固相“一步法”合成基于肿瘤靶向肽/细胞穿透肽和SN38的多肽-药物偶联物(PDCs)

doi:10.6023/A26010030

化学学报 ›› 2026, Vol. 84 ›› Issue (6): 916-932.DOI: 10.6023/A26010030 上一篇下一篇

研究论文

固相“一步法”合成基于肿瘤靶向肽/细胞穿透肽和SN38的多肽-药物偶联物(PDCs)

房长波^a^,^b^,^†, 许孜^a^,^†, 朱舒芽^a, 孟铭^b, 张彬^c, 齐昀坤^b^,^*(), 杜姗姗^a^,^*()

^a 青岛科技大学高性能有机光学聚合物与先进制造技术全国重点实验室青岛 266042
^b 青岛大学药学院青岛 266071
^c 青岛心血管病医院青岛 266034

投稿日期:2026-01-27 发布日期:2026-04-22
作者简介:
^† 同第一作者
基金资助:
山东省泰山学者青年专家项目(tsqn202312168); 山东省自然科学基金(ZR2024YQ061); 国家自然科学基金(22177058)

Solid-phase “one-step” Synthesis of Peptide-Drug Conjugates (PDCs) based on Tumor-targeting Peptide/Cell-penetrating Peptide and SN38

Changbo Fang^a^,^b, Zi Xu^a, Shuya Zhu^a, Ming Meng^b, Bin Zhang^c, Yunkun Qi^b^,^*(), Shanshan Du^a^,^*()

^a State Key Laboratory of Advanced Optical Polymer and Manufacturing Technology, College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao 266042, China
^b School of Pharmacy, Qingdao University, Qingdao 266071, China
^c Qingdao Cardiovascular Disease Hospital, Qingdao 266034, China

Received:2026-01-27 Published:2026-04-22
Contact: *E-mail: qiyunkun@qdu.edu.cn; shanshandu@qust.edu.cn
About author:
^† These authors contributed equally to this work
Supported by:
Taishan Scholar Project of Shandong Province(tsqn202312168); Natural Science Foundation of Shandong Province(ZR2024YQ061); National Natural Science Foundation of China(22177058)

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1. Supporting Information-A26010030.pdf(3346KB)

摘要/Abstract

恶性肿瘤严重威胁人类健康, 发展新型抗肿瘤药物具有重要意义. 喜树碱衍生物7-乙基-10-羟基喜树碱(7-Ethyl-10-hydroxycamptothecin, SN38)是一种强效广谱的化疗药物, 但其水溶性差, 半衰期短, 肿瘤选择性低, 限制了其临床应用. 多肽-药物偶联物(Peptide-drug conjugates, PDCs)是一类新型的靶向抗肿瘤药物, 具有对肿瘤组织穿透性强, 免疫原性低, 易于合成及结构优化等优势. 将SN38与多肽偶联可以显著改善SN38的药学特性. 前人多采用“两步法”合成多肽-SN38偶联物, 即先合成多肽片段, 然后在液相中构建多肽-SN38偶联物, 合成路线繁琐且产率较低. 本研究开发了固相“一步法”合成策略, 在固相上一次性完成多肽构建和SN38偶联, 经切肽、纯化得到目标多肽- SN38偶联物. 本研究选取肿瘤靶向肽(LHRH和奥曲肽)和细胞穿透肽(CPP12), 设计合成了三个系列的多肽-SN38偶联物. 探索了不同的偶联方式和切肽条件对偶联物合成效率的影响, 实现了三个系列多肽-SN38偶联物的固相“一步法”高效合成, 得到8条结构明确的产物. 体外实验表明, LHRH-SN38和奥曲肽-SN38偶联物具有较强的抗肿瘤活性, 显著提高了SN38对肿瘤细胞的选择性. 三个系列的多肽-SN38偶联物均能显著提高SN38的水溶性和在肿瘤细胞中的摄取效率, 并能显著增强SN38抑制肿瘤细胞迁移的能力. 本研究采用固相“一步法”合成策略, 设计并成功合成了基于三类不同结构多肽(线性肽、二硫键构象锁定环肽、酰胺键构象锁定环肽)的SN38偶联物. 本研究系统探讨了多肽固相合成-药物原位偶联一体化策略, 为基于SN38和其它喜树碱类化疗药物的PDCs分子提供了高效稳健的合成方案, 为新型抗肿瘤分子的开发提供了借鉴.

