Enhanced-permeability delivery system for hydroxyl radical-responsive NIR-II fluorescence-monitored thrombolytic therapy.

Pathological thrombus can cause serious acute diseases that present a significant threat to human health, such as myocardial infarction and stroke. Challenges remain in achieving effective thrombolysis and real-time monitoring of therapeutic effects while minimizing side effects. Herein,a multifunctional nanoplatform (TG-OPDEA@UK/MnO2-H1080) with enhanced thrombus-permeability was developed to monitor the therapeutic effect of antioxidant-thrombolysis by hydroxyl radical-responsive NIR-II fluorescence imaging. The polyzwitterion poly (oxidized N,N-Diethylaminoethyl methacrylate-co-n-butyl methacrylate) (OPDEA) was prepared as the matrix of nanoparticles to simultaneously loading urokinase (UK) and MnO2 QDs, as well as NIR-II fluorescent molecule, H-1080. Subsequently, the fibrin targeted peptide CREKA was modified on the surface of the nanoparticles. OPDEA exhibits efficient loading capacity while endowing nanoparticles with the ability to effectively increased penetration depth of UK by 94.1 % into the thrombus, for extensive thrombolysis and fluorescence monitoring. The loaded UK exhibited good thrombolytic effect and greatly reduced the risk of bleeding by 82.6 %. TG-OPDEA@UK/MnO2-H1080 showed good thrombolytic efficacy and specific thrombus monitoring in the mouse carotid artery thrombosis model induced by ferric chloride (FeCl3). This work prepares a nanoplatform for thrombolytic therapy and real-time efficacy assessment based on an independent externally forced thrombus penetration delivery strategy.

ROS-Suppression Nanoplatform Combined Activation of STAT3/Bcl-2 Pathway for Preventing Myocardial Infarction in Mice.

Myocardial infarction (MI) is the leading cause of death worldwide. The most effective way to treat myocardial infarction is to rescue ischemic cardiomyocytes. After an ischemic event, the overproduction of reactive oxygen species (ROS) is a key driver of myocardial injury. The produced ROS affects mitochondrial function and induces apoptosis in cardiomyocytes. This was accomplished by constructing platelet-membrane-encapsulated ROS-responsive drug-releasing nanoparticles (PMN@NIC-MalNPs) to deliver malonate and niclosamide (NIC). The results revealed that PMN@NIC-MalNPs degraded and released malonate and niclosamide in a high-level ROS microenvironment, effectively reducing the oxidative stress and apoptosis rate. By enhancing basal mitochondrial oxygen consumption rate (OCR), adenosine triphosphate (ATP) production, and spare respiratory capacity (SRC) in vitro, reduced the oxidative stress levels and restored mitochondrial function. In vivo studies revealed that the PMN@NIC-MalNPs improved cardiac dysfunction, inhibited succinate dehydrogenase (SDH) activity, increased ATP production, and reduced the myocardial infarct size in myocardial infarction model mice. Further, transcriptome analysis and Western blot revealed that PMN@NIC-MalNPs prevented apoptosis by activating the expressions of the signal transducer and activator of transcription 3 (STAT3) and Bcl-2, and inhibiting the expression of Bax. Thus, this study provides a novel therapeutic solution for treating myocardial infarction and predicting the viability of an antioxidant and antiapoptotic therapeutic solution in the treatment of myocardial injury.

Platelet Membrane-Encapsulated Nanocomplexes Based on Profundity Scavenging ROS Strategy for Myocardial Infarction Therapy.

Ischemia-induced myocardial injury has become a serious threat to human health, and its treatment remains a challenge. The occurrence of ischemic events leads to a burst release of reactive oxygen species (ROS), which triggers extensive oxidative damage and leads to dysfunctional autophagy, making it difficult for cells to maintain homeostasis. Antioxidants and modulation of autophagy have thus become promising strategies for the treatment of ischemic myocardial injury. This study proposes an antioxidant-activated autophagy therapeutic regimen based on combining melanin (Mel), an excellent antioxidant with metformin mimetic ploymetformin via electrostatic interactions, to obtain a nanocomplex (Met-Mel). The nanocomplex is finally encapsulated with platelet membranes (PMN) to construct a biomimetic nanoparticle (PMN@Met-Mel) capable of targeting injured myocardium. The prepared PMN@Met-Mel has good Mel loading capacity and optimal biosafety. It exhibits excellent antioxidant activity and autophagy activation, rapidly restoring mitochondrial function. Moreover, RNA sequencing (RNA-seq) analysis reveals that PMN@Met-Mel operates mechanistically by triggering the activation of the autophagy pathway. Subsequent in vivo experiments showcase promising cardioprotective effects of these nanoparticles. These discoveries present a newly devised nanoplatform with promising potential for the effective treatment of myocardial infarction.

