Pulmonary circulation-mediated heart targeting for the prevention of heart failure by inhalation of intrinsically bioactive nanoparticles

Abstract

Heart failure is a serious clinical and public health problem. Currently there is an unmet demand for effective therapies for heart failure. Herein we reported noninvasive inhalation delivery of nanotherapies to prevent heart failure. Methods: A reactive oxygen species (ROS)-scavenging material (TPCD) was synthesized, which was processed into antioxidative and anti-inflammatory nanoparticles ( i.e. , TPCD NP). By decoration with a mitochondrial-targeting moiety, a multilevel targeting nanotherapy TTPCD NP was engineered. Pulmonary accumulation of inhaled TPCD NP and underlying mechanisms were examined in mice. In vivo efficacies of nanotherapies were evaluated in mice with doxorubicin (DOX)-induced cardiomyopathy. Further, an antioxidative, anti-inflammatory, and pro-resolving nanotherapy ( i.e. , ATTPCD NP) was developed, by packaging a peptide Ac2-26. In vitro and in vivo efficacies of ATTPCD NP were also evaluated. Results: TPCD NP alleviated DOX-induced oxidative stress and cell injury by internalization in cardiomyocytes and scavenging overproduced ROS. Inhaled TPCD NP can accumulate in the heart of mice by transport across the lung epithelial and endothelial barriers. Correspondingly, inhaled TPCD NP effectively inhibited DOX-induced heart failure in mice. TTPCD NP showed considerably enhanced heart targeting capability, cellular uptake efficiency, and mitochondrial localization capacity, thereby potentiating therapeutic effects. Notably, TPCD NP can serve as bioactive and ROS-responsive nanovehicles to achieve combination therapy with Ac2-26, affording further enhanced efficacies. Importantly, inhaled TPCD NP displayed good safety at a dose 5-fold higher than the efficacious dose. Conclusions: Inhalation delivery of nanoparticles is an effective, safe, and noninvasive strategy for targeted treatment of heart diseases. TPCD NP-based nanotherapies are promising drugs for heart failure and other acute/chronic heart diseases associated with oxidative stress.

Mitochondrial Dysfunction and Therapeutic Perspectives in Cardiovascular Diseases

“…Modification of nanoparticles with different components facilitates mitochondrial directed drug penetration [126]. A team has constructed a non invasive aerosol inhalation delivery system based on antioxidant nano drugs, which can target damaged mitochondria, clear ROS, and improve the targeting ability of nano-drugs to myocardium [85]. Artificial hybrid nanozymes created by protein reconstruction technology and nanotechnology can target mitochondria and scavenge ROS, thereby reducing mitochondrial oxidative damage [127].…”

Nanoparticles in the diagnosis and treatment of vascular aging and related diseases

“…A previous study demonstrated that inhalation-based delivery of TPCD nanoparticles suppressed doxorubicin-induced heart failure in mice due to internalization in cardiomyocytes and scavenging excessive ROS. 347 Moreover, Vanillyl alcohol (PVAX)-polymer nanoparticles treatment alleviated doxorubicin-induced cardiomyopathy by inhibiting activation of poly (ADP ribose) polymerase 1 (PARP-1) and caspase-3. 348 Experimental results from a rodent diabetic cardiomyopathy model revealed that inhalation of calcium phosphate nanoparticles loaded with a therapeutic mimetic peptide markedly improved myocardial contraction and cardiac function via rapid translocation of calcium phosphate nanoparticles from pulmonary to myocardium, where the therapeutic mimetic peptide is quickly released.…”

Selective organ targeting nanoparticles: from design to clinical translation

“…133 In another study, Liu et al adopted a new approach to deliver nanoparticles for the treatment of heart failure. 134 They used triphenylphosphine-modified ROS-scavenging nanoparticles for targeting mitochondria by non-invasive inhalation. Taking advantage of the ability of particles smaller than 100 nm to enter the pulmonary circulation and accumulate in the heart through the air-blood barrier, nanoparticles deposited in the lungs were continuously delivered to the heart through the pulmonary circulation, internalized to cardiomyocytes, and scavenged ROS to treat heart failure.…”