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Temperature Sensitive Gelation of PAF-PEG-PAF Triblock Copolymer Aqueous Solution

Temperature Sensitive Gelation of PAF-PEG-PAF Triblock Copolymer Aqueous Solution
Other Titles
폴리펩타이드 삼블록 공중합체 수용액의 온도민감성 젤화
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대학원 나노과학부
이화여자대학교 대학원
Amino acids are natural resource building blocks that can give not only a variety of hydrophilic/hydrophobic, ionic/non-ionic character, but also exact stereochemistry with a special structure to the material. Therefore, the search for a novel functional material based on the amino acids has been a continuing interest among the scientists.1-3 Here we are reporting a poly(alanine-co-phenyl alalnine)- block-poly (ethylene glycol)-block-poly(alanine-co-phenyl alalnine) (PAF-PEG-PAF) aqueous solution that undergoes sol-to-gel transition as the temperature increases. The polymers formed micelles that have a core-shell structure in water at 15 oC. As the temperature increased, the poly(ethylene glycol) of the shell region was partially dehydrated and the polypeptide of the core region underwent a conformational change, whereas the apparent micelle size increased due to the significant intermicellar bridge formation. The sol-to-gel transition temperature could be controlled in a range of 13 ~ 55 oC by varying composition and concentration of the polymer. Furthermore, a gel formed in-situ by a subcutaneous injection of the polymer aqueous solution (0.5 mL; 8.0 wt. %) to the rat (in vivo) was lost more than 90 % of its original mass, whereas that was preserved as practically intact in phosphate buffer saline (in vitro) at 37 oC. The polypeptide polymer was degraded over 15 days. The current functional polypeptide might be very promising for biomedical applications including tissue engineering, cell therapy, and drug delivery. Poly(amino acid) or polypeptide has been drawing attention due to 1) its well-defined secondary structural motif such as α-helix, β-sheet, and random coil, 2) facile control of hydrophilic/hydrophobic balance by combining various amino acids, and 3) its potentiality as a biocompatible material. Silk mimicking polypeptides, reversibly reassembling nanofiber, and tissue engineering scaffold for cartilage repair, synapse and bone regeneration are typical examples.4-8 The aqueous solution undergoing sol-to-gel transition as the temperature increases (reverse thermal gelation) has been suggested as one of the most promising implantable system of the pharmaceutical agents and cells/stem cells due to its simplicity in fabrication process and non-surgical implanting procedure.9-10 Thermogelation is driven by the delicate balance between hydrophilicity and hydrophobicity of the polymers. Therefore, thermogelling polymers are prepared by copolymer consisting of hydrophilic block and hydrophobic block. 11-12 However, the strong hydrogen bonding or ionic interactions between peptides make most polypeptide systems form a stable gel phase at a low temperature. Thus, most polypeptide aqueous solutions undergo a gel-to-sol transition (gel melting), instead of sol-to-gel transition (reverse thermal gelation), as the temperature increases. The leucine-zipper franked at the end of the flexible polypeptide, poly(ethylene glycol)-poly(L-benzyl glutamate), and poly(DL-lysine)-poly(L-leucine) are typical examples of such a polypeptides.13-15 They were excellent hydrogelators at low concentrations, however, showed a gel-melting behaviour. A few cases was reported to decrease in solubility for the polypeptide such as elastin-like polypeptide of poly(valine-proline-glycine-glycine), and poly(proline-glycine)/poly(proline-alanine) copolymer.16-18 In this paper, we are reporting an aqueous solution of the polypeptide triblock copolymer of poly(alanine-co-phenyl alanine)-poly(ethylene glycol)-poly(alanine-co-phenyl alanine) (PAF-PEG-PAF). Alanine-alanine and alanine-phenylalanine sequences are degraded by elastase and cathepsins that are present in the subcutaneous layer of mammals.19-21 Therefore, PAF and PEG were selected by considering the biodegradability as well as thermogelling properties of the polymer.;본 연구는 일정한 농도 이상에서 온도를 증가시킴에 따라 수용액에서 수화젤로 전이가 일어나는 폴리에틸렌 글리콜/폴리펩타이드 (PEG/PP) 블록 공중합체에 관한 것으로 이 물질 및 의약전달, 조직공학 등 이 물질의 의학적 응용을 포함한다. 본문에서의 폴리에틸렌 글리콜의 분자량은 1000이고, 폴리펩타이드는 아미노산 5개를 포함하는 공중합체를 합성하였다. 아미노산은 알라닌, 페닐알라닌으로 구성되어 졌다. 본 연구는 온도 민감성 폴리에틸렌 글리콜-폴리(알라닌-co-페닐알라닌)(PAF-PEG-PAF)와 폴리에틸렌 글리콜-폴리(알라닌)(PA-PEG-PA) 블록 공중합체의 제조와 그들의 의약전달시스템 및 조직공학 등 의학적 응용에 관한 것이다. 이들 고분자 수용액은 상온 또는 그 이하에서는 용액 또는 졸 상태로 존재하나, 체온 (37 oC) 근처에서는 수화젤로 전이가 일어나므로 이를 이용하여 의약전달 및 조직공학 재료로 유력시 되고 있다. 즉, 졸 상태에서 의약 또는 세포와 섞은 후에 피하 또는 근육 주사를 통하여 원하는 부위에 수화젤 (depot)을 순간적으로 만들어서 약물이 서서히 방출하거나 세포가 자라서 조직이 재생될 수 있다. 이러한 생분해성 재료는 외과적 수술이 필요 없이 depot을 만들고, 살균과정이 단순한 마이크로 필터를 통하여 가능하다. 본 연구에서는 상온 또는 그 이하에서는 수용액 (졸) 상태로 존재하나, 체온에서 수화젤로 변하는 온도 민감성 졸-젤 전이 고분자에 관한 것이다. 특히, 이들 폴리펩타이드는 보관시 가수분해에 의해 안정하나, 체내 주입시에 capthesin B 등 체내 효소에 의해 분해가 될 것으로 기대되어, 보관 안정성이 뛰어나고, 분해시에 산을 방출하지 않으므로 산에 민감한 의약품의 방출 시스템으로도 기대된다.
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