近十年來，具有自組裝能力的材料被研究學者開發成載體粒子，比起微脂粒，雙親性高分子開發的載體具有較多優勢，如：仿生功能、誘發生化機制、藥物控制釋放能力及穩定性高的高分子載體粒子。1本文研究將胺基酸合成為嵌段共聚物，一端為聚賴胺酸(PLL)一端為聚酪胺酸(PLT)。PLL-b-PLT被設計成雙親性材料，由奈米沉降法在不同的溶液環境下可自組裝成超分子，如在DIW與pH12水溶液及磷酸鹽緩衝溶液等環境。經圓二色光譜儀鑑定PLL-b-PLT在DIW與pH 12下的二級結構，分別會從無規高分子纏繞變成β-摺疊、從α-螺旋變成無規高分子纏繞。隨分子量的改變，動態光散射儀器檢驗出PLL-b-PLT組裝的粒子粒徑分佈範圍在100nm 到400nm之間；使用穿隧式電子顯微鏡與靜態光散射儀可驗證PLL-b-PLT粒子的構型，發現不同分子量的PLL-b-PLT能分別組裝成微胞及液胞。具有組裝能力的PLL-b-PLT可用來包覆各種範例藥物：焦油腦、5-氟尿嘧啶、紫杉醇、阿黴素等，而從TEM觀察到包覆藥物的PLL-b-PLT粒子會因為和藥物的π鍵堆積力或氫鍵作用力使載體粒子在變形成長蟲狀的奈米粒子。PLL-b-PLT載體材料經過修飾乳醣酸後具有標靶人體肝臟細胞的能力，本研究使用化學修飾法將乳酸糖修飾在PLL-b-PLT上，讓組裝成的高分子載體提升了生物相容性及外加標靶治療的能力。2, 3

In decades, polymersomes which consist of self-assembled materials have received much attention from the sciencetist as nanoscale encapsulants. Compared with liposomes, developing novel amphiphilc copolymer for nanoparticles formation has much potential on material properties, such as stimuli responsiveness , induced biofunctionality, drug control release, and stability. On this study, we used polypeptides, polylysine and polytyrosine, as both segments of di-block copolymer. PLL-b-PLT designed as a zwitterionic diblock copolymer can form nanoparticle by nanoprecipitation in different solution condition, neutral or basic aqueous. Circular dichroism measurement shows that PLL segments adopt random coil conformation and change to β-sheet, PLT segments change from α-helical structure to random coil when pH value goes from 7 to 12. DLS shows that PLL-b-PLT has broad size distribution, 100nm~400nm, which was also evidenced by TEM figure. Different molecular weight of PLL-b-PLT demonstrated the shape of nanoparticle, micelle or vesicle, by TEM and SLS. After morphological characterization, the interaction between polymeric carrier and model drugs, pyrene, 5-fu, TAX and DOX, was investigated, also the encapsulation efficiency and loading capacity of PLL-b-PLT. TEM figure shows that when PLL-b-PLT complex with model drug, the spherical polymersomes change the conformation to worm-like nanoparticle. In the research of drug delivery system, Lactobionic acid can target the certain organ in human so we modified the target ligand on the side chain of PLL. Thus, the polymeric carrier formed by PLL-b-PLT can enhance the properties: biocompatible and targeting ability.

1. Holowka EP, Sun VZ, Kamei DT, Deming TJ. Polyarginine segments in block copolypeptides drive both vesicular assembly and intracellular delivery. Nature Materials 2007;6(1):52-57.
2. Narain R, Armes SP. Synthesis and aqueous solution properties of novel sugar methacrylate-based homopolymers and block copolymers. Biomacromolecules 2003;4(6):1746-1758.
3. Tian Z, Wang M, Zhang AY, Feng ZG. Preparation and evaluation of novel amphiphilic glycopeptide block copolymers as carriers for controlled drug release. Polymer 2008;49(2):446-454.
4. Duncan R. The dawning era of polymer therapeutics. Nature Reviews Drug Discovery 2003;2(5):347-360.
5. Faraji AH, Wipf P. Nanoparticles in cellular drug delivery. Bioorganic & Medicinal Chemistry 2009;17(8):2950-2962.
6. Schatz C, Louguet S, Le Meins JF, Lecommandoux S. Polysaccharide- block- polypeptide copolymer vesicles: towards synthetic Viral Capsids. Angewandte Chemie-International Edition 2009;48(14):2572-2575.
