Folate and lipoic acid functionalized pH/reductive dual-responsive mixed crosslinked micelles for paclitaxel delivery

Feng Minghong; He Teng; Zhao Haiqian; Chen Tao; Lin Wenjing; Yang Chufen

doi:null

Your Location：

Home >

Browse articles >

Folate and lipoic acid functionalized pH/reductive dual-responsive mixed crosslinked micelles for paclitaxel delivery

Updated：2026-08-24

- Folate and lipoic acid functionalized pH/reductive dual-responsive mixed crosslinked micelles for paclitaxel delivery
- Chinese Journal of Chemical Engineering Vol. 94, Issue 6, Pages: 102-112(2026)
- Affiliations：
  
  School of Chemical Engineering and Light Industry, Guangdong University of Technology, Guangzhou 510006, China
  Guangdong Provincial Laboratory of Chemistry and Fine Chemical Engineering Jieyang Center, Jieyang 515200, China
- Author bio：
  
  Corresponding authors. E-mail addresses: Wenjing.Lin@gdut.edu.cn(W. Lin)
  cfyang@gdut.edu.cn(C. Yang)
- Funds：
- DOI：
  CLC：
- Received：14 June 2025，
  
  Revised：2026-01-05，
  
  Accepted：14 January 2026，
  
  Online First：10 March 2026，
  
  Published：2026-06
- Accepted：
Scan QR Code
Feng Minghong, He Teng, Zhao Haiqian, et al. Folate and lipoic acid functionalized pH/reductive dual-responsive mixed crosslinked micelles for paclitaxel delivery[J]. Chinese Journal of Chemical Engineering, 2026, 94(6): 102-112.
DOI：

Feng Minghong, He Teng, Zhao Haiqian, et al. Folate and lipoic acid functionalized pH/reductive dual-responsive mixed crosslinked micelles for paclitaxel delivery[J]. Chinese Journal of Chemical Engineering, 2026, 94(6): 102-112. DOI：

摘要

Abstract

To address the challenges of poor stability and weak targeting capability in polymeric micelles

which negatively impact controlled drug release performance

pH-responsive polymers PCL-PDEAEMA-PHEMA-PPEGMA (P1

and P3) with distinct block lengths were designed and synthesized in this work. These copolymers were rigorously characterized using

H NMR

FT-IR

and GPC. Subsequently

polymer P3 was selected for modification based on comparative analyses of critical micelle concentrations (CMC) and drug-loading performance. Polymer P3 underwent esterification with lipoic acid (LA) and folic acid (FA) to yield LA-P3 and FA-P3

respectively. These derivatives were blended at a mass ratio of 1:1 (LA-P3:FA-P3)

and dithiothreitol was employed to initiate self-crosslinking

resulting in the preparation of actively targeted crosslinked mixed micelles (C-MIX). The results revealed that C-MIX@PTX drug-loaded micelles prepared at a feeding ratio of 15 mg PTX/30 mg polymer exhibited a smaller size (134.7 nm) compared to non-crosslinked micelles

with a drug-loading content of 15.31% ±1.79% and an encapsulation efficiency of 38.42% ±5.22%.

In vitro

release studies demonstrated that under neutral conditions

C-MIX@PTXachieved a cumulative drug release of 16.8% at 120 h

significantly lower than non-crosslinked micelles. Under acidic/reductive conditions

C-MIX@PTX showed a cumulative drug release of 77.1% at 120 h

slightly lower compared to non-crosslinked micelles. Cytotoxicity assays confirmed that both MIX and C-MIX were biocompatible low-toxicity carrier materials

whileLA-P3@PTX

FA-P3@PTX

MIX@PTX

and C-MIX@PTX exhibited inhibitory effects on HepG2 cells

FA-P3@PTX with folate-modified demonstrated enhanced efficacy.

关键词

Keywords

references

S.K. Hari, A. Gauba, N. Shrivastava, R.M. Tripathi, S.K. Jain, A.K. Pandey, Polymeric micelles and cancer therapy: an ingenious multimodal tumortargeted drug delivery system, Drug Deliv. Transl. Res. 13 (1) (2023) 135-163.

