合成生物学 ›› 2022, Vol. 3 ›› Issue (4): 728-747.DOI: 10.12211/2096-8280.2021-094
杨兆颖1,2, 张帆1,2, 郭建文1,2, 高卫平1
收稿日期:
2021-09-27
修回日期:
2021-11-11
出版日期:
2022-08-31
发布日期:
2022-09-08
通讯作者:
高卫平
作者简介:
基金资助:
Zhaoying YANG1,2, Fan ZHANG1,2, Jianwen GUO1,2, Weiping GAO1
Received:
2021-09-27
Revised:
2021-11-11
Online:
2022-08-31
Published:
2022-09-08
Contact:
Weiping GAO
摘要:
类弹性蛋白多肽(elastin-like polypeptide,ELP)是一种衍生于天然弹性蛋白,可人工合成的多肽聚合物。ELP具有特殊的温度响应性,它会随温度的变化表现出可逆相转变行为,并且当它与其他小分子或多肽偶联时,该温敏特性可以被充分保留。借助基因工程可以人工合成ELP与ELP融合蛋白,精确调控ELP的结构与功能,在其序列中添加反应性氨基酸或多肽。同时,ELP由天然氨基酸组成,其生物相容性好,易于生物降解,免疫原性低,无毒性作用。基于以上优势,ELP已被广泛应用于蛋白的表达纯化、体外诊断、药物递送和组织工程等生物医药领域。本文结合国内外研究报道,简要介绍了ELP的设计原理、理化特性和生物合成方法,并列举了一些ELP应用于药物递送系统中有代表性的工作,最后总结了该研究领域面临的挑战和问题。
中图分类号:
杨兆颖, 张帆, 郭建文, 高卫平. 类弹性蛋白多肽的生物合成及其药物递送应用[J]. 合成生物学, 2022, 3(4): 728-747.
Zhaoying YANG, Fan ZHANG, Jianwen GUO, Weiping GAO. Biosynthesis of elastin-like polypeptides and their applications in drug delivery[J]. Synthetic Biology Journal, 2022, 3(4): 728-747.
图3 ELP用于延长药物体内循环半衰期(a)ELP与小分子药物共价偶联,并可由连接子处断裂释放出游离药物;(b)小分子药物与带有靶向序列的ELP偶联,增强了肿瘤细胞对药物的摄取;(c)通过基因工程合成ELP融合蛋白的示意图;(d)NtTNF-VHHELP静脉注射到小鼠后物的药代谢动力学图[43];(e,f)静脉注射IFN-ELP与IFN的药代谢动力学(e)和肿瘤抑制情况(f)[44]
Fig. 3 ELPs applications in extending half-life of drugs(a) Chemically conjugated ELP to small molecule drugs by inclusion of an intervening cleavable linker which releases the free drug intracellularly after endocytic uptake and accumulation in the acidic, enzyme-rich environment of endosomes and lysosomes; (b) Enhanced cellular uptake of ELP conjugates by functionalization of ELP with cell-penetrating peptides; (c) Schematic of ELP genetically fused to peptide and protein drugs; (d) Pharmacokinetics of NtTNF-VHHELP[43]; (e, f) Pharmacometabolic kinetics (e) and in vivo antitumor effificacy (f) after intravenous injections with IFNα-ELP and IFNα[44]
图4 温度响应性ELP的局部缓释(a,b)温度响应性药物-ELP融合蛋白、药物-ELP偶联物在高于相变温度后会发生相变,形成聚集体,经皮下注射原位形成储库,并以单分子形式缓释入血液循环系统;(c)药物ELP偶联物可以通过EPR效应进入肿瘤,然后被MMP-2在肿瘤中分裂成游离的IFNα和ELP(V),从而增强肿瘤的穿透性和抗肿瘤疗效[51];(d)以MTD皮下注射Cy5标记的IFNα-MMPS-ELP(V)、IFNα-MMPS-ELP(A)、IFNα-ELP(V)和IFNα后的小鼠活体荧光成像;(e,f)以MTD皮下注射IFNα-MMPS-ELP(V)、IFNα-MMPS-ELP(A)、IFNα-ELP(V)和IFNα的药物代谢动力学(e)和抗肿瘤治疗效果(f)
Fig. 4 Depot-forming ELP for drug delivery(a, b) Drugs form a subcutaneous insoluble coacervate upon injection and slowly dissolve from their surface to their core, steadily releasing the therapeutic into circulation; (c) The drug ELP conjugates can get into a tumor through the EPR effect and then be cleaved into free IFNα and ELP(V) by MMP-2 in the tumor, resulting in enhanced tumor penetration and antitumor efficacy[51]; (d) Fluorescence imaging of mice following MTD subcutaneous injection of Cy5-labeled IFNα-MMPS-ELP (V), IFN-MMPS-ELP (A), IFN-ELP (V), and IFNα; (e,f) pharmacokinetics (e) and antitumor efficacy (f) of mice after subcutaneous injections of IFNα-MMPS-ELP(V)、IFNα-MMPS-ELP(A)、IFNα-ELP(V) and IFNα at their MTDs.
