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Enzymatically Degradable Thermogelling Poly(alanine-co-leucine)-Poloxamer-Poly(alanine-co-leucine)

Enzymatically Degradable Thermogelling Poly(alanine-co-leucine)-Poloxamer-Poly(alanine-co-leucine)
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효소분해 가능한 온도 민감성 고분자 PAL-PLX-PAL 의 연구
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대학원 화학·나노과학과
이화여자대학교 대학원
Aqueous solutions of thermogelling polymers undergo sol-to-gel transition as the temperature increases. Therefore, the drug or cells are mixed as a sol state , followed by injection at a target site of subcutaneous layer to make an implanted depot system. The conventional syringe injection without the need of surgical procedure makes the thermogelling polymers solution as a minimally invasive delivery system. Homo- and co-polymers of lactic acid, glycolic acid, and caprolactone, chitosan, polyphosphazene, poloxamer derivatives, polycarbonate, polycyanoacrylate, β-lactoglobulin, elastin-like polypeptide (ELP) based polymer, and silk-elastin-like polymer have been reported as biodegradable thermogelling polymer aqueous solutions.1-9 However, most of thermogelling polymers suffer from reconstitution of the formulation due to the slow dissolution kinetics of the polymer in water. As the temperature increases, the aqueous solubility of the thermogelling polymer decreases. Therefore, the traditional method to prepare the aqueous solution of the themrogelling polymer is to dissolve the polymer at cold water, requiring a long time for reconstitution of the drug formulation as a solution. On the other hand, thermogelling polymers with enzymatic degradability can detour the solubility problem by storing the polymer as an enzyme-free buffer solution. The polymer begins to be degraded by the enzymes only after in vivo application, suggesting the storage stability and ready-to-use formulation of the thermogelling polymer as an aqueous solution, rendering a significant improvement of the convenience for medical application. Recently, we reported a poly(ethylene glycol)-poly(alanine-co-phenylalanine) (PEG-PAF) that underwent degradation by cathepsin B, cathepsin C, and elastase.10,11 The polymer showed stability in phosphate buffered saline (in vitro) without any significant mass loss (< 10 %), whereas 90 % of mass loss in the subcutaneous layer of rat (in vivo). As an extension of the enzymatic degradable sequence for a thermogelling system, here, we are reporting poly(alanine-co-leucine)-poloxamer-poly(alanine-co-leucine) (PAL-PLX-PAL). The polypeptide is expected not only to develop self-assembly with specific secondary structures but also to show unique enzymatic degradability.12-14 Physicochemical properties of the polymer aqueous solution was investigated by dynamic mechanical analysis, circular dichroism, dynamic light scattering, transmission electron microscopy, FTIR, and 13C-NMR. The degradation of the gel was studied in buffer solutions containing enzymes (in vitro) as well as in the subcutaneous layer of rats (in vivo). Tissue compatibility of the in-situ formed gel depot was investigated. In addition, the drug release profiles of a model protein drug, bovine serum albumin (BSA), were investigated by a preset gel-injection strategy to reduce the initial burst.;이 연구는 효소적으로 분해 가능한 온도 민감성 고분자에 대한 것으로, 폴리(알라닌-co-류신)이 양끝에 씌워져 있는 폴리(프로필렌 글리콜)-폴리(에틸렌 글리콜)-폴리(프로필렌 글리콜)) (PAL-PLX-PAL)에 대해 보고하고자 한다. 이 고분자 수용액은 온도가 증가함에 따라 온도겔화를 나타낸다. 실험결과, 수용액의 농도가 3.0 wt.% ~ 10.0 wt.% 일 때 20~40oC의 온도 범위에서 졸-겔 전이를 보인다. 이러한 양친매성 고분자는 소수성인 PAL (폴리(알라닌-co-류신)) 펩타이드 블록이 중심부를 형성하고 친수성인 PLX(폴리(프로필렌 글리콜)-폴리(에틸렌 글리콜)-폴리(프로필렌 글리콜))가 껍질부분을 형성함으로써 수용액상에서 미셸을 형성한다. 폴리(폴리(알라닌-co-류신))의 α-나선 이차구조는 20~50oC에서 안정한 반면, PLX는 졸-겔 전이를 하는 동안 분자 운동이 현저하게 감소됨을 보인다. 이 고분자는 MMP (매트릭스 메탈로프로테인아제), Elastase (엘라스타아제)같은 단백질 가수분해 효소에 분해되는 반면, Cathepsin B (카텝신 B), Cathepsin C (카텝신 C)와 Chymotrypsin (키모트립신)효소와 PBS 버퍼에 대해서는 비교적 안정하였다. In-situ에서 형성된 겔을 쥐에 피하주사 하였을 때, 겔 지속성, 조직적합성을 45일 동안 알아보았다. 이 연구는 PAL-PLX-PAL가 주사 가능한 생체 물질로서 매우 유망하다는 것을 보여준다.
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