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

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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
- Dual character of surface engineering on SN38 prodrug nano-assemblies: divergent effects on in vitro and in vivo behavior
- Military Medical Research 2026年13卷第3期页码：385-399
- 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：
  
  the National Key R&D Program of China(2022YFE0111600);the National Natural Science Foundation of China(82204318);the Youth Innovation Team of Liaoning Province Department of Education(LJ222410163049);the Shenyang Young and Middle-aged Science and Technology Innovation Talent Support Program(RC220389);the Liaoning Revitalization Talents Program(XLYC2203083);Blood analyses were performed at Shenyang Companion Animal Hospital
- DOI：10.1186/s40779-025-00648-6
  中图分类号：
- 收稿：2024-12-24，
  
  录用：2025-09-08，
  
  网络首发：2025-09-22，
  
  纸质出版：2026-03
- Accepted：
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Ya-Qiao Li, Zhi-Yu Kuang, Bao-Yuan Zhang, 等. 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.

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.
Ya-Qiao Li, Zhi-Yu Kuang, Bao-Yuan Zhang, 等. 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.

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

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