Highly efficient singlet oxygen generation, two-photon photodynamic therapy and melanoma ablation by rationally designed mitochondria-specific near-infrared AIEgens.

Photosensitizers (PSs) with multiple characteristics, including efficient singlet oxygen (1O2) generation, cancer cell-selective accumulation and subsequent mitochondrial localization as well as near-infrared (NIR) excitation and bright NIR emission, are promising candidates for imaging-guided photodynamic therapy (PDT) but rarely concerned. Herein, a simple rational strategy, namely modulation of donor-acceptor (D-A) strength, for molecular engineering of mitochondria-targeting aggregation-induced emission (AIE) PSs with desirable characteristics including highly improved 1O2 generation efficiency, NIR emission (736 nm), high specificity to mitochondria, good biocompatibility, high brightness and superior photostability is demonstrated. Impressively, upon light irradiation, the optimal NIR AIE PS (DCQu) can generate 1O2 with efficiency much higher than those of commercially available PSs. The excellent two-photon absorption properties of DCQu allow two-photon fluorescence imaging of mitochondria and subsequent two-photon excited PDT. DCQu can selectively differentiate cancer cells from normal cells without the aid of extra targeting ligands. Upon ultralow-power light irradiation at 4.2 mW cm-2, in situ mitochondrial photodynamic activation to specifically damage cancer cells and efficient in vivo melanoma ablation are demonstrated, suggesting superior potency of the AIE PS in imaging-guided PDT with minimal side effects, which is promising for future precision medicine.

Pulsed Microwave-Pumped Drug-Free Thermoacoustic Therapy by Highly Biocompatible and Safe Metabolic Polyarginine Probes.

Serious side effects are plaguing traditional chemotherapy, and the development of drug-free treatment is expected to ease the dilemma. Herein, drug-free polyarginine probes are fabricated from the co-polymerization of arginine monomer and slight amount of rhodamine B monomer, which are efficient for thermoacoustic imaging and therapy with high biocompatibility and safe metabolism. Polyarginine can be strongly pumped upon pulsed microwave irradiation, generating significant thermoacoustic shockwaves, namely thermocavitation, which can in situ destroy mitochondria to initiate programmed cancer cell apoptosis. In vivo explorations demonstrate the high theranostic efficiency for cancer thermoacoustic imaging and cancer inhibition, exhibiting low systemic cytotoxicity and good biocompatibility after systemic administration. Herein, pulsed microwave-pumped biocompatible polyarginine is promising for drug-free precision theranostics without any detectable side effects, and the deep penetration potency of microwave makes it potentially able to treat deep-seated diseases in future biomedicine.

Explosible nanocapsules excited by pulsed microwaves for efficient thermoacoustic-chemo combination therapy.

Microwave irradiation is a powerful non-invasive approach for treating deep-seated diseases in a clinical setting. Pulsed microwave-induced thermoacoustic cavitation allows precise cancer treatment with microwave-absorbing materials. This differs from the traditional continuous microwave-induced thermotherapy which may be harmful to off-target tissues. Here we first report the integration of thermocavitation and cytoplasmic drug release into highly explosible cell-penetrating nanocapsules for effective tumor inhibition under pulsed microwave irradiation. The nanocapsules were formulated from arginine-tethered reduction-responsive copolymers, P(ArgMA-co-DMA)-b-PPOPMA, microwave-absorbing AB and chemotherapeutic DOX using a double-emulsion method. The nanocapsules were internalized by cancer cells rapidly via major energy-independent pathways. Upon pulsed microwave irradiation, AB absorbed energy to generate a giant thermoacoustic shockwave, simultaneously decomposing into carbon dioxide and ammonia which enforced the cavitation damage effect. The thermoacoustic shockwave and gas burst also mechanically disrupted the intracellular organelles resulting in high-ratio cell necrosis and promoted the cytosolic release of DOX into the nucleus to initiate cell death. Importantly, in vivo results demonstrated significantly suppressed tumor growth by the pulsed microwave-triggered thermocavitation and drug release, and minimal systemic toxicity from the microwave treatment. Therefore, our study provides a new strategy for effectively engineering pulsed microwave-responsive nanomaterials for smart cancer therapy.