Z. Li, J.H. Zou, X.Y. Chen, In response to precision medicine: current subcellular targeting strategies for cancer therapy, Adv. Mater. 35 (21) (2023) e2209529.

F. Chen, L. Yin, T. He, T. Chen, H.B. Yue, C.F. Yang, Fabrication of dual pH/reduction-responsive P(CL- co -ACL)-based cross-linked polymeric micelles for PTX delivery, Langmuir 39 (46) (2023) 16358-16366.

H.X. Wei, M.H. Liu, T.Y. Wang, M.H. Shih, J. Yu, Y.C. Yeh, Fabrication of pH-and ultrasound-responsive polymeric micelles: the effect of amphiphilic block copolymers with different hydrophilic/hydrophobic block ratios for self-assembly and controlled drug release, Biomacromolecules 26 (4) (2025) 2116-2130.

A.Z. Juthi, M. Aquib, M.A. Farooq, S. Ghayas, F. Khalid, G.F. Boafo, D.P. Wande, D.H. Khan, T.Z. Bithi, R. Bavi, B. Wang, Theranostic applications of smart nanomedicines for tumor-targeted chemotherapy: a review, Environ. Chem. Lett. 18 (5) (2020) 1509-1527.

Y.F. Cai, J.P. Qi, Y. Lu, H.S. He, W. Wu, The in vivo fate of polymeric micelles, Adv. Drug Deliv. Rev. 188 (2022) 114463.

Z.Q. Zhang, X.X. Xu, J.W. Du, X. Chen, Y.E. Xue, J.Q. Zhang, X. Yang, X.Y. Chen, J. B. Xie, S.H. Ju, Redox-responsive polymer micelles co-encapsulating immune checkpoint inhibitors and chemotherapeutic agents for glioblastoma therapy, Nat. Commun. 15 (1) (2024) 1118.

T. Ozbek, H. Demir, S. Dokuz, S. Tasdurmazli, U. Ozbey, M. Ozbil, M. Topuzogullari, I. Cinar, M. Karamese, S.A. Karamese, S. Acar, O.F. Bayrak, E. Cadirci, Phage-inspired targeting of antibiotic-loaded polymeric micelles for enhanced therapeutic efficacy against monomicrobial sepsis, J. Contr. Release 380 (2025) 773-786.

D. Wan, S.F. Li, J.X. Zhang, G.L. Ma, J. Pan, Intelligent self-assembly prodrug micelles loading doxorubicin in response to tumor microenvironment for targeted tumors therapy, Chin. J. Chem. Eng. 39 (2021) 219-227.

X.H. Pu, L.L. Zhao, J. Li, R.F. Song, Y.L. Wang, K.K. Yu, X.Q. Hou, P. Qiao, L.L. Zong, S. Chang, A polymeric micelle with an endosomal pH-sensitivity for intracellular delivery and enhanced antitumor efficacy of hydroxycamptothecin, Acta Biomater. 88 (2019) 357-369.

K.J. Luo, W.X. Guo, Y.T. Yu, S.M. Xu, M. Zhou, K.Q. Xiang, K. Niu, X.Q. Zhu, G.Y. Zhu, Z. An, Q.S. Yu, Z.H. Gan, Reduction-sensitive platinum (IV)-prodrug nano-sensitizer with an ultra-high drug loading for efficient chemoradiotherapy of Pt-resistant cervical cancer in vivo , J. Contr. Release 326 (2020) 25-37.

M.Q. Wang, J.R. Long, S.M. Zhang, F.J. Liu, X.L. Zhang, X.S. Zhang, L. Sun, L.W. Ma, C.Y. Yu, H. Wei, Folate-targeted anticancer drug delivery via a combination strategy of a micelle complex and reducible conjugation, ACS Biomater. Sci. Eng. 6 (3) (2020) 1565-1572.