7. Jeong YI, Cheon JB, Kim SH, Clonazepam release from core-shell type nanoparticles in vitro. Journal of Controlled Release 1998;51(2-3):169-178.
8. Cohen BE, Bangham AD. Diffusion of small nonelectrolytes across liposome membranes. Nature 1972;236(5343):173-&.
9. Discher BM, Won YY, Ege DS, Polymersomes: Tough vesicles made from diblock copolymers. Science 1999;284(5417):1143-1146.
10. Ahmed F, Discher DE. Self-porating polymersomes of PEG-PLA and PEG-PCL: hydrolysis-triggered controlled release vesicles. Journal of Controlled Release 2004;96(1):37-53.
11. Owen RL, Strasters JK, Breyer ED. Lipid vesicles in capillary electrophoretic techniques: Characterization of structural properties and associated membrane-molecule interactions. Electrophoresis 2005;26(4-5):735-751.
12. Schmidt CF, Svoboda K, Lei N, Existence of a flat phase in red-cell membrane skeletons. Science 1993;259(5097):952-954.
13. Photos PJ, Bacakova L, Discher B, Bates FS, Discher DE. Polymer vesicles in vivo: correlations with PEG molecular weight. Journal of Controlled Release 2003;90(3):323-334.
14. Rijcken CJF, Soga O, Hennink WE, van Nostrum CF. Triggered destabilisation of polymeric micelles and vesicles by changing polymers polarity: An attractive tool for drug delivery. Journal of Controlled Release 2007;120(3):131-148.
15. Jain S, Bates FS. On the origins of morphological complexity in block copolymer surfactants. Science 2003;300(5618):460-464.
16. Ahmed F, Pakunlu RI, Brannan A, Bates F, Minko T, Discher DE. Biodegradable polymersomes loaded with both paclitaxel and doxorubicin permeate and shrink tumors, inducing apoptosis in proportion to accumulated drug. Journal of Controlled Release 2006;116(2):150-158.
17. Yang XQ, Grailer JJ, Rowland IJ, Multifunctional SPIO/DOX-loaded wormlike polymer vesicles for cancer therapy and MR imaging. Biomaterials 2010;31(34):9065-9073.
18. Zhang WQ, Shi LQ, Wu K, An YG. Thermoresponsive micellization of poly(ethylene glycol)-b-poly(N-isopropylacrylamide) in water. Macromolecules 2005;38(13):5743-5747.
19. Li X, Mya KY, Ni XP, He CB, Leong KW, Li J. Dynamic and static light scattering studies on self-aggregation behavior of biodegradable amphiphilic poly(ethylene oxide)-poly (R)-3-hydroxybutyrate -poly(ethylene oxide) triblock copolymers in aqueous solution. Journal of Physical Chemistry B 2006;110(12):5920-5926.
20. Deng YH, Li YB, Wang XG. Colloidal sphere formation, H-aggregation, and photoresponsive properties of an amphiphilic random copolymer bearing branched azo side chains. Macromolecules 2006;39(19):6590-6598.
21. Rodriguez-Hernandez J, Lecommandoux S. Reversible inside-out micellization of pH-responsive and water-soluble vesicles based on polypeptide diblock copolymers. Journal of the American Chemical Society 2005;127(7):2026-2027.
22. Nichifor M, Schacht EH, Seymour LW. Polymeric prodrugs of 5-fluorouracil. Journal of Controlled Release 1997;48(2-3):165-178.
23. Le Hellaye M, Fortin N, Guilloteau J, Soum A, Lecommandoux S, Guillaume SM. Biodegradable polycarbonate-b-polypeptide and polyester-b-polypeptide block copolymers: Synthesis and nanoparticle formation towards biomaterials. Biomacromolecules 2008;9(7):1924-1933.
24. Van Hest JCM. Biosynthetic-synthetic polymer conjugates. Polymer Reviews 2007;47(1):63-92.
25. Schmid B, Chung DE, Warnecke A, Fichtner I, Kratz F. Albumin-binding prodrugs of camptothecin and doxorubicin with an ala-leu-ala-leu-linker that are cleaved by cathepsin B: Synthesis and antitumor efficacy. Bioconjugate Chemistry 2007;18(3):702-716.
26. Huang YC, Arham M, Jan JS. Alkyl chain grafted poly(L-lysine): self-assembly and biomedical application as carriers. Soft Matter 2011;7(8):3975-3983.
