Mutually Synergistic Nanoparticles for Effective Thermo‐Molecularly Targeted Therapy

Abstract

Photothermal therapy (PTT) is of particular importance as a highly potent therapeutic modality in cancer therapy. However, a critical challenge still remains in the exploration of highly effective strategy to maximize the PTT efficiency due to tumor thermoresistance and thus frequent tumor recurrence. Here, a rational fabrication of the micelles that can achieve mutual synergy of PTT and molecularly targeted therapy (MTT) for tumor ablation is reported. The micelles generate both distinct photothermal effect from Cypate through enhanced photothermal conversion efficiency and pH-dependent drug release. The micelles further exhibit effective cytoplasmic translocation of 17-allylamino-17-demethoxygeldanamycin (17AAG) through reactive oxygen species mediated lysosomal disruption caused by Cypate under irradiation. Translocated 17AAG specifically bind with heat shock protein 90 (HSP90), thereby inhibiting antiapoptotic p-ERK1/2 proteins for producing preferable MTT efficiency through early apoptosis. Meanwhile, translocated 17AAG molecules further block stressfully overexpressed HSP90 under irradiation and thus inhibit the overexpression of p-Akt for achieving the reduced thermoresistance of tumor cells, thus promoting the PTT efficiency through boosting both early and late apoptosis of Cypate. Moreover, the micelles possess enhanced resistance to photobleaching, preferable cellular uptake, and effective tumor accumulation, thus facilitating mutually synergistic PTT/MTT treatments with tumor ablation. These findings represent a general approach for potent cancer therapy.

Activation of Prodrugs by NIR‐Triggered Release of Exogenous Enzymes for Locoregional Chemo‐photothermal Therapy

“…[21] However,t he relative level of p-AKT in the MYR@HGNs + GRE + NIR group was only 34.5 %, which was lower than that in the MYR + GRE group,p robably owing to the inhibition of Hsp90 ( Figure S15). [21] However,t he relative level of p-AKT in the MYR@HGNs + GRE + NIR group was only 34.5 %, which was lower than that in the MYR + GRE group,p robably owing to the inhibition of Hsp90 ( Figure S15).…”

Activation of Prodrugs by NIR‐Triggered Release of Exogenous Enzymes for Locoregional Chemo‐photothermal Therapy

“…As shown in Figure e, the level of AKT changed little in any group, but the significant decrease in levels of phosphorylated AKT (p‐AKT) were observed in MYR + GRE and MYR@HGNs + GRE +NIR groups, which revealed SFE could induce 4T1 cell apoptosis by inhibiting the PI3K‐AKT signaling pathway. In addition, the level of p‐AKT did not change in the HGNs + NIR group, illustrating that the hyperthermia could not affect the level of p‐AKT because of the protection of Hsp90 . However, the relative level of p‐AKT in the MYR@HGNs + GRE +NIR group was only 34.5 %, which was lower than that in the MYR + GRE group, probably owing to the inhibition of Hsp90 (Figure S15).…”

“…Zuschriften 7812 www.angewandte.de illustrating that the hyperthermia could not affect the level of p-AKT because of the protection of Hsp90. [21] However,t he relative level of p-AKT in the MYR@HGNs + GRE + NIR group was only 34.5 %, which was lower than that in the MYR + GRE group,p robably owing to the inhibition of Hsp90 ( Figure S15). Therefore,w et ested the effects of all the treatments on Hsp90 and the p50 Cdc37 (cochaperone of Hsp90) and found that the level of Hsp90 did not show obvious change in any group,w hile the levels of p50 Cdc37 were significantly reduced in the MYR + GRE and MYR@HGNs + GRE + NIR groups,w hich means that SFE could inhibit the function of Hsp90 by disrupting the interactions between Hsp90 and p50 Cdc37 ,resulting in aPTT-induced decrease in the level of p-AKT.T ogether,o ur data strongly evidenced the excellent ability of photoresponsive HGN-mediated MYR-GRE chemo-photothermal therapy in inducing the apoptosis of 4T1 cancer cells through the synergy of chemo-photothermal therapy.…”

Environmentally responsive dual-targeting nanotheranostics for overcoming cancer multidrug resistance

“…How to specifically deliver anticancer therapeutics and their sensitizers to tumor sites and effectively reduce the exposure of healthy tissues is a major challenge facing MDR cancer treatment. Toward this end, nanotechnology brings a new era in cancer research since it revolutionizes both the diagnosis and treatment by refining tumor-specific targeting [13][14][15]. Recent studies have suggested that nanomedicine offers great promise for eradicating MDR by increasing and tailoring the intracellular delivery of therapeutic agents [6,[16][17][18][19][20][21][22].…”