Dual character of surface engineering on SN38 prodrug nano-assemblies: divergent effects on in vitro and in vivo behavior

Ya-Qiao Li; Zhi-Yu Kuang; Bao-Yuan Zhang; Yan-Zhong Hao; Ling-Xiao Li; Jing-Xuan Zhang; Ya-Fan Xiao; Bo-Wen Zhang; Xian-Bao Shi; Xiao-Hui Pu; Zhong-Gui He; Bing-Jun Sun

doi:10.1186/s40779-025-00648-6

Your Location：

Home >

Browse articles >

Dual character of surface engineering on SN38 prodrug nano-assemblies: divergent effects on in vitro and in vivo behavior

RESEARCH | Updated：2026-05-08

- Dual character of surface engineering on SN38 prodrug nano-assemblies: divergent effects on in vitro and in vivo behavior
- Military Medical Research Vol. 13, Issue 3, Pages: 385-399(2026)
- Affiliations：
  
  1.Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China
  2.Department of Bioengineering, Graduate School of Engineering, the University of Tokyo, Tokyo 113-0033, Japan
  3.Department of Pharmacy, the First Affiliated Hospital of Jinzhou Medical University, Jinzhou 121001, Liaoning, China
  4.State Key Laboratory of Antiviral Drugs, School of Pharmacy, Henan University, Kaifeng 475004, Henan, China
  5.Joint International Research Laboratory of Intelligent Drug Delivery Systems, Ministry of Education, Shenyang 110016, China
- Author bio：
  
  * Zhong-Gui He hezhonggui@syphu.edu.cn
  Bing-Jun Sun sunbingjun@syphu.edu.cn
- Funds：
- DOI：10.1186/s40779-025-00648-6
  CLC：
- Received：24 December 2024，
  
  Accepted：08 September 2025，
  
  Online First：22 September 2025，
  
  Published：2026-03
- Accepted：
Scan QR Code
Ya-Qiao Li, Zhi-Yu Kuang, Bao-Yuan Zhang, et al. Dual character of surface engineering on SN38 prodrug nano-assemblies: divergent effects on in vitro and in vivo behavior[J]. Military Medical Research, 2026, 13(3): 385-399.
DOI：

Ya-Qiao Li, Zhi-Yu Kuang, Bao-Yuan Zhang, et al. Dual character of surface engineering on SN38 prodrug nano-assemblies: divergent effects on in vitro and in vivo behavior[J]. Military Medical Research, 2026, 13(3): 385-399. DOI： 10.1186/s40779-025-00648-6.

摘要

Abstract

Background

Surface engineering has emerged as a promising strategy to enhance the performance of nanomedicines. In particular

the PEGylation levels for chemotherapy drug 7-Ethyl-10-hydroxycamptothecin (SN38) prodrug nanoparticles (NPs) play a crucial role in determining their stability

drug release kinetics

cytotoxicity

cellular uptake

in vivo pharmacokinetics

biodistribution

and antitumor efficacy. The study aims to investigate the surface engineering for chemotherapy drugs

providing new solutions for improving their in vivo delivery.

Methods

We systematically evaluated the effects of different PEGylation levels on NPs (W

DSPE-mPEG2k

prodrug

; 0%

20%

40%

60%

80%

100%

150%

and 200% NPs) incorporated on SN38 prodrug NPs via surface engineering. Drug release was measured using high-performance liquid chromatography (HPLC)

while cytotoxicity was assessed via the 3-(4

5-dimethylthiazol-2-yl)-2

5-diphenyltetrazolium bromide (MTT) assay. Cellular uptake was accurately quantified using liquid chromatography–mass spectrometry (LC–MS). The in vivo pharmacokinetics of the NPs were evaluated in Sprague–Dawley rats

and the biodistribution and antitumor efficacy were assessed using a CT26 colon tumor-bearing BALB/c mice model. Additionally

we examined intestinal toxicity to evaluate the safety profile.

