A novel GSH responsive poly(alpha-lipoic acid) nanocarrier bonding with the honokiol-DMXAA conjugate for combination therapy

Abstract

The key to improve the therapeutic efficacy for cancer treatment is to increase the delivery of drugs to tumors. For this purpose, tumor-microenvironment stimuliresponsive materials have great potential. Here, we prepared a new nanomedicine by bonding the conjugate of honokiol (HNK) and 5,6-dimethylxanthenone-4-acetic acid (DMXAA) to a glutathione (GSH)-responsive nanocarrier, poly(α-lipoic acid) polyethylene glycol. The nanomedicine would disintegrate due to the high level of GSH at the tumor sites, achieving the co-delivery of HNK and DMXAA, and realizing the combination therapy through close-range killing by HNK and long-range striking by DMXAA together. In a murine 4T1 breast tumor model, this strategy exhibited high tumor inhibition rate of 93%, and provided a valuable therapeutic choice for cancer therapy.

A ROS-Stimulus-Responsive Nanocarrier Loading with Guanidine-Modified Hydroxycamptothecin Prodrug for Enhanced Anti-Tumor Efficacy

“…Owing to the formation of ester bonds between HCPT and GA, the chemical shift of peaks f, g, h, and i in HCPT moved to a lower field (peak j, k, m, and n of HCPT-GA), and the formation of new peaks c, d, and e in HCPT-GA also showed the successful synthesis of HCPT-GA. Meanwhile, 13 C NMR quantitative spectrum (Figure 2c) showed that the integration ratio of peak u, v, or x to peak w or y is 1∶1, which also proved that HCPT-GA had indeed been obtained and the residual anhydride had been removed thoroughly. Subsequently, HCPT-Gu was characterized by 1 H NMR in DMSO-d6 and ESI-MS (ESI+).…”

“…HCPT-GA was characterized by 1 H NMR and 13 C NMR in DMSO-d6. As shown in Figure 2b, a new carboxyl peak p of HCPT-GA appeared, while the hydroxyl peak j of HCPT disappeared.…”

“…5 Among them, research on nanomedicines sensitive to tumor site-targeting characteristics has been highly promising. 6 Some of the strategies in use are pH manipulations, [7][8][9] targeting of reactive oxygen species (ROS) signaling, 10 as well as glutathione (GSH) synthesis/utilization, [11][12][13] which have yielded good results. For instance, ROS are often overproduced locally in diseased cells and tissues, 14 and they individually or synchronously contribute to many of the abnormalities associated with local pathogenesis.…”

Engineered nanomedicines for tumor vasculature blockade therapy

“…The activation of local chemotherapy combined with thrombosis achieved excellent tumor suppression in mouse. Furthermore, the GSH‐responsive nanoparticle combined with DMXAA had also been reported (Z. Liu et al, 2020). In another study, a CDDP‐loaded nanoparticle targeted by coagulation factors was used in combination with DMXAA (Song, Tang, Zhang, Li, et al, 2016; Song, Tang, Zhang, Wen, et al, 2016).…”

Employing the thiol-ene click reaction via metal-organic frameworks for integrated sonodynamic-starvation therapy as an oncology treatment

“…The antitumor effect of SDT is highly dependent on the reactive oxygen species (ROS) caused by acoustic sensitizers and low-intensity ultrasound (US). During the SDT process, tumor cells typically produce high levels of endogenous antioxidant anti-glutathione (GSH) [5][6][7][8][9], attenuating the intracellular ROS level and hindering the efficiency of SDT. To address this issue, researchers often use nanomaterials, such as MnWO X [10], MnO 2 [11,12], and Au [13] to achieve GSH depletion [7,14].…”