27. Kuo SW, Tsai HT. Control of peptide secondary structure on star shape polypeptides tethered to polyhedral oligomeric silsesquioxane nanoparticle through click chemistry. Polymer 2010;51(24):5695-5704.
28. Li D, Ping YA, Xu FJ, Construction of a Star-Shaped Copolymer as a Vector for FGF Receptor-Mediated Gene Delivery In Vitro and In Vivo. Biomacromolecules 2010;11(9):2221-2229.
29. Mooguee M, Omidi Y, Davaran S. Synthesis and In Vitro Release of Adriamycin from Star-Shaped Poly(Lactide-co-Glycolide) Nano- and Microparticles. Journal of Pharmaceutical Sciences 2010;99(8):3389-3397.
30. Gaspard J, Silas JA, Shantz DF, Jan JS. Supramolecular assembly of lysine-b-glycine block copolypeptides at different solution conditions. Supramolecular Chemistry 2010;22(3):178-185.
31. Takae S, Miyata K, Oba M, PEG-detachable polyplex micelles based on disulfide-linked block catiomers as bioresponsive nonviral gene vectors. Journal of the American Chemical Society 2008;130(18):6001-6009.
32. Darbre T, Reymond JL. Peptide dendrimers as artificial enzymes, receptors, and drug-delivery agents. Accounts of Chemical Research 2006;39(12):925-934.
33. Upadhyay KK, Le Meins JF, Misra A, Biomimetic Doxorubicin Loaded Polymersomes from Hyaluronan-block-Poly(gamma-benzyl glutamate) Copolymers. Biomacromolecules 2009;10(10):2802-2808.
34. Li LJ, Wang HY, Ong ZY, Polymer- and lipid-based nanoparticle therapeutics for the treatment of liver diseases. Nano Today 2010;5(4):296-312.
35. Zhang Y, Li JS, Lang MD, Tang XL, Li L, Shen XZ. Folate-functionalized nanoparticles for controlled 5-Fluorouracil delivery. Journal of Colloid and Interface Science 2011;354(1):202-209.
36. Sonaje K, Lin YH, Juang JH, Wey SP, Chen CT, Sung HW. In vivo evaluation of safety and efficacy of self-assembled nanoparticles for oral insulin delivery. Biomaterials 2009;30(12):2329-2339.
37. Yu TX, Rao JN, Zou TT, Competitive Binding of Occludin mRNA to COG-binding Protein 1 and HuR Regulates Its Translation and Epithelial Barrier Function. Gastroenterology 2011;140(5):S502-S503.
38. Lu YJ, Low PS. Folate-mediated delivery of macromolecular anticancer therapeutic agents. Advanced Drug Delivery Reviews 2002;54(5):675-693.
39. Franks NP, Lieb WR. Molecular and cellular mechanisms of general-anesthesia. Nature 1994;367(6464):607-614.
40. Raemdonck K, Demeester J, De Smedt S. Advanced nanogel engineering for drug delivery. Soft Matter 2009;5(4):707-715.
41. Prabaharan M, Grailer JJ, Steeber DA, Gong SQ. Thermosensitive Micelles Based on Folate-Conjugated Poly(N-vinylcaprolactam)-block-Poly(ethylene glycol) for Tumor-Targeted Drug Delivery. Macromolecular Bioscience 2009;9(8):744-753.
42. Zhao PQ, Wang HJ, Yu M, Paclitaxel-Loaded, Folic-Acid-Targeted and TAT-Peptide-Conjugated Polymeric Liposomes: In Vitro and In Vivo Evaluation. Pharmaceutical Research 2010;27(9):1914-1926.
43. Lestini BJ, Sagnella SM, Xu Z, Surface modification of liposomes for selective cell targeting in cardiovascular drug delivery. Journal of Controlled Release 2002;78(1-3):235-247.
44. Araujo FA, Kelmann RG, Araujo BV, Finatto RB, Teixeira HF, Koester LS. Development and characterization of parenteral nanoemulsions containing thalidomide. European Journal of Pharmaceutical Sciences 2011;42(3):238-245.
45. Chen HY, Gu YQ, Hu YZ. Comparison of two polymeric carrier formulations for controlled release of hydrophilic and hydrophobic drugs. Journal of Materials Science-Materials in Medicine 2008;19(2):651-658.
46. Wang Y, Gao SJ, Ye WH, Yoon HS, Yang YY. Co-delivery of drugs and DNA from cationic core-shell nanoparticles self-assembled from a biodegradable copolymer. Nature Materials 2006;5(10):791-796.