Results

All the different PEGylation levels of SN38 prodrug NPs exhibited high drug loading (> 25%) but distinct behaviors depending on the PEGylation level. Low PEGylation (20%) led to poor colloidal stability

reduced cellular uptake

and rapid clearance by the mononuclear phagocyte system (MPS)

resulting in unfavorable pharmacokinetics. Moderate PEGylation (80%) improved in vitro stability and uptake but remained insufficient to prevent rapid clearance in vivo. In contrast

high PEGylation (150%) significantly enhanced pharmacokinetic profiles

prolonged circulation

and increased tumor accumulation. The 150% NPs also showed superior antitumor efficacy without triggering antipolyethylene glycol (PEG) immune responses or accelerated blood clearance (ABC) effects. Although high PEGylation slightly reduced cellular uptake

it conferred essential stability for systemic delivery

improving in vivo therapeutic outcomes.

Conclusions

The high PEGylation (150% NPs) exhibited the best antitumor effect and the lowest degree of intestinal toxicity. Our findings underscore the critical impact of PEGylation level on enhancing the performance and safety of SN38 prodrug NPs.

关键词

Keywords

references

Möhring C , Graffe FJF , Bartels A , Sadeghlar F , Zhou T , Mahn R , et al . Second-line and third-line therapy with nanoliposomal irinotecan (nal-IRI) in pancreatic cancer: a single-center experience and review of literature . J Gastrointest Oncol. 2023 ; 14 ( 1 ): 352 .

Armand J , Ducreux M , Mahjoubi M , Abigerges D , Bugat R , Chabot G , et al . CPT-11 (irinotecan) in the treatment of colorectal cancer . Eur J Cancer. 1995 ; 31 ( 7–8 ): 1283 - 7 .

Federico I , Deanna LK , Erin S , Eileen M , Jacqueline D , Mary R , et al . Comprehensive pharmacogenetic analysis of irinotecan neutropenia and pharmacokinetics . J Clin Oncol. 2009 ; 27 ( 16 ): 2604 - 14 .

Li GT , Jin QH , Xia FL , Fu SW , Zhang XB , Xiao HY , et al . Smart stimuli-responsive carrier-free nanoassembly of SN38 prodrug as efficient chemotherapeutic nanomedicine . Acta Mater Med. 2023 ; 2 ( 1 ): 54 - 63 .

Chabot GG , Abigerges D , Catimel G , Culine S , de Forni M , Extra JM , et al . Population pharmacokinetics and pharmacodynamics of irinotecan(CPT-11) and active metabolite SN-38 during phase I trials . Ann Oncol. 1995 ; 6 ( 2 ): 141 - 51 .

Michael M , Mick T , Rod JH , Paul LM , Andrew E , Alvin DM , et al . Relationship of hepatic functional imaging to irinotecan pharmacokinetics and genetic parameters of drug elimination . J Clin Oncol. 2006 ; 24 ( 26 ): 4228 - 35 .

Guichard SM , Morton CL , Krull EJ , Stewart CF , Danks MK , Potter PM . Conversion of the CPT-11 metabolite APC to SN-38 by rabbit liver carboxylesterase . Clin Cancer Res. 1998 ; 4 ( 12 ): 3089 - 94 .

Allyson JO , Alexander NS , Aditya B , Linda TV , Steven JI , Michael G , et al . Sacituzumab govitecan (IMMU-132), an anti-Trop-2-SN-38 antibody-drug conjugate for the treatment of diverse epithelial cancers: safety and pharmacokinetics . Cancer. 2017 ; 123 ( 19 ): 3843 - 54 .

Clinton FS , John CP , Melinda AOS , Stacy LT , Charles HF , Thandranese O , et al . UGT1A1 promoter genotype correlates with SN-38 pharmacokinetics, but not severe toxicity in patients receiving low-dose irinotecan . J Clin Oncol. 2007 ; 25 ( 18 ): 2594 - 600 .

