Liposome encapsulated polydopamine nanoparticles: Enhancing ferroptosis and activating hypoxia prodrug activity.

The short lifespan of active oxygen species and depressed O2 level during ferroptosis treatment in tumor cells weaken ferroptosis therapy. How to improve the utilization efficiency of active oxygen species generated in real time is pivotal for anticancer treatment. Herein, the tirapazamine (TPZ) loaded polydopamine-Fe nanoparticles (PDA-Fe-TPZ) was modified with unsaturated liposome (Lip), which was constructed to overcome the drawbacks of traditional ferroptosis therapy. The Lip@PDA-Fe-TPZ nanoliposomes can react with H2O2 to produce •OH by Fenton reaction, which then attacks Lip and transforms into radical intermediate (L•) and phospholipid peroxide radical (LOO•) to avoid the annihilation of •OH. The introduced Lip enhances lipid peroxidation and promotes oxygen consumption, resulting in increased hypoxia at tumor site. The introduced TPZ can be triggered by reductase in tumor cells under hypoxia, which can reduce to transient oxidative free radicals by reductase enzymes and destroy the structure of the surrounding biomacromolecules, thus achieving the synergistic treatment of ferroptosis and chemotherapy. In this work, we organically combined enhanced ferrroptosis with hypoxic activated chemotherapy to achieve efficient and specific tumor killing effect, which can sever as a promising treatment of cancer in the future.

Mechanism of Self-Oxidative Copolymerization and its Application with Polydopamine-pyrrole Nano-copolymers.

Currently, the copolymer of dopamine (DA) and pyrrole (PY) via chemical and electrochemical oxidation usually requires additional oxidants, and lacks flexibility in regulating the size and morphology, thereby limiting the broad applications of DA-PY copolymer in biomedicine. Herein, the semiquinone radicals produced by the self-oxidation of DA is ingeniously utilized as the oxidant to initiate the following copolymerization with PY, and a series of quinone-rich polydopamine-pyrrole copolymers (PDAm -nPY) with significantly enhanced absorption in near-infrared (NIR) region without any additional oxidant assistance is obtained. Moreover, the morphology and size of PDAm -nPY can be regulated by changing the concentration of DA and PY, thereby optimizing nanoscale PDA0.05 -0.15PY particles (≈ 150 nm) with excellent NIR absorption and surface modification activity are successfully synthesized. Such PDA0.05 -0.15PY particles show effective photoacoustic (PA) imaging and photothermal therapy (PTT) against 4T1 tumors in vivo. Furthermore, other catechol derivatives can also copolymerize with PY under the same conditions. This work by fully utilizing the semiquinone radical active intermediates produced through the self-oxidation of DA reduces the dependence on external oxidants in the synthesis of composite materials and predigests the preparation procedure, which provides a novel, simple, and green strategy for the synthesis of other newly catechol-based functional copolymers.

Pyrrole-Doped Polydopamine-Pyrrole (PDA-nPY) Nanoparticles with Tunable Size and Improved NIR Absorption for Photothermal Therapy.

Polydopamine (PDA) as a melanin-like biomimetic material with excellent biocompatibility, full spectrum light absorption capacity and antioxidation property has been extensively applied in the biomedical field. Based on the high reactivity of dopamine (DA), exploiting new strategies to fabricate novel PDA-based nano-biomaterials with controllable size and improved performance is valuable and desirable. Herein, we reported a facile way to synthesize pyrrole-doped polydopamine-pyrrole nanoparticles (PDA-nPY NPs) with tunable size and enhanced near-infrared (NIR) absorption capacity through self-oxidative polymerization of DA with PY in an alkaline ethanol/H2O/NH4OH solution. The PDA-nPY NPs maintain excellent biocompatibility and surface reactivity as PDA. By regulating the volume of added PY, PDA-150PY NPs with a smaller size (<100 nm) and four-fold higher absorption intensity at 808 nm than that of PDA can be successfully fabricated. In vitro and in vivo experiments effectively further demonstrate that PDA-150PY NPs can effectively inhibit tumor growth and completely thermally ablate a tumor. It is believed that these PY doped PDA-nPY NPs can be a potential photothermal (PT) agent in biomedical application.

Unsaturated phospholipid modified FeOCl nanosheets for enhancing tumor ferroptosis.

Iron-dependent accumulation of reactive oxygen species (ROS) and lipid peroxidation play key roles in ferroptosis, which has been an attractive strategy to kill tumor cells. However, the rapid annihilation of hydroxyl radicals (˙OH) produced from the Fenton reaction has become a major obstacle in inducing lipid peroxidation in cells. In this study, we develop a nano-delivery system of unsaturated phospholipid (Lip) and polyacrylic acid (PAA) functionalized FeOCl nanosheets (FeOCl@PAA-Lip). In this system, the ˙OH radicals produced from the Fenton reaction between FeOCl nanosheets and endogenous H2O2 of tumor cells attack Lip on the nanosheets in situ to initiate the lipid peroxidation chain reaction, which not only realizes free radical conversion but also leads to the amplification of ROS and lipid peroxides, thus enhancing tumor ferroptosis. The in vitro and in vivo results confirmed that FeOCl@PAA-Lip nanosheets exhibited specific tumor cell-killing effects, good biocompatibility, long circulation time, low side effects, high tumor targeting and an excellent tumor inhibition rate (73%). The Lip functionalization strategy offers a paradigm of enhancing ferroptosis treatment by conversion of ˙OH/phospholipid radicals/lipid peroxyl radicals and strengthening lipid peroxidation.

Ferrocene-liposome-PEG: a robust ˙OH/lipid peroxide nano-converter for inducing tumor ferroptosis.