关键词: 固相“一步法”, 多肽-药物偶联物, 多肽合成, LHRH, 奥曲肽, CPP12, SN38, 肿瘤靶向肽

Tumors, particularly drug-resistant malignant tumors, pose a severe threat to human health, underscoring the importance of developing novel antitumor therapeutics. 7-Ethyl-10-hydroxycamptothecin (SN38), a representative derivative of camptothecin (CPT), is a highly potent chemotherapeutic agent that exhibits broad-spectrum antitumor activity. Nevertheless, the clinical application of SN38 has been significantly limited by its poor water solubility, short half-life, and low tumor selectivity. Peptide-drug conjugates (PDCs) represent an emerging class of targeted antitumor therapeutics, offering distinct advantages including strong tumor tissue penetration, low immunogenicity and ease of synthesis and structural optimization. Conjugating SN38 with peptides could markedly improve its water solubility, tumor targeting capability, and antitumor potential. Conventional synthesis of peptide-SN38 based conjugates typically relies on a “two-step” strategy, involving solid-phase peptide synthesis (SPPS) to prepare the peptide segment, followed by solution-phase construction of peptide-SN38 conjugates. This approach is cumbersome, often leading to poor yields and a time-consuming workflow. In this study, we developed a streamlined solid-phase “one-step” synthesis strategy, wherein both peptide assembly and SN38 conjugation were performed sequentially on the solid support. The target peptide-SN38 conjugates could be readily obtained through direct peptide cleavage and purification. Utilizing different tumor-targeting peptides (LHRH and Octreotide) and cell-penetrating peptide (CPP12), three distinct series of peptide-SN38 conjugates were designed and efficiently synthesized. We systematically investigated the effects of different conjugation linkers and cleavage conditions on the synthetic efficiency, establishing the straightforward solid-phase “one-step” synthesis strategy. Ultimately, three conjugate series, LHRH-SN38, octreotide-SN38, and CPP12-SN38 were efficiently synthesized, yielding eight structurally well-defined peptide-SN38 conjugates. In vitro cytotoxicity assays indicated that both LHRH-SN38 and octreotide-SN38 conjugates exhibit potent antitumor activity, significantly enhancing SN38's selectivity toward tumor cells while reducing its toxicity to normal cells. Solubility and cellular uptake experiments demonstrated that all three series of peptide-SN38 conjugates substantially improved the aqueous solubility of SN38 and significantly enhanced SN38 uptake by tumor cells. Furthermore, wound-healing assays indicated that conjugation of SN38 to three kinds of peptides notably enhanced its inhibitory effect on tumor cell migration. By employing the “one-step” solid-phase synthesis strategy, this study systematically investigated the synthetic approaches for peptide-SN38 conjugates derived from diverse peptide architectures, including linear peptide (LHRH), disulfide-bridged cyclic peptide (Octreotide), and amide-bridged cyclic peptide (CPP12). This study not only provides the robust and efficient synthetic strategy for PDCs based on SN38 and other CPT-derived chemotherapeutics, but also offers valuable insights for the development of novel antitumor therapeutics.

Key words: CPP12, LHRH, octreotide, peptide-drug conjugates (PDCs), peptide synthesis, SN38, solid-phase "one-step" synthesis strategy, tumor-targeting peptide

引用此文

房长波, 许孜, 朱舒芽, 孟铭, 张彬, 齐昀坤, 杜姗姗. 固相“一步法”合成基于肿瘤靶向肽/细胞穿透肽和SN38的多肽-药物偶联物(PDCs)[J]. 化学学报, 2026, 84(6): 916-932.

Changbo Fang, Zi Xu, Shuya Zhu, Ming Meng, Bin Zhang, Yunkun Qi, Shanshan Du. Solid-phase “one-step” Synthesis of Peptide-Drug Conjugates (PDCs) based on Tumor-targeting Peptide/Cell-penetrating Peptide and SN38[J]. Acta Chimica Sinica, 2026, 84(6): 916-932.