Renu P , Aleksandra G , Jennifer C , Andrew JB , Stefano T . Stable isotope dilution LC-HRMS assay to determine free SN-38, total SN-38, and SN-38G in a tumor xenograft model after intravenous administration of antibodydrug conjugate (sacituzumab govitecan) . Anal Chem. 2019 ; 92 ( 1 ): 1260 - 7 .

Robert MS , William JM , Thomas MC , Serengulam VG , Yang W , Edmund AR , et al . Enhanced delivery of SN-38 to human tumor xenografts with an anti-trop-2-SN-38 antibody conjugate (sacituzumab govitecan) . Clin Cancer Res. 2015 ; 21 ( 22 ): 5131 - 8 .

Wang JQ , Sun XR , Mao WW , Sun WL , Tang JB , Sui MH , et al . Tumor redox heterogeneity-responsive prodrug nanocapsules for cancer chemotherapy . Adv Mater. 2013 ; 25 ( 27 ): 3670 - 6 .

Liu X , Lynn BC , Zhang J , Song L , Bom D , Du W , et al . A versatile prodrug approach for liposomal core-loading of water-insoluble camptothecin anticancer drugs . J Am Chem Soc. 2002 ; 124 ( 26 ): 7650 - 1 .

Li LX , Zuo SY , Dong FD , Liu T , Gao YL , Yang YX , et al . Small changes in the length of diselenide bond-containing linkages exert great influences on the antitumor activity of docetaxel homodimeric prodrug nanoassemblies . Asian J Pharm Sci. 2021 ; 16 ( 3 ): 337 - 49 .

Wei Q , Yang T , Zhu JY , Zhang ZW , Yang L , Zhang YC , et al . Spatiotemporal quantification of HER2-targeting antibody-drug conjugate bystander activity and enhancement of solid tumor penetration . Clin Cancer Res. 2024 ; 30 ( 5 ): 984 - 97 .

Li LX , Liu T , Zuo SY , Li YQ , Zhao EW , Lu Q , et al . Satellite-type sulfur atom distribution in trithiocarbonate bond-bridged dimeric prodrug nanoassemblies: achieving both stability and activatability . Adv Mater. 2024 ; 36 ( 4 ): 2310633 .

Zuo SY , Liu T , Li LX , Xu HZ , Guo JY , Wang Q , et al . Tetrasulfide bond boosts the anti-tumor efficacy of dimeric prodrug nanoassemblies . Cell Rep Med. 2024 ; 5 ( 3 ): 101432 .

Liu T , Li LX , Wang S , Dong FD , Zuo SY , Song JX , et al . Hybrid chalcogen bonds in prodrug nanoassemblies provides dual redox-responsivity in the tumor microenvironment . Nat Commun. 2022 ; 13 ( 1 ): 7228 .

Li YQ , Li LX , Hao YZ , Zhang JX , Liu CY , Zhao EW , et al . Optimizing structural design in SN38 delivery: more assembly stability and activation efficiency . Nano Today. 2024 ; 58 : 102450 .

Cabral H , Matsumoto Y , Mizuno K , Chen Q , Murakami M , Kimura M , et al . Accumulation of sub-100 nm polymeric micelles in poorly permeable tumours depends on size . Nat Nanotechnol. 2011 ; 6 ( 12 ): 815 - 23 .

Cabral H , Li J , Miyata K , Kataoka K . Controlling the biodistribution and clearance of nanomedicines . Nat Rev Bioeng. 2024 ; 2 ( 3 ): 214 - 32 .

Li YQ , Li LX , Jin QH , Liu T , Sun J , Wang YJ , et al . Impact of the amount of PEG on prodrug nanoassemblies for efficient cancer therapy . Asian J Pharm Sci. 2022 ; 17 ( 2 ): 241 - 52 .

Zhang BW , Liu WY , Liu JR , Huang ML , Li YQ , Zhao EW , et al . Rational engineering of cholesterol-modified prodrug nanoassemblies for improving the tumor selectivity and safety of mitoxantrone . Fundam Res. 2024 . https://doi.org/10.1016/j.fmre.2024.06.006 .

