Cancer cells immersed in inherent oxidative stress are more vulnerable to exogenous oxidative damages than normal cells. Reactive oxygen species (ROS)-mediated oxidation therapy preferentially aggravating tumor oxidative stress to disrupt redox homeostasis, has emerged as an effective and specific anticancer treatment. Herein, following an ingenious strategy of “broaden sources and reduce expenditure”, we designed a versatile tumor-specific oxidative stress nanoamplifier enabling economized photodynamic therapy (PDT), to achieve synergistic oxidative stress explosion for superior oxidation therapy.
Methods:
Cinnamaldehyde (CA) as a therapeutic ROS generator was first conjugated to hyaluronic acid (HA) through acid-labile hydrazone bond to synthesize tailored amphiphilic HA@CA conjugates, which could surprisingly self-assemble into uniform nanofibers in aqueous media. Photosensitizer protoporphyrin (PpIX) was efficiently encapsulated into HA@CA nanofibers and transformed HA@CA nanofibers to final spherical HA@CAP.
Results:
With beneficial pH-responsiveness and morphology transformation, improved bioavailability and selective tumor accumulation, HA@CAP combining ROS-based dual chemo/photodynamic treatment modalities could induce cytotoxic ROS generation in a two-pronged approach to amplify tumor oxidative stress, termed “broaden sources”. Moreover, utilizing CA-induced H
2
O
2
production and cascaded Fenton reaction in mitochondria to consume intracellular overloaded Fe(II), HA@CAP could skillfully block endogenic heme biosynthesis pathway on site to restrain undesired elimination of PpIX for economized PDT, termed “reduce expenditure”. Both
in vitro
and
in vivo
results demonstrated the superior antitumor performance of HA@CAP.
Conclusion:
This study offered an inspiring strategy of “broaden sources and reduce expenditure” to specifically boost tumor oxidative stress for reinforced oxidation therapy.
Nanoparticles with ROS-responsive properties could realize spatial and temporal drug release under NIR irradiation and the excess ROS could be used for PDT.
Layered double hydroxide (LDH) nanoparticles are emerging as one of the promising nanomaterials for biomedical applications, but their systemic toxicity in vivo has received little attention. In the present study, the effects of inorganic nanoparticle aggregation on their systemic toxicity were examined. Remarkably, aggregation was observed after the mixing of naked LDH nanoparticles with saline or erythrocytes. Significant accumulation of the naked LDH nanoparticles in the lungs of mice was detected 1 h after intravenous administration, and the survival rate of mice was 0% after 6 repeated injections. Furthermore, flocculent precipitates in the alveoli and congestion in the lung interstitium were observed in the dead mice. However, lipid membrane-coated LDH nanoparticles would not form aggregates and could be injected intravenously >6 times without causing death. These findings suggested that repeated injections of LDH were lethal even at low dose (30 mg/kg), and lipid membrane coating can be considered as an approach for reducing this risk.
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