Near‐Infrared Laser‐Triggered Nitric Oxide Nanogenerators for the Reversal of Multidrug Resistance in Cancer

Abstract

The potential therapeutic implications of nitric oxide (NO) for diverse diseases have been under consideration for years; however, the development of precisely controllable NO generation system with potential for clinical application has remained elusive. Herein, intelligent near‐infrared (NIR) laser‐triggered NO nanogenerators for the treatment of multidrug‐resistant (MDR) cancer are fabricated by integrating photothermal agents and heat‐sensitive NO donors into a single nanoparticle. Such nanogenerators can absorb 808 nm NIR photons and convert them into ample heat to trigger NO release. The generated NO molecules are demonstrated to successfully achieve multidrug‐resistance reversal by inhibiting the expression of P‐glycol protein. Consequently, the intracellular accumulation of doxorubicin is effectively increased, resulting in high toxicity to MDR cancer cells in vitro. By virtue of surface modification with targeting ligands, these nanoparticles are able to selectively accumulate in tumor tissue. The therapeutic effects of the nanogenerators are validated in a humanized MDR cancer model. The in vivo experiment indicates that the nanoparticles possess excellent tumor suppression functionality with few side effects upon NIR laser exposure. Therefore, this novel photothermal conversion‐based NO‐releasing platform is expected to be a potential alternative to clinical MDR cancer treatment and may provide insights with regard to other NO‐relevant medical treatments.

Dual Stimuli‐Responsive Controlled Release Nanocarrier for Multidrug Resistance Cancer Therapy

“…After the templates were removed, sulfhydryl (SH) groups were modified on the surface of CuS@MSN. Afterward, NO was conjugated to the CuS@MSN by reacting tert‐butyl nitrite (TBN) with the −SH group, as reported previously . The scanning electron microscopy (SEM), as shown in Figure a, indicates that the CuS@MSN‐NO was monodispersed with an average diameter of 60 nm.…”

Multifunctional Nanotherapeutics for Photothermal Combination Therapy of Cancer

“…Among them, light-triggered release systems are most promising in clinic for the precise control of location, timing, and dosage. [115] In our design, nitrosothiol groups (-SNO, BDE 150 kJ mol −1 ), [116] a kind of heatsensitive NO donor, are conjugated to a photothermal nanocarrier (schemed in Figure 8a). [114] Last year, our group reported a photothermal-triggered NO release platform for the combination treatment of cancer.…”

“…[114] Last year, our group reported a photothermal-triggered NO release platform for the combination treatment of cancer. [115] In our design, nitrosothiol groups (-SNO, BDE 150 kJ mol −1 ), [116] a kind of heatsensitive NO donor, are conjugated to a photothermal nanocarrier (schemed in Figure 8a). Upon NIR laser irradiation, heat generated by photothermal nanocarrier cleaves the nitrosothiol groups and the release of NO is thus accelerated (Figure 8b).…”

“…Reproduced with permission [115]. b) On/off generation of NO upon NIR laser irradiation (808 nm, 0.3 W cm −2 , 5 min) and the nanocarriers are used as negative control.…”

Gas Therapy: An Emerging “Green” Strategy for Anticancer Therapeutics

“…NO can be released after the nanocarriers arrive in the tumor tissue after the stimulation of acidic tumor microenvironment. Suchyta NO CaCO 3 -mineralized nanoparticles (GSNO-MNPs) pH (5.0) [11] NO Dipalmitoylphosphatidylcholine-based liposomes pH (5.4) [13] NO Mesoporous nanoparticles with calcium phosphate (CaP) coating Light/pH (5.0) [12c] NO Liposomes composed of phospholipids Temperature [12a] NO Nitrate functionalized d-α-tocopheryl polyethylene glycol succinate (TNO 3 ) G S H [15] NO PEGylated disulfide-doped hybrid nanocarriers (PDHNs) with glutathione (GSH)-responsive shells Glutathione S-transferases π(GSTπ)/GSH [16] NO Hollow mesoporous organosilica nanoparticle H 2 O 2 [19] NO Monomethoxy(polyethylene glycol)-poly(lactic-co-glycolic acid) (mPEG-PLGA) Light [20] NO Fe-S clusters LED [21] NO Metal Roussin's black salts (Me-RBSs) NIR [22] NO Fe 3 O 4 @polydopamine@mesoporous silica NIR/temperature [26] NO Superparamagnetic iron oxide-encapsulated mesoporous silica nanoparticles (SPION@hMSN) Ultrasound [28] H 2 S Aldehyde functionalized poly(2-(4-formylbenzoyloxy)ethyl methacrylate) Cysteine/GSH [50a] H 2 S S-aroylthiooxime (SATO) functionalized amphiphilic block copolymer micelles Cysteine [51] H 2 S Aromatic peptide amphiphile NA [50c] H 2 S Polymers synthesized by copolymerization of l-lactide and a lactide functionalized with 4-hydroxythiobenzamide NA [55] H 2 S Magnetic nanoliposomes Cystathionine-β synthase (CBS) and cystathionine-γ -lyase (CSE) [53] CO Transition-metal-free carbon monoxide-releasing molecules based on BODIPY chromophores (COR-BDPs)…”