. Release can therefore be tuned by altering hydrogel components and the PEGMA’s temperature sensitivity without the need for traditional controlled release mechanisms such as particle encapsulation or affinity interactions. Combining local LCST depression technology and degradable zwitterionic hydrogels, complete release of the conjugate was achieved over 13 days.
Highlights
Polymer conjugation to protein therapeutics is a common technique to enhance therapeutic efficacy by minimizing immunogenicity and increasing plasma and tissue residence times due to slower clearance rates [1,2]
poly(oligo(ethylene glycol) methyl ether methacrylate) (PEGMA) is an attractive polymer for protein conjugation due to low antigenicity, ease of polymerization and successful demonstrations in the production of polymer-protein conjugates [6,7,8]
[7] PEGMA with side chains of only 2–3 ethylene glycol repeat units do not bind to anti-poly(ethylene) glycol (PEG) antibodies, potentially reducing immune recognition of the polymer [6]
Summary
Polymer conjugation to protein therapeutics is a common technique to enhance therapeutic efficacy by minimizing immunogenicity and increasing plasma and tissue residence times due to slower clearance rates [1,2]. To further improve the efficacy of polymer-protein conjugates, alternatives to PEG are being explored to maintain therapeutic effects while further minimizing antigenic or immunogenic effects [1,4]. Despite the greater plasma and tissue half-lives provided upon polymer conjugation, repeated dosing of polymer-protein conjugates are often required to maintain therapeutic. Despite the greater plasma and tissue half-lives provided upon polymer conjugation, 2 of 12 repeated dosing of polymer-protein conjugates are often required to maintain therapeutic drug concentrations at disease sites. This has prompted research into stimuli responsive drug dderpuogtscothnactensltorwatliyonrselaetadseisepaosleymsiteers-p. PEgGlyMcoAl mcoepthoylylmetehresromf deitehtahcyrlyenlaetegl(yTc)oPl (mDextThyy)l ewthereer msyentthhaecsriyzleadtet(oDa)cahnidevterietethmypleenraetgulryec-osel nsitive mtwoieutthhnsydulepidertgtoeahoslbyeilgpmrenhmaeeanrdessdtethwhotariycutadhrnnyrssdoliuaetgtiiretoegalno(bpTslpre)wohPamian(tDshodeitxnheTtrdyyba)dupnwrtshoienatgrisoeoeetlnstopsyruranwotntsmihsitdiheotesiitoneiozndbefsdputfhhtoteoanrshoAaeytcbthdor(uiarDeontvxsgsTeiiedytlt)ie.eo. mTnoshfpetfehocreraoAhtnuyjburd(egDr-aosxtegTenesysl)w.i.tiTevrheeepdcoeolsnyijgmungeeardstes were
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