NIR-controlled morphology transformation and pulsatile drug delivery based on multifunctional phototheranostic nanoparticles for photoacoustic imaging-guided photothermal-chemotherapy.

Stimuli-responsive nanoparticles are focused to promote the pathological specificity and controlled therapeutic activation in biomedicine, but the multifunctional modulation remains challenging. Herein, size and morphology switchable phototheranostic nanoparticles are developed for photoacoustic (PA) imaging-guided photothermal-chemotherapy. Multifunctional polypyrrole (PPy) nanoparticles with the template of upper critical solution temperature (UCST) polymers are designed to achieve light-controlled pulsatile drug release and concurrent activation of photothermal therapy (PTT). Wherein the UCST-featured inner core is loaded with camptothecin (CPT), the outer corona is tethered with thermo-cleavable doxorubicin (DOX) prodrug and further in-situ coated with PPy, affording the resultant CPT@DOX-UCST/PPy nanoparticles. Upon 808 nm continuous laser illumination, significant heating generated from light-absorbable PPy results in DOX prodrug cleavage and considerable size swelling (∼125-fold), which in turn promotes simultaneous dual drug release, and thus triggering the combined therapeutic activation of PTT and chemotherapy. When laser is switched off, the discontinued photothermal generation makes the nanoparticle shrink back, thereby avoiding the leakage of CPT and DOX. In vivo experiments demonstrate the favorable tumor accumulation and prolonged tumor retention (>24 h) for long-term PA imaging-guided combination therapy. Current multifunctional nanoparticles integrated with light-controlled swelling/shrinking and synergistic therapeutic activation/silence represent a promising platform for precision cancer theranostics.

Concurrent Drug Unplugging and Permeabilization of Polyprodrug-Gated Crosslinked Vesicles for Cancer Combination Chemotherapy.

Combination chemotherapy with both hydrophobic and hydrophilic therapeutic drugs is clinically vital toward the treatment of persistent cancers. Though conventional liposomes and polymeric vesicles possessing hydrophobic bilayers and aqueous interiors can serve as codelivery nanocarriers, it remains a considerable challenge to achieve synchronized release of both types of drugs due to distinct encapsulation mechanisms; premature release of water-soluble cargos from unstable liposomes and ruptured vesicles is also a major concern. Herein, the fabrication of physiologically stable polyprodrug-gated crosslinked vesicles (GCVs) via the self-assembly of camptothecin (CPT) polyprodrug amphiphiles and in situ bilayer crosslinking through traceless sol-gel reaction is reported. Polyprodrug-GCVs possess high CPT loading (>30 wt%) and minimized leakage of encapsulated hydrophilic doxorubicin (DOX) hydrochloride due to the suppressed permeability of crosslinked membrane, exhibiting extended blood circulation (t 1/2 > 13 h) with caged cytotoxicity in physiological circulation. Upon cellular uptake by cancer cells, cytosolic reductive milieu-triggered CPT unplugging from vesicle bilayers is demonstrated to generate hydrophilic mesh channels and make the membrane highly permeable. Concurrently, it will promote DOX corelease from hydrophilic lumen (≈36-fold increase). The reduction-activated combination chemotherapeutic potency based on polyprodrug-GCVs is confirmed by both in vitro and in vivo explorations.

Visible light-induced crosslinking and physiological stabilization of diselenide-rich nanoparticles for redox-responsive drug release and combination chemotherapy.

