Multidrug resistance (MDR) is a major factor contributing to the failure of cancer therapy and is a public health issue of particular concern (Chen et al., 2019, Shibue and Weinberg, 2017, Vasan et al., 2019, Zhong et al., 2019). Currently, several cellular mechanisms of MDR have been reported, including inactivation of transcriptional signaling pathways that regulate apoptosis, alterations in the tumor microenvironment that induce acquired drug resistance, and overexpression of drug resistance genes (Gottesman et al., 2002, Mir et al., 2022, Zhang et al., 2023). Among these mechanisms, the reduction in drug accumulation mediated by the P-glycoprotein (P-gp) efflux pumps in tumor cells is considered one of the key factors contributing to MDR (Fan et al., 2023, Hanssen et al., 2021). It is noteworthy that the functioning of P-gp, an ATP-dependent transport protein, is closely associated with mitochondrial activity. In the context of tumor multidrug-resistant cells, metabolic pathways in the mitochondria undergo certain modifications that facilitate a substantial provision of energy for P-gp. Furthermore, aberrant mitochondrial functioning disrupts the autophagy and apoptosis mechanisms within tumor multidrug-resistant cells, thereby enabling these cells to evade programmed cell death (Zhang et al., 2017, Zhou et al., 2022a, Zhou et al., 2022b). To address this problem, a viable approach is the administration of combination therapies based on P-gp inhibitors and chemotherapeutic drugs (Ieiri, 2012, Mirzaei et al., 2022). However, the application of multi-drug combination therapies is severely restricted by reductions in loading efficiency and uncontrollable drug release ratios associated with drug interactions or incompatibilities between different nano-systems.

With on-going advances in materials science, certain surfactants such as d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) and P-188 have been discovered to have inhibitory effects on multidrug resistance in tumor cells (Dutta et al., 2020, Hegazy et al., 2022, Luo et al., 2021). For example, TPGS undergoes activation within the tumor microenvironment, thereby promoting the excess generation of reactive oxygen species (ROS) that inhibit P-gp efflux pump activity by disrupting mitochondrial function (Dong et al., 2008, Rathod et al., 2021, Yan et al., 2021). In addition to its effects on ROS, TPGS also acts on several cellular processes to reduce multidrug resistance, including affecting membrane fluidity, stalling cell cycle progression, and down-regulating the expression of anti-apoptotic proteins(such as Bcl-2 and Survivin) (Liang and Qiu, 2021, Rathod et al., 2021). Among other compounds, curcumin (Cur) has been shown to effectively mitigate the cardiotoxicity induced by doxorubicin (Dox, first-line chemotherapy medication) (Cagel et al., 2017, Goncalves et al., 2020), and decrease the expression and function of P-gp (Hosseini-Zare et al., 2021, Nasery et al., 2022, Rahiman et al., 2022), Moreover, it has been demonstrated to have a synergistic anti-MDR effect when used in combination with TPGS. However, the limited solubility, bioavailability, and stability of Cur pose significant challenges in facilitating its application for cancer treatment (Pan-On, et al., 2022). On the basis of these considerations, the combination of chemotherapeutic drugs and nanotechnology-based P-gp inhibitors (Li and Xu, 2020) is believed to represent a potentially effective strategy for overcoming MDR and improving treatment efficacy.

In this study, we developed a novel nanocarrier material with “pharmacological activity” by grafting the biosafe P-gp inhibitor TPGS onto the multi-target point dendrimers of poly(amidoamine) (PAMAM)–NH2 via amide bonding. Two nano-micelle (NM) systems, Dox-NMs and Cur-NMs, were constructed using this material with Dox and Cur as model drugs. The co-delivery system, designated Dox-NMs&Cur-NMs, was prepared through physical mixing. The aim of using this co-delivery system was to develop a strategy that could be employed to reverse MDR by capitalizing on the advantages of the multidrug/material combination. The multiple advantages of this system are as follows: (1) the enhanced solubility and bioavailability of Cur, which facilitates direct blocking of the expression and activity of P-gp; (2) the ability to adjust Dox and Cur co-delivery by selecting the most effective Dox/Cur ratio; (3) the synergistic effect of Cur and Dox in significantly reducing the Dox-induced toxicity to the heart, liver, spleen, and other organs; (4) rapid drug release in acidic tumor cell environments; and (5) the inhibition of P-gp efflux pumps via TPGS-induced mitochondrial dysfunction, achieved through a reduction in ATP supply. The combination of these effects contributes to an enhancement in drug accumulation and a heightened tumor inhibitory effect when combined with drugs and materials. In summary, the newly constructed multidrug/material co-delivery system effectively overcomes the limitations of traditional multi-drug combination therapy models and optimizes the drug delivery process.