바이오응용을위한그래핀 / 자극감응형 폴리머복합체연구동향 성균관대학교나노소재기반휴먼인터페이스융합연구센터선임연구원윤옥자

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1 바이오응용을위한그래핀 / 자극감응형 폴리머복합체연구동향 성균관대학교나노소재기반휴먼인터페이스융합연구센터선임연구원윤옥자

2 1. 서론 Ø 자극감응형고분자인하이드로젤은온도, ph, 전기, 응력, 압력, 이온강도, 소리및농도등의외부자극에의한가역적또는비가역적으로하이드로젤네트워크의구조적변화를일으키고수용액상에서물에팽윤할수있는친수성고분자이다 1-3. Ø 생물의학분야에서의자극감응형하이드로젤고분자는우수한생체적합성, 외부환경에대한감응성등에의하여생물계에내재된자극반응능력과특이성, 약물전달시스템으로적용이가능하여다양한응용연구가진행되고있다 4. Ø 최근, 자극감응형하이드로젤은기능성약물전달, 조직공학재생, 바이오센서등의소재로서각광을받고있다 5. Ø 따라서, in vitro 상에온도, PH, 약물전달시스템등에적용된그래핀과자극감응형폴리머복합체의바이오응용연구가최근보고되고있다. Ø 본정보는그래핀과자극감응형고분자복합체바이오응용에대한최근동향에대해기술하고자한다

3 2. 바이오응용하기위한온도, PH 감응형그래핀산화물 / 자극감응형폴리머복합체제조및물성연구 Ø A one-step strategy for thermal- and ph-responsive graphene oxide interpenetrating polymer hydrogel networks 6 - Sun et al. 은 GO/PNIPAM IPN (Graphene oxide/ poly(n-isopropylacrylamide) 하이드로젤네트워크를간단한제조방법에의하여수용상태에서 GO sheets 와 PNIPAM-co- AA microgels 의공유결합에의하여형성하였음. - GO/PNIPAM IPN 하이드로젤네트워크는온도와 PH 의두가지감응의가역성이좋아짐을입증함. - GO sheets 는하이드로젤네트워크안에균일하게잘분산되었고높은 cross-linking reaction 의결과로 mechanical strength 가향상되었으며, 이러한향상된물성은약물전달과같은바이오응용가능성을보임. - 이와같은간단한제조방법은다른자극감응형나노복합하이드로젤에응용이가능함을보여주고물성향상을증명함.

Fig. 1 (a) Formation of GO/PNIPAM interpenetrating hydrogel networks via the reaction between ECH and carboxyl groups in GO

98 C for incubation while ECH would permeate into the aqueous phase to induce the cross-linking reaction Fig.

heating and cooling. The volume and color changes are completely reversible.

4 Fig. 1 (a) Formation of GO/PNIPAM interpenetrating hydrogel networks via the reaction between ECH and carboxyl groups in GO sheets and PNIPAMco-AA microgels (b) Structural sketch of GO/PNIPAM IPN hydrogel (c) The sealed reaction tube was placed at 98 C for incubation while ECH would permeate into the aqueous phase to induce the cross-linking reaction Fig. 2 Top: (a) Photographs of swollen PNIPAM microgel network in water at different temperatures from 20 C to 50 C during heating and cooling. The volume and color changes are completely reversible. Bottom: DSC (b) heating and (c) cooling curves (10 C min1) of GO/ PNIPAM IPN hydrogel and PNIPAM microgel network at different phs compared to PNIPAM microgel aqueous dispersion (3.7wt%)

Ø Stimuli-responsive polymer covalent functionalization of graphene oxide by Ce(IV)-Induced redox polymerization 7 - 자극감응형폴리머인 poly(acrylic acid) 와 poly(n-isopropylacrylamide) 는간단한 Ce(IV)-induced

5 Ø Stimuli-responsive polymer covalent functionalization of graphene oxide by Ce(IV)-Induced redox polymerization 7 - 자극감응형폴리머인 poly(acrylic acid) 와 poly(n-isopropylacrylamide) 는간단한 Ce(IV)-induced redox polymerization 에의하여그래핀산화물표면에공유결합으로기능화함. - GO-PAAs 와 GO-PNIPAMs 의성분분석과열무게분석에의하면폴리머에의하여기능화된밀도는 monomers 의양이많을수록증가되고제어가능함을보임. - 수용액상태에서 GO-PAAs와 GO-PNIPAMs의 assemble-disassemble behaviors 는다양한온도와 PH 의하여제어가능성을입증. - 이러한방법은 water-soluble vinyl monomers 활용에따른그래핀산화물의기능화하기위한간단한방법을제시함. Fig. 3 Schematic synthetic route of polymer-grafted GO