Undesired physiological instability of nanocarriers and premature drug leakage during blood circulation result in compromised therapeutic efficacy and severe side effects, which have significantly impeded the development of nanomedicine. Facile crosslinking of drug-loaded nanocarriers while keeping the potency of site-specific degradation and drug release has emerged as a viable strategy to overcome these drawbacks. Additionally, combination therapy has already shown advantages in inhibiting advanced tumors and life extension than single drug therapy. Herein, three kinds of diselenide-rich polymers were fabricated with distinct hydrophobic side chains. The component effect was interrogated to screen out PEG-b-PBSe diblock copolymer due to its favorable self-assembly controllability and high drug loading of camptothecin (CPT) and doxorubicin (DOX) that had synergistic antitumor property. Facile visible light-induced diselenide metathesis and regeneration was employed to crosslink nanocarriers for the first time. The dual drug-loaded crosslinked micelles (CPT/DOX-CCM) were stable in physiological conditions with minimal drug leakage, possessing extended blood circulation, whereas hand-in-hand dual drug release was significantly accelerated in tumor's redox microenvironments. In vitro cytotoxicity evaluation and in vivo tumor suppression with low dosage drugs further demonstrated the favorable potency of the redox-responsive nanoplatform in tumor combination chemotherapy.

The Essential Role of Drp1 and Its Regulation by S-Nitrosylation of Parkin in Dopaminergic Neurodegeneration: Implications for Parkinson's Disease.

AIMS: Dysfunctional regulation of mitochondrial dynamics, which switches the balance to fission, is involved in neurodegeneration in Parkinson's disease (PD). Dynamin-related protein-1 (Drp1), a key regulator of mitochondrial fission, has been attributed recently to such neurodegeneration in PD. However, the machinery that connects Drp1 to the pathophysiology of PD is unclear. RESULTS: We demonstrated that nitric oxide (NO) was overproduced on 1-methyl-4-phenylpyridinium ion (MPP+) treatment, which subsequently engendered S-nitrosylation of Parkin (SNO-Parkin), and thus decreased the interaction with Drp1, leading to elevated Drp1 expression. Consistent with this, Drp1 was elevated in the ventral midbrain of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated PD mouse models, a region usually affected by PD. Concomitantly, in a mouse model of MPTP-induced PD, both SNO-Parkin and Drp1 levels were increased, whereas no significant difference in SNO-Drp1 protein levels were found in these mice. In addition, NO stress, induced by MPP+, triggered the phosphorylation of Drp1 Ser616 and caused its subsequent recruitment to the mitochondria. These events create a death-prone environment that contributes to the loss of dopaminergic neurons. INNOVATION: We first showed that SNO-Parkin reduced its ability as a suppressor of Drp1 expression, leading to upregulation of Drp1 in neurotoxin-based PD models, in vitro and in vivo. CONCLUSION: Our results provide a molecular explanation for the contribution of Drp1 to the pathogenesis of sporadic PD. These findings indicate that the SNO-Parkin pathway may be a novel therapeutic target to treat PD. Antioxid. Redox Signal. 25, 609-622.

Dihydroartemisinin and transferrin dual-dressed nano-graphene oxide for a pH-triggered chemotherapy.

Dihydroartemisinin (DHA) is a unique anti-malarial drug isolated from the plant Artemisia annua. Recently, it has been studied as an alternative modality for cancer therapy, utilizing its reactive oxygen species (ROS) yielding mechanism from interacting with Ferrous ion (Fe (II)). In this work, a novel nanodrug (DHA-GO-Tf) is constructed based on nanoscale Graphene oxide (GO) dual-dressed with DHA and Transferrin (Tf). Tf dually functions as a pilot for the nanoparticle to target tumor cell with over expressed Transferrin receptor (TfR) and a ferric ion carrier. Upon tumor cellular endocytosis, Ferric ion (Fe(III)) is released from the Tf, triggered by the low pH in the lysosomes of the tumor cell. The intracellular Fe (III) is reduced to Fe (II) and interacts with DHA to increase its cytotoxicity. The potential of this alternative anti-tumor modality is demonstrated both in vitro and in vivo. Comparing with DHA alone, the nanodrug DHA-GO-Tf resulted in a significantly enhanced tumor delivery specificity and cytotoxicity, and achieved a complete tumor cure in mice with minimal side-effects.