47. Putnam D, Kopecek J. Enantioselective release of 5-fluorouracil from N-(2-hydroxypropyl)methacrylamide-based copolymers via lysosomal-enzymes. Bioconjugate Chemistry 1995;6(4):483-492.
48. Lin FH, Lee YH, Jian CH, Wong JM, Shieh MJ, Wang CY. A study of purified montmorillonite intercalated with 5-fluorouracil as drug carrier. Biomaterials 2002;23(9):1981-1987.
49. Chen AZ, Pu XM, Kang YQ, Liao L, Yao YD, Yin GF. Preparation of 5-fluorouracil- poly(L-lactide) microparticles using solution-enhanced dispersion by supercritical CO2. Macromolecular Rapid Communications 2006;27(15):1254-1259.
50. Wang TW, Li MJ, Gao HX, Wu Y. Nanoparticle carriers based on copolymers of poly(epsilon-caprolactone) and hyperbranched polymers for drug delivery. Journal of Colloid and Interface Science 2011;353(1):107-115.
51. Liu KH, Chen SY, Liu DM, Liu TY. Self-assembled hollow nanocapsule from amphiphatic carboxymethyl-hexanoyl chitosan as drug carrier. Macromolecules 2008;41(17):6511-6516.
52. Tewes F, Munnier E, Antoon B, Comparative study of doxorubicin-loaded poly(lactide-co-glycolide) nanoparticles prepared by single and double emulsion methods. European Journal of Pharmaceutics and Biopharmaceutics 2007;66(3):488-492.
53. Wang F, Wang YC, Yan LF, Wang J. Biodegradable vesicular nanocarriers based on poly(epsilon-caprolactone)-block-poly(ethyl ethylene phosphate) for drug delivery. Polymer 2009;50(21):5048-5054.
54. Deming TJ. Facile synthesis of block copolypeptides of defined architecture. Nature 1997;390(6658):386-389.
55. Kim JD, Han G, Zee OP, Jung YH. Deprotection of benzyl and p-methoxybenzyl ethers by chlorosulfonyl isocyanate-sodium hydroxide. Tetrahedron Letters 2003;44(4):733-735.
56. Subramanian G, Hjelm RP, Deming TJ, Smith GS, Li Y, Safinya CR. Structure of complexes of cationic lipids and poly(glutamic acid) polypeptides: A pinched lamellar phase. Journal of the American Chemical Society 2000;122(1):26-34.
57. Takahashi S, Hasumi K, Ohnishi A, Koshino H, Matsumoto S. Synthesis and biological activities of analogs of D-glucosyl-L-tyrosine, a humoral factor that stimulates transcription of the acyl-CoA binding protein in the pheromone gland of the Silkmoth, Bombyx mori. Bioorganic & Medicinal Chemistry 2007;15(1):97-103.
58. Felix AM, Heimer EP, Lambros TJ, Tzougraki C, Meienhofer J.Rapid removal of protecting groups from peptides by catalytic transfer hydrogenation with 1,4-cyclohexadiene. Journal of Organic Chemistry 1978;43(21):4194-4196.
59. Rao JY, Zhang YF, Zhang JY, Liu SY. Facile Preparation of Well-Defined AB(2) Y-Shaped Miktoarm Star Polypeptide Copolymer via the Combination of Ring-Opening Polymerization and Click Chemistry. Biomacromolecules 2008;9(10):2586-2593.
60. Andrew CD, Bhattacharjee S, Kokkoni N, Hirst JD, Jones GR, Doig AJ. Stabilizing interactions between aromatic and basic side chains in alpha-helical peptides and proteins. Tyrosine effects on helix circular dichroism. Journal of the American Chemical Society 2002;124(43):12706-12714.
61. Fasman G, Bodenheimer E, Lindblow C. Optical rotatory dispersion studies of poly-l-tyrosine and copolymers of l-glutamic acid and l-tyrosine. significance of the tyrosyl cotton effects with respect to protein conformation*. Biochemistry 1964;3(11):1665-1674.
62. Geng Y, Discher DE. Hydrolytic degradation of poly(ethylene oxide)-block-polycaprolactone worm micelles. Journal of the American Chemical Society 2005;127(37):12780-12781.
63. Cai CH, Lin JP, Chen T, Tian XH. Aggregation behavior of graft copolymer with rigid backbone. Langmuir 2010;26(4):2791-2797.