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图/表 17

图1. (A)喜树碱及其衍生物结构式; (B) SN38 pH依赖性内酯型和羧酸型结构; (C) Boc-SN38-COOH的合成方法

Figure 1. (A) The structures of camptothecin and its derivatives; (B) Structures of pH-dependent lactone and carboxylate forms of SN38; (C) Method for the synthesis of Boc-SN38-COOH

图2. (A) SN38与LHRH、奥曲肽和CPP12偶联构建的PDCs; (B) SN38与多肽偶联之后理化性质得到改善

Figure 2. (A) PDCs constructed by conjugating SN38 with LHRH, Octreotide, and CPP12; (B) Physical and chemical property improvements of SN38 after conjugation with the polypeptide

图3. (A)“两步法”合成多肽-SN38偶联物; (B)“一步法”合成多肽-SN38偶联物

Figure 3. (A) Two-step synthesis of peptide-SN38 conjugates; (B) One-step synthesis of peptide-SN38 conjugates

图4. (A) LS-1a~LS-3c的多肽固相合成流程; (B) LS-1a~LS-3c的结构式

Figure 4. (A) The solid phase peptide synthesis process for LS-1a~LS-3c; (B) The structures of LS-1a~LS-3c

图5. (A) LS-1a*; (B) LS-1b*; (C) LS-1c*; (E) LS-2a; (F) LS-2b; (G) LS-2c*; (I) LS-3a; (J) LS-3b; (K) LS-3c的分析型RP-HPLC色谱图和ESI-MS质谱图. (D) LS-1a*和LS-1b*; (H) LS-2a和LS-2b; (L) LS-3a, LS-3b和LS-3c的共进样分析型RP-HPLC色谱图

Figure 5. Analytical RP-HPLC and ESI-MS spectra of the (A) LS-1a*; (B) LS-1b*; (C) LS-1c*; (E) LS-2a; (F) LS-2b; (G) LS-2c*; (I) LS-3a; (J) LS-3b; (K) LS-3c. Analytical RP-HPLC spectra for the co-injection of (D) LS-1a* and LS-1b*; (H) LS-2a and LS-2b; (L) LS-3a, LS-3b and LS-3c

Peptides		Peptide sequence	Peptide cleavage cocktails	ESI-MS		RP-HPLC purity^a/%
Peptides		Peptide sequence	Peptide cleavage cocktails	Calculated mass/Da	Observed mass/Da	RP-HPLC purity^a/%
LS-1	LS-1a*	pGlu-HWSYk(-AEEA-SN38)LRPG-NH₂	TFA/TIPS/H₂O	1873.090	1499.484	—
	LS-1b*		TFA/TIPS	1873.090	1498.146	—
	LS-1c*		TFA/H₂O	1873.090	—	—
LS-2	LS-2a	pGlu-HWSYk(-rrrr-SN38)LRPG-NH₂	TFA/TIPS/H₂O	2352.659	2352.505	32.4
	LS-2b		TFA/TIPS	2352.659	2352.454	26.7
	LS-2c*		TFA/H₂O	2352.659	—	—
LS-3	LS-3a	pGlu-HWSYk(-SN38)LRPG-NH₂	TFA/TIPS/H₂O	1727.903	1727.679	39.3
	LS-3b		TFA/TIPS	1727.903	1727.803	46.9
	LS-3c		TFA/H₂O	1727.903	1727.412	26.9

表1. LS-1~LS-3的多肽序列、肽裂解条件、分子量及反相高效液相色谱纯度

Table 1. The peptide sequence, peptide cleavage conditions, molecular weight and RP-HPLC purity for peptide LS-1~LS-3

图6. (A) OS-1a~OS-4b的多肽固相合成流程; (B) OS-1a~OS-4b的结构式

Figure 6. (A) The solid phase peptide synthesis process for OS-1a~OS-4b; (B) The structures of OS-1a~OS-4b

图7. (A) OS-1a; (B) OS-1b; (D) OS-2a; (E) OS-2b; (G) OS-3a; (H) OS-3b*; (J) OS-4a; (K) OS-4b的分析型RP-HPLC色谱图和ESI-MS质谱图. (C) OS-1a和OS-1b; (F) OS-2a和OS-2b; (I) OS-3a; (L) OS-4a和OS-4b的共进样分析型RP-HPLC色谱图