Table 1 Graft ratio of PNIPAM evaluated by elemental

4 (A) Photographs of aqueous solutions of GO-PAA-3

3 (b) ph= 4, (c) ph= 5, and (d) ph = 6 (B) Schematic

5 (A) Photographs of aqueous solution of GO-PNIPAM-3

6 Table 1 Graft ratio of PNIPAM evaluated by elemental analysis Fig. 4 (A) Photographs of aqueous solutions of GO-PAA-3 upon standing for 3 h at different ph values: (a) ph= 3 (b) ph= 4, (c) ph= 5, and (d) ph = 6 (B) Schematic illustration of ph responsibility of GO-PAA Fig. 5 (A) Photographs of aqueous solution of GO-PNIPAM-3 at (a) 25 C for 3 h and (b) 35 C for 10 min (B) Schematic illustration of thermal responsibility of GO-PNIPAM

3. 인공근육장치로응용하기위한자극감응형부피변화를가지는그래핀 / 자극감응형폴리머복합체 Ø Graphene-polymer hydrogels with stimulus-sensitive volume changes 8 - 가역적인부피변화를가지는그래핀 / poly(n-isopropylacrylamide) 하이드젤 3D 네트워크구조는 hydrothermal

7 3. 인공근육장치로응용하기위한자극감응형부피변화를가지는그래핀 / 자극감응형폴리머복합체 Ø Graphene-polymer hydrogels with stimulus-sensitive volume changes 8 - 가역적인부피변화를가지는그래핀 / poly(n-isopropylacrylamide) 하이드젤 3D 네트워크구조는 hydrothermal 방법에의하여준비하였고 PNIPAAm 체인은그래핀을따라다공벽을형성함. - 물성은높은역학적강도, 전기적전도도, 가역적인부피변화, swelling/shrinking 성질등을나타냄. - 전기적자극에따라가역적인부피변화를나타냄으로써인공근육과같은바이오자극분야의응용성을제시하고있음. Fig. 6 FESEM images for the freeze-dried P@G gels, and photographs (inset) of the hydrogels. (a) and (b) the as-prepared sample; (c) the shrunk sample and (d) the swelled sample Fig. 7 (a) Electrical conductivity and volume changes (inset) for the P@Ghydrogel (25:2 mg/ml PNIPAAm/GO) at 21V; length in mm; (b) the extended electrical conductivity change experiment

8 4. 약물전달에응용하기위한그래핀 / 자극감응형폴리머복합체 Ø Water-Soluble Poly( N -isopropylacrylamide) Graphene Sheets Synthesized via Click Chemistry for Drug Delivery 9-50% 폴리머로되어있는 PNIPAM-GS(PNIPAM-grafted graphene sheets) 에서그래핀은높은용해성과안정성, amphiphilicity 을보이며 33 에서소수성이였던상태전이 (hydrophobic phase transition) 가친수성 (hydrophilic) 으로바뀜. - 이는그래핀과 grafted PNIPAM 의상호작용에의하여 PNIPAM homopolymer의상태전이온도 37.8 보다낮아졌음을보여주고있음. - PNIPAM-GS 와 aromatic drug 의 π π stacking 과 hydrophobic interaction 에의하여, CPT (camptothecin) 라는항암제를탑재한 PNIPAM- GS-CPT complex 합성함. - PNIPAM-GS 는세포독성이발현하지않았으나 PNIPAM-GS-CPT complex 는 in vitro 에서암세포 (skin tumor cells A-5RT3 ) 를죽이는효과를입증하였음. - 결과적으로, 폭넓은바이오메디컬응용이가능한나노물질로서 PNIPAM-GS 는항암제약물전달과방출제어의수단으로사용하기에높은효과를증명함.

Fig. 8 A) Schematic drawing for the CPT loaded PNIPAM- GS, and, B) UV vis absorption spectra of PNIPAM-GS and PNIPAM-GS-CPT with different concentrations.

