Self-Assembly Dual-Responsive NO Donor Nanoparticles for Effective Cancer Therapy

Abstract

Drug resistance and the serious side effects caused by classical chemotherapy drugs necessitate the development of novel targeted drug delivery systems. The high lipophilicity and short half-life of nitric oxide (NO), a gas with strong antitumor activity, make it difficult to reach the tumor site and result in a poor therapeutic effect in vivo. In order to overcome the deficiencies of the existing NO donors and NO delivery vehicles, a novel strategy was proposed to deliver NO for cancer chemotherapy by the prodrug dimer self-assembly nanoparticles of NO donors. Specifically, phenylsulfonylfuroxan (FZ) was chosen as the NO donor to synthesize the prodrug dimer precursor (FZ-SS-FZ) by disulfide linkages and ester bonds. The insertion of disulfide linkages promotes the self-assembly of FZ-SS-FZ in water. After this, the dual-responsive and tumor-targeting NO delivery system (FZ-SS-FZ@FA NPs) will finally be fabricated by further introducing folic acid on the surface of nanoparticles. FZ-SS-FZ can self-assemble to form uniform nanoparticles in water, which can effectively deliver NO to the tumor site and be uptaken by tumor cells, thus resulting in specific NO release in tumor cells and inducing tumor cell apoptosis. FZ-SS-FZ@FA NPs significantly improve the drug loading and delivery efficiencies of NO for chemotherapy, while enhancing its efficacy, providing a novel strategy for the tumortargeted delivery of NO and at the same time laying a theoretical basis for the clinical translation of NO-based gas chemotherapy, opening up a new approach for cancer chemotherapy.

Recent advances in diverse nanosystems for nitric oxide delivery in cancer therapy

“…This review discusses recent developments in NO donor delivery strategies categorized from inorganic and organic delivery systems. It will provide ideas for future research trends in NO transport ( Table 2 ) 123 , 128 , 130 , 131 , 132 , 133 , 134 , 135 , 136 , 137 , 138 , 139 , 140 , 141 , 142 , 143 , 144 , 145 , 146 , 147 , 148 , 149 , 150 , 151 , 152 .…”

“…In addition to adding ligands for targeting tumor tissues on the loaded Si system, it is also important to integrate the knowledge of different physiological characteristics of tumor tissues. For instance, the fibrinogen content of the pancreatic cancer cell matrix is more abundant than other tumors, the mesoporous Si carrier system constructed by Zhang and colleagues 123 , 128 , 130 , 131 , 132 , 133 , 134 , 135 , 136 , 137 , 138 , 139 , 140 , 141 , 142 , 143 , 144 , 145 , 146 , 147 , 148 , 149 , 150 , 151 , 152 were modified with fibrinogen cyclic decapeptide CGLIIQKNEC (CLT1-G-propargy1). l -Arginine as H 2 O 2 responsive NO donor in this platform was found to possess seven-fold higher retention rate in a subcutaneous xenograft mouse model of Panc-1.…”

Enhancing the therapeutic efficacy of nanoparticles for cancer treatment using versatile targeted strategies

“…The insertion of disulfide bonds facilitates the self-assembly of polymers in solution. Subsequently, the multiresponsive tumor-targeting NO nanoparticles can be obtained by adding FA onto the surface, which can achieve the effective delivery of NO to tumor regions, leading to accurate NO release and inducing tumor cell apoptosis [ 167 ]. Researchers have also developed other NO donors, such as Roussin’s black salt, metal NO complexes, and S-nitrosothiols [ 168 – 171 ].…”

Sustained Release of Nitric Oxide and Cascade Generation of Reactive Nitrogen/Oxygen Species via an Injectable Hydrogel for Tumor Synergistic Therapy

“…[24] To enhance the stability of NO donors and realize the targeted delivery of NO, various nano-delivery systems have been developed, such as polymeric nanoparticles (NPs) (e.g., micelles, nano lip osomes), [13,18,[25][26][27][28][29] metal-organic frameworks, [15,30] inorganicand metal-based NPs, [14,20] and nano-assemblies composed of small molecules. [22,31] Nevertheless, the low donor loading efficiency and the leakage of NO during the blood circulation lead to insufficient NO release in tumors, [22,32] which significantly offset the efficacy of NO-associated tumor therapy.…”