Y. Lu, E.S. Zhang, J.H. Yang, Z.Q. Cao, Strategies to improve micelle stability for drug delivery, Nano Res. 11 (10) (2018) 4985-4998.

L. Zhang, R.B. Guo, M.H. Chen, M. Liu, Y. Liu, Y. Yu, J. Zang, L. Kong, X.T. Li, Inhibition of ovarian cancer growth, metastasis and reverse the tumor microenvironment by dual drug-loaded polymer micelle targeting tumor microenvironment, Int. J. Nanomed. 20 (2025) 2969-2990.

Y.G. Wu, S.B. Chen, J.T. Zhu, Hydrogen-bond-dr iven core-crosslinked supramolecular micelles with pH/thermal/glutathione-responsive drug release toward enhanced cancer therapy, Chem. Mater. 35 (18) (2023) 7655-7670.

J. Kaur, M. Gulati, N.K. Jha, J. Disouza, V. Patravale, K. Dua, S.K. Singh, Recent advances in developing polymeric micelles for treating cancer: breakthroughs and bottlenecks in their clinical translation, Drug Discov. Today 27 (5) (2022) 1495-1512.

A.B. Ebrahim Attia, Z.Y. Ong, J.L. Hedrick, P.P. Lee, P.L.R. Ee, P.T. Hammond, Y. Y. Yang, Mixed micelles self-assembled from block copolymers for drug delivery, Curr. Opin. Colloid Interface Sci. 16 (3) (2011) 182-194.

M. Cagel, F.C. Tesan, E. Bernabeu, M.J. Salgueiro, M.B. Zubillaga, M.A. Moretton, D.A. Chiappetta, Polymeric mixed micelles as nanomedicines:achievements and perspectives, Eur. J. Pharm. Biopharm. 113 (2017) 211-228.

A.M. Butt, M.C.I.M. Amin, H. Katas, N.A. Abdul Murad, R. Jamal, P. Kesharwani, Doxorubicin and siRNA codelivery via chitosan-coated pH-responsive mixed micellar polyplexes for enhanced cancer therapy in multidrug-resistant tumors, Mol. Pharm. 13 (12) (2016) 4179-4190.

Z.L. Cao, X.L. Zuo, X.C. Liu, G.X. Xu, K.T. Yong, Recent progress in stimuliresponsive polymeric micelles for targeted delivery of functional nanoparticles, Adv. Colloid Interface Sci. 330 (2024) 103206.

C.F. Yang, W.Y. Liu, J.Y. Xiao, C. Yuan, Y.X. Chen, J.W. Guo, H.B. Yue, D.Y. Zhu, W.J. Lin, S.Q. Tang, X.Y. Dong, pH-sensitive mixed micelles assembled from PDEAEMA-PPEGMAand PCL-PPEGMA for doxorubicin delivery: experimental and DPD simulations study, Pharmaceutics 12 (2) (2020) 170.

C.F. Yang, D.L. Wang, W.Y. Liu, Z.X. Yang, T. He, F. Chen, W.J. Lin, Folate modified dual pH/reduction-responsive mixed micelles assembled using FA-PEG-PDEAEMAand PEG-SS-PCL for doxorubicin delivery, Phys. Chem. Chem. Phys. 25 (17) (2023) 12458-12468.

W.Q. Yang, P.W. Chen, E. Boonstra, T. Hong, H. Cabral, Polymeric micelles with pH-responsive cross-linked core enhance in vivo mRNA delivery, Pharmaceutics 14 (6) (2022) 1205.

J.J. Sun, Z. Wang, A.M. Cao, R.L. Sheng, Synthesis of crosslinkable diblock terpolymers PDPA-b-P(NMS-co-OEG) and preparation of shell-crosslinked pH/redox-dual responsive micelles as smart nanomaterials, RSC Adv. 9 (59) (2019) 34535-34546.

Y.T. Zheng, Y. Oz, Y.M. Gu, N. Ahamad, K. Shariati, J. Chevalier, D. Kapur, N. Annabi, Rational design of polymeric micelles for targeted therapeutic delivery, Nano Today 55 (2024) 102147.

