NIR-Light-Triggered Mild-Temperature Hyperthermia to Overcome the Cascade Cisplatin Resistance for Improved Resistant Tumor Therapy.

Currently, cisplatin resistance has been recognized as a multistep cascade process for its clinical chemotherapy failure. Hitherto, it remains challenging to develop a feasible and promising strategy to overcome the cascade drug resistance (CDR) issue for achieving fundamentally improved chemotherapeutic efficacy. Herein, a novel self-assembled nanoagent is proposed, which is constructed by Pt(IV) prodrug, cyanine dye (cypate), and gadolinium ion (Gd3+), for systematically conquering the cisplatin resistance by employing near-infrared (NIR) light activated mild-temperature hyperthermia in tumor targets. The proposed nanoagents exhibit high photostability, GSH/H+-responsive dissociation, preferable photothermal conversion, and enhanced cellular uptake performance. In particular, upon 785-nm NIR light irradiation, the generated mild temperature of ≈ 43 °C overtly improves the cell membrane permeability and drug uptake, accelerates the disruption of intracellular redox balance, and apparently enhances the formation of Pt-DNA adducts, thereby effectively overcoming the CDR issue and achieves highly improved therapeutic efficacy for cisplatin-resistant tumor ablation.

Near-infrared light-triggered nanobomb for in situ on-demand maximization of photothermal/photodynamic efficacy for cancer therapy.

Currently, the in situ on/off switch of PTT/PDT reagents for tumor treatment has evoked considerable interest in the field of cancer therapy. However, the actual PTT/PDT therapy efficacy in tumor treatment is largely restricted by the PTT/PDT reagents' aggregation issues during their release from the hydrophobic carrier to the hydrophilic tumor microenvironment. Thus, it remains a challenge to break through the therapy barrier caused by the PTT/PDT agent aggregation and achieve substantial improvement of anticancer efficacy. In this work, we developed a novel near-infrared (NIR) light-responsive and gas bubble-generated liposomal nanobomb (Cy/Ce6/CO2-Lip-FA) through the co-encapsulation of PTT/PDT reagents with gas precursor into the hydrophobic and hydrophilic regions of liposomes, respectively, in order to overcome the aggregation issues and substantially improve the synergistic PTT/PDT efficacy. Upon arrival at the tumor region, the PS phototoxicity of Cy/Ce6/CO2-Lip-FA could be effectively switched on through CO2 generation induced by the PTT effect of Cypate upon NIR irradiation. The gas bubble burst can remarkably suppress the aggregation of Cypate/Ce6 and extremely enhance the synergistic PTT/PDT efficacy. These results indicate that the proposed NIR-responsive and gas bubble-functionalized liposomal nanobomb is a highly promising platform for tumor treatment with better therapeutic efficacy.

pH-sensitive charge-conversional and NIR responsive bubble-generating liposomal system for synergetic thermo-chemotherapy.

A charge-conversional and NIR responsive rapid release liposomal system (PSD/DOX/Cypate-BTSL) was developed to enhance therapeutic efficacy of cancer therapy. The cationic liposomes containing Cypate, doxorubicin (DOX) and NH4HCO3 were shielded by pH-sensitive poly(methacryloyl sulfadimethoxine) (PSD) through electrostatic interaction at pH 7.4. At the tumor site (pH 6.5), PSD was deshielded and the liposomes displayed pH-sensitive charge reversal capability. The DOX released from PSD/DOX/Cypate-BTSL with irradiation was markedly higher than the other groups, indicating NIR irradiation and NH4HCO3 had a significant effect on the drug release. After irradiation, the hyperthermia induced by Cypate could produce CO2 bubbles quickly on account of the decomposition of NH4HCO3, achieving the rapid drug release. In 4T1 cells, PSD/DOX/Cypate-BTSL improved cellular uptake and cytotoxicity with irradiation at pH 6.5. In vivo results implied that the liposomes with irradiation could efficiently enhance the tumor accumulation and antitumor efficacy, and reduce systemic side effects of DOX. In conclusion, PSD/DOX/Cypate-BTSL is a promising candidate as a carrier for synergistic effects of PTT and chemotherapy.

NIR responsive liposomal system for rapid release of drugs in cancer therapy.

To design a rapid release liposomal system for cancer therapy, a NIR responsive bubble-generating thermosensitive liposome (BTSL) system combined with photothermal agent (Cypate), doxorubicin (DOX), and NH4HCO3 was developed. Cypate/DOX-BTSL exhibited a good aqueous stability, photostability, and photothermal effect. In vitro release suggested that the amounts of DOX released from BTSL were obviously higher than that of (NH4)2SO4 liposomes at 42°C. After NIR irradiation, the hyperthermic temperature induced by Cypate led to the decomposition of NH4HCO3 and the generation of a large number of CO2 bubbles, triggering a rapid release of drugs. Confocal laser scanning microscope and acridine orange staining indicated that Cypate/DOX-BTSL upon irradiation could facilitate to disrupt the lysosomal membranes and realize endolysosomal escape into cytosol, improving the intracellular uptake of DOX clearly. MTT and trypan blue staining implied that the cell damage of Cypate/DOX-BTSL with NIR irradiation was more severe than that in the groups without irradiation. In vivo results indicated that Cypate/DOX-BTSL with irradiation could dramatically increase the accumulation of DOX in tumor, inhibit tumor growth, and reduce systemic side effects of DOX. These data demonstrated that Cypate/DOX-BTSL has the potential to be used as a NIR responsive liposomal system for a rapid release of drugs in thermochemotherapy.