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. 2025 Apr 23:20:5181-5192.
doi: 10.2147/IJN.S517291. eCollection 2025.

Stimuli-Responsive Nodal Dual-Drug Polymer Nanoparticles for Cancer Therapy

Gaizhen Kuang  1   2 , Jiaze Ding  1   2 , Weiyi Xie  1   2 , Zihui Ye  1   2 , Qingfei Zhang  1   2
Affiliations

Stimuli-Responsive Nodal Dual-Drug Polymer Nanoparticles for Cancer Therapy

Gaizhen Kuang et al. Int J Nanomedicine. .

Abstract

Background: Polymeric drug delivery systems (DDSs) have gained significant attention in cancer therapy. However, these systems often respond to a single biological stimulus in tumor tissues or cells, limiting their effectiveness. While multi-sensitive DDSs improve therapeutic precision, their complex synthesis involving multi-step modifications remains challenging. Developing functionally integrated and simplified multiple stimuli-responsive DDSs is crucial to addressing tumor diversity and enhancing treatment efficacy.

Methods and results: Here, we develop a dual-sensitive nodal dual-drug polymer nanoparticle (DDPoly NP) system for cancer therapy. This system combines a platinum(IV) prodrug (Cisplatin(IV)) with Demehylcantharidin (DMC) to create a dual-drug molecule (DDM). Then DDM is conjugated with methoxypolyethylene glycol (MPEG), forming a nodal dual-drug polymer (DDPoly). The amphiphilic polymer is capable of self-assembling into nanoparticles (DDPoly NPs) when in aqueous solution. The drug release experiments displayed that lower pH and reductive conditions simulating tumor microenvironment promoted the release of Cisplatin and DMC. Cytotoxicity studies demonstrated that DDPoly NPs exhibited superior anti-cancer activity compared to the single-drug system (SDPoly NPs). The IC50 values of DDPoly NPs against A549 cells (15.37 μM) and HeLa cells (17.05 μM) were significantly lower than those observed for SDPoly NPs, which were 40.48 μM for A549 cells and 38.11 μM for HeLa cells, respectively.

Conclusion: The study developed dual stimuli-responsive DDPoly NPs based on acid- and reduction-sensitive DDM, enabling tumor-specific activation without additional responsive components. DDPoly NPs triggered Pt(II) release via reduction and generated DMC through acid hydrolysis. The synergistic effect of DDPoly NPs lies in that DMC could inhibit the expression of serine/threonine protein phosphatase 2A (PP2A) and further elevate the expression of hyper-phosphorylated Akt (pAKt), thus blocking DNA repair to enhance Pt(II)-induced apoptosis. DDPoly NPs showed enhanced anti-cancer efficacy against cancer cells compared to SDPoly NPs, highlighting its potential for nanomedicine development.

Keywords: cancer therapy; chemotherapy; platinum drug; polymer nanoparticle; stimuli-responsive.

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Conflict of interest statement

The author(s) report no conflicts of interest in this work.

Figures

Figure 1
Figure 1
Schematic illustration of nodal dual-drug polymer nanoparticles (DDPoly NPs) for synergistic therapy. (A) Illustration of structure and self-assembly of DDPoly, and dual stimuli-responsive degradation of DDPoly NPs. (B) Anti-cancer mechanisms of DDPoly NPs after endocytosis by cancer cells. The schematic diagram was generated by Figdraw.
Figure 2
Figure 2
(A) 1H NMR spectrum of the single-drug molecule (SDM) in DMSO-d6. δ (ppm): 2.48 and 2.37 (a and b, -CH2-CH2-), 6.49 (c, -NH3), and 12.04 (d, -COOH). (B) 1H NMR spectrum of the dual-drug molecule (DDM) in DMSO-d6. δ (ppm): 6.18 (a, -NH3), 2.96 (b, -CH-), 4.60 and 4.70 (c, -CH-), and 1.49 (d, -CH-). (C) ESI-MS spectrum of SDM. (D) ESI-MS spectrum of DDM.
Figure 3
Figure 3
(A) 1H NMR spectrum of the nodal single-drug polymer (SDPoly) in DMSO-d6. δ (ppm): 2.43 and 2.27 (a and b, -CH2-CH2-), 6.52 (c, -NH3), and 3.68–3.43 (PEG). (B) 1H NMR spectrum of the nodal dual-drug polymer (DDPoly) in DMSO-d6. δ (ppm): 6.19 (a, -NH3), 2.82 (b, -CH-), 4.62 and 4.73 (c, -CH-), 1.46 (d, -CH-), and 3.68–3.40 (PEG). (C) 1H NMR spectrum of the nodal single-drug polymer nanoparticles (SDPoly NPs) in D2O. δ (ppm): 3.66 (PEG). (D) 1H NMR spectrum of the nodal single-drug polymer nanoparticles (DDPoly NPs) in D2O. δ (ppm): 3.66 (PEG).
Figure 4
Figure 4
(A–C) Self-assembly process (A), TEM image (B), and size distribution (C) of DDPoly NPs. (D–F) Self-assembly process (D), TEM image (E), and size distribution (F) of SDPoly NPs. The scale bars are 200 nm.
Figure 5
Figure 5
(A) Stimuli-responsive disassembly processes of DDPoly NPs. (B) Drug release profiles of DDPoly NPs after different treatments in 48 h. (C) Size distribution and morphology changes of DDPoly NPs after different treatments for 48 h. (D) Stimuli-responsive disassembly processes of SDPoly NPs. (E) Drug release profiles of SDPoly NPs after different treatments in 48 h. (F) Size distribution and morphology changes of SDPoly NPs after different treatments for 48 h. The inset TEM images are DDPoly NPs or SDPoly NPs after incubation with GSH at pH 5.0 for 48 h. The scale bars are 1 μm.
Figure 6
Figure 6
(A and B) CLSM images of A549 cells after incubation with SDPoly@NR NPs (A) or DDPoly@NR NPs (B) for 0.5 h or 4 h. The scale bars are 50 μm. (C) The cellular uptake analysis of SDPoly@NR NPs or DDPoly@NR NPs by flow cytometry. (D) The mean fluorescence intensity of cells incubated with SDPoly@NR NPs or DDPoly@NR NPs for different time intervals. n.s.: no significance. *** p < 0.001.
Figure 7
Figure 7
(A and B) Cell viability of A549 cells (A) and Hela cells (B) after treatment with different drugs for 48 h. (C) Immunofluorescent staining of γH2AX after treatment with different drugs for 48 h. The scale bars are 50 μm. (D) Immunofluorescent staining of p-Akt after treatment with different drugs for 48 h. The scale bars are 20 μm.
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