Yuan KD , Du XX , Dong L , Pan JH , Xue W . Modeling the tumor microenvironment in vitro in prostate cancer: current and future perspectives . View. 2024 ; 5 ( 5 ): 20240074 .

Yang YX , Sun BJ , Zuo SY , Li XM , Zhou S , Li LX , et al . Trisulfide bond–mediated doxorubicin dimeric prodrug nanoassemblies with high drug loading, high self-assembly stability, and high tumor selectivity . Sci Adv. 2020 ; 6 ( 45 ): eabc1725 .

Xiang XJ , Feng X , Lu SJ , Jiang BW , Hao DY , Pei Q , et al . Indocyanine green potentiated paclitaxel nanoprodrugs for imaging and chemotherapy . Exploration. 2022 ; 2 ( 4 ): 20220008 .

Sun BJ , Luo C , Zhang XB , Guo MR , Sun MC , Yu H , et al . Probing the impact of sulfur/selenium/carbon linkages on prodrug nanoassemblies for cancer therapy . Nat Commun. 2019 ; 10 ( 1 ): 3211 .

Zhang JX , Fang HK , Dai YB , Li YQ , Li LX , Zuo SY , et al . Cholesterol sulfatemediated ion-pairing facilitates the self-nanoassembly of hydrophilic cationic mitoxantrone . J Colloid Interface Sci. 2024 ; 669 : 731 - 9 .

Wang S , Liu T , Huang YT , Du CY , Wang DP , Wang XY , et al . The effect of lengths of branched-chain fatty alcohols on the efficacy and safety of docetaxel-prodrug nanoassemblies . Acta Pharm Sin B. 2024 ; 14 ( 3 ): 1400 - 11 .

Cao ZC , Liu X , Zhang WQ , Zhang KY , Pan LX , Zhu MR , et al . Biomimetic macrophage membrane-camouflaged nanoparticles induce ferroptosis by promoting mitochondrial damage in glioblastoma . ACS Nano. 2023 ; 17 ( 23 ): 23746 - 60 .

Suk JS , Xu Q , Kim N , Hanes J , Ensign LM . Pegylation as a strategy for improving nanoparticle-based drug and gene delivery . Adv Drug Deliv Rev. 2016 ; 99 ( Pt A ): 28 - 51 .

Zalba S , Ten Hagen TL , Burgui C , Garrido MJ . Stealth nanoparticles in oncology: facing the PEG dilemma . J Control Release. 2022 ; 351 : 22 - 36 .

Snyder DT , Harvey SR , Wysocki VH . Surface-induced dissociation mass spectrometry as a structural biology tool . Chem Rev. 2022 ; 122 ( 8 ): 7442 - 87 .

Akbulut O , Mace CR , Martinez RV , Kumar AA , Nie Z , Patton MR , et al . Separation of nanoparticles in aqueous multiphase systems through centrifugation . Nano Lett. 2012 ; 12 ( 8 ): 4060 - 4 .

Sanchez L , Yi Y , Yu Y . Effect of partial PEGylation on particle uptake by macrophages . Nanoscale. 2017 ; 9 ( 1 ): 288 - 97 .

Dancy JG , Wadajkar AS , Schneider CS , Mauban JR , Goloubeva OG , Woodworth GF , et al . Non-specific binding and steric hindrance thresholds for penetration of particulate drug carriers within tumor tissue . J Control Release. 2016 ; 238 : 139 - 48 .

Choi CHJ , Zuckerman JE , Webster P , Davis ME . Targeting kidney mesangium by nanoparticles of defined size . Proc Natl Acad Sci U S A. 2011 ; 108 ( 16 ): 6656 - 61 .

Perrault SD , Walkey C , Jennings T , Fischer HC , Chan WC . Mediating tumor targeting efficiency of nanoparticles through design . Nano Lett. 2009 ; 9 ( 5 ): 1909 - 15 .