图5 温度响应性ELP用于局部递送(药物注射后在原位形成储库,限制了向非靶向组织的扩散)
Fig. 5 ELP applied to local delivery(Reservoirs were formed in situ after drug injection, reducing diffusion to non-targeted tissues.)
图6 ELP用于肿瘤热靶向治疗示意图(对肿瘤组织局部加热,蛋白-ELP偶联物在加热部位相变、富集)
Fig. 6 Schematic of ELPs in thermal targeting(The tumor tissue was locally heated, and the protein-ELP conjugates were phase transformed and enriched at the heating site.)
图7 (a)二嵌段ELP的组装示意图,低于两段ELP的Tt的温度下,两亲性ELP是可溶的;在相对疏水的ELP(绿色,Tt 2)和相对亲水的ELP(蓝色,Tt 1)之间的温度(T)下,疏水性ELP选择性脱水,从而聚集形成致密的疏水核心;(b)亲水和疏水比不同的二嵌段ELP形成组装体的冷冻电镜图[70];(c,d)静脉注射IFNα-ELPdiblock, IFNα-ELP(A),PEGASYS 和IFNα的药物代谢动力学图(c),肿瘤生长抑制图(d)[73]
Fig. 7 (a) ELP micelles formed by diblock ELP, at a temperature between the Tt of the more hydrophobic ELP block (green, Tt 2) and the more hydrophilic ELP (blue, Tt1), the more hydrophobic block transitions and aggregates while the more hydrophilic block remains soluble, leading to self-assembly into micelles; (b) Cryo-TEM micrograph of ELP micelles[70]; (c,d) Pharmacokinetics (c) and antitumor efficacy (d) after intravenous injections with IFNα-ELPdiblock, IFNα-ELP(A), PEGASYS and IFNα [73]
图9 (a)ELP混合组装体装载疏水药物分子示意图,疏水药物在组装时作为组装体的核心被装载在核心内;(b)LHRH-ELP2-DOX纳米颗粒的合成示意图;(c)LHRH-ELP2-DOX和ELP2-DOX的冷冻电镜分析图像;(d)LHRH-ELP2-DOX在小鼠体内药代动力学表现;(e)LHRH-ELP2-DOX加HIFU治疗后24 d内肿瘤体积变化[78]
Fig. 9 (a) Schematic of ELP hybrid nanoparticles loading hydrophobic drug molecules. Hydrophobic drugs are loaded in the core; (b) Synthetic route of LHRH-ELP-DOX nanoconjugates; (c) Cryo-TEM images of LHRH-ELP2-DOX and ELP2-DOX; (d) Pharmacokinetics of LHRH-ELP2-DOX in a DOX-resistant breast tumor mouse model; (e) Tumor volume changes after LHRH-ELP-DOX plus HIFU treatment [78]
图10 (a)ELP混合组装体装载亲水药物分子示意图,其中的疏水序列在组装时作为组装体的核心,亲水药物被装载在疏水核心内;(b)冷冻透射电镜图像拍摄到的ATBP-GEM纳米颗粒;(c)原子力显微镜拍摄到的ATBP-GEM组装体;(d)ATBP-GEM与游离GEM相比,延迟了肿瘤的生长;(e)ATBP-GEM与游离GEM相比,提高了生存率[80]
Fig. 10 (a) Schematic of ELP hybrid nanoparticles loading hydrophilic drug molecules where hydrophobic sequences act as the core of the assembly when assembled and hydrophilic drugs are loaded within the hydrophobic core; (b) Cryo-TEM micrograph of ATBP-GEM conjugate; (c) AFM image of ATBP-GEM nanoparticles; (d,e) ATBP-GEM delayed the tumor growth (d) and improved the cumulative survival (e) of mice [80]