D. Xiong, L.Y. Wen, S.Y. Peng, J.C. Xu, L.J. Zhang, Reversible cross-linked mixed micelles for pH triggered swelling and redox triggered degradation for enhanced and controlled drug release, Pharmaceutics 12 (3) (2020) 258.

G.Z. Kuang, Q.F. Zhang, S.S. He, Y.J. Wu, Y.B. Huang, Reduction-responsive disulfide linkage core-cross-linked p olymeric micelles for site-specific drug delivery, Polym. Chem. 11 (44) (2020) 7078-7086.

C.F. Yang, J.Y. Xiao, W.F. Xiao, W.J. Lin, J.R. Chen, Q. Chen, L.J. Zhang, C.Y. Zhang, J.W. Guo, Fabrication of PDEAEMA-based pH-responsive mixed micelles for application in controlled doxorubicin release, RSC Adv. 7 (44) (2017) 27564-27573.

L. Cai, X.J. Qin, Z.H. Xu, Y.Y. Song, H.J. Jiang, Y. Wu, H.J. Ruan, J. Chen, Comparison of cytotoxicity evaluation of anticancer drugs between real-time cell analysis and CCK-8 method, ACS Omega 4 (7) (2019) 12036-12042.

P.L. Ritger, N.A. Peppas, A simple equation for description of solute release I. Fickian and non-fickian release from non-swellable devices in the form of slabs, spheres, cylinders or discs, J. Contr. Release 5 (1) (1987) 23-36.

X.X. Han, F.R. Gong, L.L. Chi, C.C. Feng, J. Sun, Y.Y. Chen, J.W. Liu, Y.L. Shen, Cancer-targeted and glutathione-responsive micellar carriers for controlled delivery of cabazitaxel, Nanotechnology 30 (5) (2019) 055601.

J. Guan, Z.Q. Zhou, M.H. Chen, H.Y. Li, D.N. Tong, J. Yang, J. Yao, Z.Y. Zhang, Folate-conjugated and pH-responsive polymeric micelles for target-cell-specific anticancer drug delivery, Acta Biomater. 60 (2017) 244-255.

X.Q. Yi, D. Zhao, Q. Zhang, J.Q. Xu, G.D. Yuan, R.X. Zhuo, F. Li, Preparation of multilocation reduction-sensitive core crosslinked folate-PEG-coated micelles for rapid release of doxorubicin and tariquidar to overcome drug resistance, Nanotechnology 28 (8) (2017) 085603.

L.L. Zhao, Y.J. Zhang, J. Shao, H.Z. Liang, H.N. Na, J. Zhu, Folate-conjugated dually responsive micelles for targeted anticancer drug delivery, RSC Adv. 6 (42) (2016) 35658-35667.

Views

Downloads

CSCD

Alert me when the article has been cited

Submit

Tools

Publicity Resources

A durable fluorine-free polyurethane-coated fabric with switchable super-wetting properties under mild pH conditions for controllable oil/water separation

Engineering stable multi-component pH responsive nanomedicine for enhanced photothermal/photodynamic therapy

B-COPNA resin formation from ethylene tar light fractions: Process development and mechanical exploration by molecular simulation

Crosslinked P84 copolyimide/MXene mixed matrix membrane with excellent solvent resistance and permselectivity

Polymer-based membranes for solvent-resistant nanofiltration:A review

Related Author

Mao Taoyan

Xie Fengwei

Song Minzimo

Rong Yingchao

Chen Jiale

Lin Chuyan

Wu Junrong

Naveed Ramzan

Related Institution

Nottingham Ningbo China Beacons of Excellence Research and Innovation Institute, University of Nottingham Ningbo China

Guangzhou Tinci Materials Technology Co., Ltd.

School of Chemistry and Chemical Engineering, Guangzhou University

International Joint Research Center of Green Energy Chemical Engineering, East China University of Science and Technology

Department of Physics, University of Engineering and Technology

⁰