Figure 7. Analytical RP-HPLC and ESI-MS spectra of the (A) OS-1a; (B) OS-1b; (D) OS-2a; (E) OS-2b; (G) OS-3a; (H) OS-3b*; (J) OS-4a; (K) OS-4b. Analytical RP-HPLC spectra for the co-injection of (C) OS-1a and OS-1b; (F) OS-2a and OS-2b; (I) OS-3a; (L) OS-4a and OS-4b

Peptides		Peptide sequence	Peptide cleavage cocktails	ESI-MS		RP-HPLC purity^a/%
Peptides		Peptide sequence	Peptide cleavage cocktails	Calculated mass/Da	Observed mass/Da	RP-HPLC purity^a/%
OS-1	OS-1a		TFA/TIPS/H₂O	1669.398	1668.610	52.1
OS-1	OS-1b		TFA/TIPS	1669.398	1668.656	52.7
OS-2	OS-2a		TFA/TIPS/H₂O	2148.454	2147.980	50.2
OS-2	OS-2b		TFA/TIPS	2148.454	2148.236	26.5
OS-3	OS-3a		TFA/TIPS/H₂O	1523.698	1523.304	37.2
OS-3	OS-3b*		TFA/TIPS	1523.698	—	—
OS-4	OS-4a		TFA/TIPS/H₂O	1693.910	1693.574	31.7
OS-4	OS-4b		TFA/TIPS	1693.910	1693.768	30.0

表2. OS-1~OS-4的多肽序列、切肽条件、分子量及反相高效液相色谱纯度

Table 2. The peptide sequence, peptide cleavage condition, molecular weight and RP-HPLC purity for peptide OS-1~OS-4

图8. (A) CS-1和CS-2的多肽固相合成流程; (B) CS-1和CS-2的结构式

Figure 8. (A) The solid phase peptide synthesis of CS-1 and CS-2; (B) The structures of CS-1 and CS-2

图9. (A) CS-1和(C) CS-2的分析型RP-HPLC色谱图和ESI-MS质谱图. (B) CS-1和(D) CS-2分离纯化后的分析型RP-HPLC色谱图

Figure 9. Analytical RP-HPLC and ESI-MS spectra of the (A) CS-1 and (C) CS-2. Analytical RP-HPLC spectra of (B) purified CS-1 and (D) purified CS-2

Peptides	Peptide sequence	Peptide cleavage cocktails	ESI-MS		RP-HPLC purity^a/%
Peptides	Peptide sequence	Peptide cleavage cocktails	Calculated mass/Da	Observed mass/Da	RP-HPLC purity^a/%
CS-1		TFA/TIPS/H₂O	1992.280	1992.184	39.4
CS-2		TFA/TIPS/H₂O	1847.122	1846.877	38.2

表3. CS-1和CS-2的多肽序列、切肽条件、分子量及反相高效液相色谱纯度

Table 3. The peptide sequence, peptide cleavage conditions, molecular weight and RP-HPLC purity for peptide CS-1 and CS-2

	OS-1	OS-2	OS-3	OS-4	LS-2	LS-3	CS-1	CS-2	SN38
MDA-MB-231	6.1±0.5	3.7±0.3	10.1±0.9	8.9±0.9	2.7±0.2	4.7±0.4	3.6±0.3	5.4±0.6	<0.3
MCF-7	1.2±0.1	0.3±0.1	6.3±0.7	3.6±0.2	0.5±0.1	1.9±0.2	3.1±0.3	4.7±0.5	<0.3
HepG2	2.6±0.2	1.3±0.2	5.1±0.5	4.1±0.4	4.3±0.6	6.5±0.6	3.9±0.3	4.6±0.6	<0.3
HUVEC	64.4±4.6	26.3±2.2	>100	>100	26.9±2.7	73.7±5.3	4.0±0.4	5.4±0.5	<0.3
L929	40.6±3.7	20.8±2.3	>100	>100	16.6±1.2	47.1±4.0	4.9±0.3	6.7±0.7	<0.3
SI^a	53.7	87.7	—	—	53.8	38.8	1.3	1.1	—
SI^b	33.8	69.3	—	—	33.2	24.8	1.6	1.4	—

