Biomimetic Engineering of a Scavenger‐Free Nitric Oxide‐Generating/Delivering System to Enhance Radiation Therapy

Abstract

Nitric oxide (NO) is a potent tumor‐cell radiosensitizer but it can be readily scavenged by hemoglobin (Hb) in vivo. A biomimetic incubator that can generate and deliver NO in a scavenger (Hb)‐free environment to enhance its radiosensitizing effect to maximize its efficacy in radiotherapy is proposed. This NO incubator comprises a poly(lactic‐co‐glycolic acid) (PLGA) hollow microsphere (HM) that contains an NO donor (NONOate) and a surfactant molecule (sodium caprate, SC) in its aqueous core. In acidic tumorous environments, the PLGA shell of the HM allows the penetration of protons from the outside, activating the hydrolytic cleavage of NONOate, spontaneously generating NO bubbles, which are immediately trapped/stabilized by SC. The SC‐stabilized NO bubbles in the HM are then squeezed through the spaces of its PLGA matrices by the elevated internal pressure. Upon leaving the HM, the entrapped NO molecules may passively diffuse through their SC‐stabilized/protected layer gradually to the tumor site, having a long‐lasting radiosensitizing effect and inhibiting tumor growth. The entire process of NO generation and delivery is conducted in a scavenger (Hb)‐free environment, mimicking the development of young ovoviviparous fish inside their mothers' bodies in the absence of predators before birth.

Advanced and Innovative Nano-Systems for Anticancer Targeted Drug Delivery

“…S-nitrosoglutathione (GSNO) is a prodrug that can generate nitric oxide (NO) under the presence of glutathione (GSH) [ 99 ]. Many studies have revealed that NO has the potential to overcome multidrug resistance (MDR) with low side effects [ 100 ]. However, GSNO is unstable and its stability can be easily affected by ambient temperature, pH and other factors.…”

PLGA Core-Shell Nano/Microparticle Delivery System for Biomedical Application

“…Layers of SC surfactant then trap and stabilize NO molecules and they are together released from the PLGA shell due to the increased pressure. Outside the PLGA shell, NO molecules slowly diffuse from the encapsulation of SC, providing elongated radiosensitizing effects which inhibit tumor growth [58]. In another study, gold core-mesoporous silica shell rod-like nanoparticles (AuMSSs) and salicylic acid (SA) were loaded inside the microspheres made of PLGA, poly (vinyl alcohol) (PVA), and D-α-tocopherol polyethylene glycol succinate (TPGS).…”

Multifunctional Mitochondria-Targeting Nanosystems for Enhanced Anticancer Efficacy

“…On the other hand, nitric oxide (NO) can effectively inhibit tumor cell respiration and facilitate tumor vessel normalization, which thereby increase the perfusion of blood, alleviate tumor hypoxia, polarize M2 macrophages to the M1 phenotype, and reduce the number of myeloid-derived suppressor cells (MDSCs) ( Ramesh et al, 2020 ). Furthermore, many studies have demonstrated that NO could react with the ROS produced by PDT or SDT, which could generate more powerful oxidant reactive nitrogen species (RNS) to reverse the immunosuppressive TME and achieve more effective antitumor effect ( An et al, 2020 ; Lin et al, 2020 ; Xiang et al, 2021 ). Therefore, Ji et al (2021) constructed a mitochondria-targeting, US-responsive nanoparticle (named PIH-NO), which could deliver O 2 and NO at the same time to amplify SDT and increase immune response.…”