药物递送策略 | 应用 | ELP药物 | ELP序列信息 | 文献 |
---|---|---|---|---|
延长药物体内循环半衰期 | 髓样乳腺癌 | SynB1-ELP-DOX | (VPGXG)150 X=V5G3A2 | [ |
感染性休克 | NtTNF-VHHELP | (VPGXG)100 X=V5G3A2 | [ | |
淋巴瘤 | IFN-ELP | (VPGXG)90 X=V5G3A2 | [ | |
药物储库 | 2型糖尿病 | (GLP-1)-ELP | (GVGVP)120 | [ |
卵巢癌和黑色素瘤 | IFN-ELP | (VPGVG)90 | [ | |
胶质母细胞瘤 | IFN-ELP和替莫唑胺联合用药 | (VPGVG)90 | [ | |
黑色素瘤和卵巢癌 | IFN-MMPS-ELP | (VPGVG)90 | [ | |
创伤后关节炎 | xELP[IL-1Ra] | VPGKG(VPGVG)16~102 | [ | |
神经炎症 | ELP-curcumin | [VPGXG] L=60,80,160; X = V/I/E [1∶3∶1] | [ | |
骨损伤 | rhBMP-2-ELP | (VPGVG)40[(VPGVG)2(VPGCG)(VPGVG)2]2 | [ | |
热靶向治疗 | 卵巢癌、宫颈癌、人源咽鳞癌 | ELP1 | (VPGXG)150 X=V5G3A2 | [ |
两亲性自组装体 | 卵巢癌 | IFNα-ELPdiblock | ELP(A)48-ELP(V)48 | [ |
乳腺癌 | FKBP-ELP | G(Val-Pro-Gly-Ile-Gly)48(Val-Pro-Gly-Ser-Gly)48Y | [ | |
混合组装体 | 乳腺癌 | LHRH-ELP-DOX | (VPGXG)160 X=V1A8G7 | [ |
结肠癌 | ELP-(YG)6-(CGG)8-GEM | (VPGAG)160 | [ | |
乳腺癌 | DOXENC,M-ELP90A,120 | (VPGXG)120 X=A9V1 | [ | |
黑色素瘤 | DOX/PPy-ELP-F3 | (XGVPG)160 | [ | |
黑色素瘤、颈瘤、膀胱癌 | ELP-AuNP | (VPGVG)60 | [ | |
ELP水凝胶 | 骨再生 | CDEc | (VPGVG)120 | [ |
表1 ELP用于药物递送的实例
Tab. 1 Applications of ELP in drug delivery
药物递送策略 | 应用 | ELP药物 | ELP序列信息 | 文献 |
---|---|---|---|---|
延长药物体内循环半衰期 | 髓样乳腺癌 | SynB1-ELP-DOX | (VPGXG)150 X=V5G3A2 | [ |
感染性休克 | NtTNF-VHHELP | (VPGXG)100 X=V5G3A2 | [ | |
淋巴瘤 | IFN-ELP | (VPGXG)90 X=V5G3A2 | [ | |
药物储库 | 2型糖尿病 | (GLP-1)-ELP | (GVGVP)120 | [ |
卵巢癌和黑色素瘤 | IFN-ELP | (VPGVG)90 | [ | |
胶质母细胞瘤 | IFN-ELP和替莫唑胺联合用药 | (VPGVG)90 | [ | |
黑色素瘤和卵巢癌 | IFN-MMPS-ELP | (VPGVG)90 | [ | |
创伤后关节炎 | xELP[IL-1Ra] | VPGKG(VPGVG)16~102 | [ | |
神经炎症 | ELP-curcumin | [VPGXG] L=60,80,160; X = V/I/E [1∶3∶1] | [ | |
骨损伤 | rhBMP-2-ELP | (VPGVG)40[(VPGVG)2(VPGCG)(VPGVG)2]2 | [ | |
热靶向治疗 | 卵巢癌、宫颈癌、人源咽鳞癌 | ELP1 | (VPGXG)150 X=V5G3A2 | [ |
两亲性自组装体 | 卵巢癌 | IFNα-ELPdiblock | ELP(A)48-ELP(V)48 | [ |
乳腺癌 | FKBP-ELP | G(Val-Pro-Gly-Ile-Gly)48(Val-Pro-Gly-Ser-Gly)48Y | [ | |
混合组装体 | 乳腺癌 | LHRH-ELP-DOX | (VPGXG)160 X=V1A8G7 | [ |
结肠癌 | ELP-(YG)6-(CGG)8-GEM | (VPGAG)160 | [ | |
乳腺癌 | DOXENC,M-ELP90A,120 | (VPGXG)120 X=A9V1 | [ | |
黑色素瘤 | DOX/PPy-ELP-F3 | (XGVPG)160 | [ | |
黑色素瘤、颈瘤、膀胱癌 | ELP-AuNP | (VPGVG)60 | [ | |
ELP水凝胶 | 骨再生 | CDEc | (VPGVG)120 | [ |
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