Cahn D , Stern A , Buckenmeyer M , Wolf M , Duncan GA . Extracellular matrix limits nanoparticle diffusion and cellular uptake in a tissue-specific manner . ACS Nano. 2024 ; 18 ( 46 ): 32045 - 55 .

Jeon S , Jun E , Chang H , Yhee JY , Koh EY , Kim Y , et al . Prediction the clinical EPR effect of nanoparticles in patient-derived xenograft models . J Control Release. 2022 ; 351 : 37 - 49 .

Li J , Chen C , Xia T . Understanding nanomaterial-liver interactions to facilitate the development of safer nanoapplications . Adv Mater. 2022 ; 34 ( 11 ): e2106456 .

Jiang XY , Du BJ , Zheng J . Glutathione-mediated biotransformation in the liver modulates nanoparticle transport . Nat Nanotechnol. 2019 ; 14 ( 9 ): 874 - 82 .

Wang ZR , Li WP , Jiang YH , Park JH , Gonzalez KM , Wu XM , et al . Cholesterolmodified sphingomyelin chimeric lipid bilayer for improved therapeutic delivery . Nat Commun. 2024 ; 15 ( 1 ): 2073 .

Zhang GS , Song DD , Ma RL , Li M , Liu BY , He ZG , et al . Artificial mucus layer formed in response to ROS for the oral treatment of inflammatory bowel disease . Sci Adv. 2024 ; 10 ( 30 ): eado8222 .

Kozma GT , Shimizu T , Ishida T , Szebeni J . Anti-PEG antibodies: properties, formation, testing and role in adverse immune reactions to PEGylated nano-biopharmaceuticals . Adv Drug Deliv Rev. 2020 ; 154 : 163 - 75 .

Li MY , Jiang S , Simon J , Paßlick D , Frey ML , Wagner M , et al . Brush conformation of polyethylene glycol determines the stealth effect of nanocarriers in the low protein adsorption regime . Nano Lett. 2021 ; 21 ( 4 ): 1591 - 8 .

Kano MR , Komuta Y , Iwata C , Oka M , Shirai YT , Morishita Y , et al . Comparison of the effects of the kinase inhibitors imatinib, sorafenib, and transforming growth factor-β receptor inhibitor on extravasation of nanoparticles from neovasculature . Cancer Sci. 2009 ; 100 ( 1 ): 173 - 806 .

Holzleitner N , Fischer S , Maniyankerikalam I , Beck R , Lapa C , Wester HJ , et al . Significant reduction of activity retention in the kidneys via optimized linker sequences in radiohybrid-based minigastrin analogs . EJNMMI Res. 2024 ; 14 ( 1 ): 23 .

Børresen B , Henriksen JR , Clergeaud G , Jørgensen JS , Melander F , Elema DR , et al . Theranostic imaging may vaccinate against the therapeutic benefit of long circulating PEGylated liposomes and change cargo pharmacokinetics . ACS Nano. 2018 ; 12 ( 11 ): 11386 - 98 .

Barenholz YC . Doxil ® —the first FDA-approved nano-drug: lessons learned . J Control Release. 2012 ; 160 ( 2 ): 117 - 34 .

Li CL , Zhao X , Wang YJ , Yang HY , Li HX , Li H , et al . Prolongation of time interval between doses could eliminate accelerated blood clearance phenomenon induced by pegylated liposomal topotecan . Int J Pharm. 2013 ; 443 ( 1–2 ): 17 - 25 .

Li CL , Cao JN , Wang YJ , Zhao X , Deng CX , Wei N , et al . Accelerated blood clearance of pegylated liposomal topotecan: influence of polyethylene glycol grafting density and animal species . J Pharm Sci. 2012 ; 101 ( 10 ): 3864 - 76 .

Views

Downloads

CSCD

Alert me when the article has been cited

Submit

Tools

Publicity Resources

Synthesis and delivery characteristics of colon-specific dexamethasone prodrug

Related Author

No data

Related Institution

No data

⁰