9 Fig. 8 A) Schematic drawing for the CPT loaded PNIPAM- GS, and, B) UV vis absorption spectra of PNIPAM-GS and PNIPAM-GS-CPT with different concentrations. The inset represents the linear relationship between drug and carrier s concentration for samples 1 4 Fig. 9 (A) Relative cell viability of A-5RT3 cells treated with PNIPAMGS-CPT and free CPT versus CPT oncentration. (B) Relative cell viability of A-5RT3 cells treated with PNIPAM-GS and PNIPAM-GS-CPT at various concentrations. (C) Optical microscopic images of A-5RT3 cells before and after incubated with free CPT and PNIPAM-GS-CPT

10 4. 결론 Ø 그래핀 / 자극감응형폴리머복합체의바이오응용은아직그래핀과의복합에따른물성향상개발및측정이나 in vitro 상에서의약물전달정도에적용되어보고되어있고 in vivo 에서의응용에대한보고는발표되지않았다. 이러한복합체개발제조방법이나물성향상은다양한분야에중요한소재로응용이확대될것이다. Ø 그래핀 / 자극감응형폴리머복합체개발은바이오응용이외에센서소자의전기적적용 10 이나 magnetic graphene/ PNIPAAm microgels hybrids는 microreactors에서 switch materials로의응용을시도했고 11, 그래핀산화물 / infrared-light 감응형 PNIPAAM 하이드로젤나노복합체는 microfluidic actuators 12 등다양한분야의소재와소자로의응용이보고되고있다. Ø 이러한결과는 in vitro 에서의바이오응용뿐만아니라 in vivo 에서적용또한매우흥미로운결과를기대할수있으며이외에도바이오센서나조직공학적적용에따른결과를기대해본다.

11 5. 참고문헌 1. S. P. Zhao, M. J. Cao, L. Y. Li, W. L. Xu, Synthesis and properties of biodegradable thermo- and phsensitive poly[(n-isopropylacrylamide)-co-(methacrylic acid)] hydrogels, Poly. Degrad. Stab. 95 (2010) K. Katalin, W. Erzsebet, G. Erik, L. Krisztina, Distribution of phenols in thermoresponsive hydrogels. Macromolecules 40 (2007) K. Wang, S. Z. Fu, Y. C. Gu, X. Xu, P. W. Dong, G. Guo, X. Zhao, Y. Q. Wei, Z. Y. Qian, Synthesis and characterization of biodegradable ph-sensitive hydrogels based on poly(3-caprolactone),methacrylic acid, and poly(ethylene glycol). Polym. Degrad. Stab. 94 (2009) Y. Akiyama, A. Kikuchi, M. Yamato, T. Okano, Ultrathin Poly(N-isopropylacrylamide) Grafted Layer on Polystyrene Surfaces for Cell Adhesion/Detachment Control Langmuir 20 (2004) 강윤미, 김이슬, 이상효, 손진수, 이봉, 김재호, 김문석, 고분자과학과기술제 20 권 3 호 2009년 6월 5. 이상효, 손진수, 강윤미, 김이슬, 이해방, 민병현, 김재호, 김문석, 재료마당제22권제2호, 2009년 4월 6. S. Sun, P. Wu, A one-step strategy for thermal- and ph-responsive graphene oxide interpenetrating polymer hydrogel networks J. Mater. Chem. 21 (2011) B. Wang, D. Yang, J. Z. Zhang, C. Xi, J. Hu, Stimuli-responsive polymer covalent functionalization of graphene oxide by Ce(IV)-induced redox polymerization J. Phys. Chem. C 115 (2011) C. Hou, Q. Zhang, Y. Li, H. Wang, Graphene-polymer hydrogels with stimulus-sensitive volume changes carbon in press 9. Y. Pan, H. Bao, N. G. Sahoo, T. Wu, L. Li, Water-Soluble Poly( N -isopropylacrylamide) Graphene Sheets Synthesized via Click Chemistry for Drug Delivery Adv. Funct. Mater. XX (2011) P. Mukhopadhyay, R. K. Gupta, Trends and Frontiers in Graphene-Based Polymer Nanocomposites, PLASTICS ENGINEERING (2011) C. Hou, Q. Zhang, H. Wang, Y. Li, Functionalization of PNIPAAm microgels using magnetic graphene and their application in microreactors as switch materials, J. Mater. Chem., 21 (2011) C. W. Lo, D. Zhu, H. jiang, Microfluidic actuators based on infrared-light responsive PNIPAAm hydrogel nanocomposite incorporating graphene-oxide Transducers 11, Beijing, China, June 5-9 (2011)

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