表4. SN38及其多肽偶联物孵育48 h后的IC50值(μmol•L−1)

Table 4. IC50 values for SN38 and its peptide conjugates after 48 h of incubation

图10. (A) SN38的紫外-可见光谱. 不同浓度下(B) LS-2; (C) OS-2; (D) CS-1; (E) CS-2; (F) SN38的标准曲线. λ=365 nm, n=3, mean±SEM. (G)和(H) SN38及其多肽偶联物水溶性. n=3, mean±SEM, ****P<0.0001

Figure 10. (A) UV-vis spectrum of SN38. Standard curves for (B) LS-2; (C) OS-2; (D) CS-1; (E) CS-2; (F) SN38 at different concentrations. λ=365 nm, n=3, mean±SEM. (G) and (H) Water solubility of SN38 and its peptide conjugates. n=3, mean±SEM, ****P<0.0001

图11. (A)多肽OS-1, OS-2, OS-3和OS-4与MCF-7细胞共孵育的细胞荧光图像; (B)多肽LS-2和LS-3与MCF-7细胞共孵育的细胞荧光图像; (C)多肽CS-1和CS-2与MCF-7细胞共孵育的细胞荧光图像; (D) SN38与MCF-7细胞共孵育的细胞荧光图像; (E) OS-1, OS-2, OS-3, OS-4和SN38摄取细胞数的定量统计图, n=3, mean±SD; (F) LS-2, LS-3和SN38摄取细胞数的定量统计图, n=3, mean±SD; (G) CS-1, CS-2和SN38摄取细胞数的定量统计图, n=3, mean±SD. ns: 无显著性差异, *P<0.05, **P<0.01, ***P<0.001

Figure 11. (A) Fluorescence images of MCF-7 cells treated with OS-1, OS-2, OS-3 and OS-4. (B) Fluorescence images of MCF-7 cells treated with LS-2 and LS-3. (C) Fluorescence images of MCF-7 cells treated with CS-1 and CS-2. (D) Fluorescence images of MCF-7 cells treated with SN38. (E) Quantification of uptake ratios for OS-1, OS-2, OS-3, OS-4 and SN38. n=3, mean±SD. (F) Quantification of uptake ratios for LS-2, LS-3 and SN38. n=3, mean±SD. (G) Quantification of uptake ratios for CS-1, CS-2 and SN38. n=3, mean±SD. ns: not significant, *P<0.05, **P<0.01, ***P<0.001

图12. SN38, CS-1, CS-2, LS-2和OS-2对MCF-7和HepG2细胞的抗迁移作用. (A)在0 h、12 h和24 h MCF-7细胞的迁移图像; (B) 12 h和24 h MCF-7细胞伤口愈合率的量化图, n=3, mean±SD; (C)在0 h、12 h和24 h的HepG2细胞迁移图像; (D) 12 h和24 h HepG2细胞伤口愈合率的量化图, n=3, mean±SD. *P<0.05, **P<0.01, ***P<0.001

Figure 12. Anti-migration effects of SN38, CS-1, CS-2, LS-2 and OS-2 against HepG2 cells. (A) Migration images of MCF-7 cells at 0, 12, and 24 h. (B) Quantification of wound healing rate of MCF-7 cells at 12 h and 24 h. n=3, mean±SD. (C) Migration images of HepG2 cells at 0, 12, and 24 h. (D) Quantification of wound healing rate of HepG2 cells at 12 h and 24 h. n=3, mean±SD. *P<0.05, **P<0.01, ***P<0.001

图13. 血清稳定性实验. (A) CS-1, (B) OS-2和(C) LS-2在人血清中水解的分析型RP-HPLC谱图; (D) CS-1、OS-2和LS-2的血清稳定性

Figure 13. Serum stability assay. Analytical RP-HPLC spectra of the hydrolysis of (A) CS-1, (B) OS-2 and (C) LS-2 by human serum; (D) Human serum stability of CS-1, OS-2 and LS-2

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固相“一步法”合成基于肿瘤靶向肽/细胞穿透肽和SN38的多肽-药物偶联物(PDCs)

Solid-phase “one-step” Synthesis of Peptide-Drug Conjugates (PDCs) based on Tumor-targeting Peptide/Cell-penetrating Peptide and SN38

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