Ferroptosis induced by iron-dependent accumulation of lipid peroxides (LPOs) has received increasing attention in cancer therapy, especially chemodynamic therapy (CDT). However, the quick annihilation of hydroxyl radicals (˙OH) severely restricts the ˙OH/LPO conversion efficiency, which has become one of the key factors that influences the therapeutic efficacy of ferroptosis-based CDT. Herein, we designed a ˙OH/LPO nano-converter with a high LPO generation efficiency via loading ferrocene (Fc), a green Fenton catalyst, in the phospholipid bilayer of liposome-PEG (Fc-Lp-PEG). Under catalysis with Fc, the over-expressed H2O2 in tumors can be decomposed to ˙OH. The generated ˙OH in situ reacts with unsaturated lipids on the liposome, and is converted into LPOs, which spread the lipid peroxidation chain reaction to the remote membranes of cells and organelles, triggering efficient cancer cell ferroptosis. Systematic in vitro and in vivo therapeutic outcomes showed the high tumor inhibition ratio (74.0%) and the low side effects of Fc-Lp-PEG on 4T1 tumor-bearing mice. This novel strategy for improving the ˙OH/LPO conversion efficiency might provide new insights for the clinical development of ferroptosis-based CDT.

Self-assembling Bioadhesive Inspired by the Fourth Repetitive Sequence of Balanus albicostatus Cement Protein 20 kDa (Balcp-20 k).

Barnacle cement proteins are multi-protein complexes composed of a series of functionally related synergistic proteins that enable barnacles to adhere strongly and consistently to various underwater substrates. There is no post-translational modification of barnacle cement proteins, which provides a possibility for the synthesis of similar adhesive materials. Balcp-20 k has four repetitive sequences with multiple conserved cysteine groups. Whether these repeats are separate functional units and the role of cysteine in adhesion is not clear. In order to investigate the adhesion properties of Balcp-20 k, we amplified and expressed R4 (DHLACNAKHPCWHKHCDCFC)4, which is a quadruple repeat of Balcp-20 k's fourth repetitive sequence, and S0R4 (DHLASNAKHPSWHKHSDSFS)4, all cysteine of R4 replaced by serine. Analysis showed that R4 had a similar structure to Balcp-20 k, and the amyloid fibrils structure formed by self-assembly of R4 played an important role in improving the adhesion strength. The absence of disulfide bonds in S0R4 prevents self-assembly, and the failure of self-assembly after the reduction of disulfide bonds of R4 by DTT indicates that disulfide bonds play an important role in self-assembly. With adhesion and coating analysis, it was found that R4 has good adhesion on different materials surfaces, which is better than Balcp-20 k, while S0R4 has weak adhesion, which is only better than BSA.

Polydopamine-Based Nanocomposite as a Biomimetic Antioxidant with a Variety of Enzymatic Activities for Parkinson's Disease.

Overproduction of reactive oxygen species (ROS) and cumulative oxidative stress induce the degeneration of neuromelanin-containing dopaminergic neurons in the substantia nigra pars compacta (SNpc) of PD patients. Due to its redox property, melanin-like polydopamine (PDA) has been studied for its ability to remove ROS with a series of antioxidant enzyme mimetic activities including superoxide dismutase (SOD) and catalase (CAT). Glutathione peroxidase (GPx) is important for maintaining ROS metabolic homeostasis, but only a few GPx-like nanozymes have been studied for in vivo therapy. As we know, selenocysteine is essential for the antioxidant activity of GPx. Hence, we co-synthesized PDA with selenocystine (SeCys) to prepare a nanocomposite (PDASeCys) with GPx-like activity. The results showed that the PDASeCys nanocomposite has the same CAT and SOD enzymatic activities as PDA but better free radical scavenging efficiency and additional GPx enzymatic activity than PDA. In the 1-methyl-4-phenyl-pyridine ion (MPP+)-induced PD cell model, PDASeCys could increase intracellular GPx levels effectively and protect SH-SY5Y neuronal cells from oxidative stress caused by MPP+. In vivo, the PDASeCys nanocomposite effectively inhibited 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridinium (MPTP)-induced Parkinson-related symptoms of mice when it was injected into the substantia nigra (SN). This polydopamine-based nanocomposite containing selenocystine with a variety of enzymatic activities including GPx-like activity synthesized by a one-pot method provides convenience and safety in the neuromelanin-like nanozyme-based therapeutic strategy for oxidative stress-induced PD.

Aß-responsive metformin-based supramolecular synergistic nanodrugs for Alzheimer's disease via enhancing microglial Aß clearance.

Here, inspired by the concept of supramolecular inclusion complex, we successfully fabricate metformin (Met)-based supramolecular nanodrugs with the Aß-responsive on-demand drug release for synergistic Alzheimer's disease (AD) therapy via enhancing microglial Aß clearance. Interestingly, the introduction of low-dosage Met (1.1 mg/kg) can not only significantly improve the structural stability of nanodrugs but also exert a synergistic anti-dementia effect with donepezil (Don). Besides, such nanodrugs with outstanding physiological stability can selectively penetrate the blood-brain barrier (BBB), target brain, increase efficient uptake of microglia and neurons, and then achieve simultaneous spatiotemporal on-demand drug release under stimuli of the overexpressed amyloid-beta (Aß). Furthermore, Met and Don released from nanodrugs exhibit a superior synergistic anti-dementia effect by enhancing microglial phagocytosis and Aß clearance through the lysosomal pathway. Taken together, we report a synergistic strategy based on Aß-responsive supramolecular nanodrugs for AD therapy, which can be expected to provide a novel clinical therapeutic idea for ameliorating central nervous system disease.

Trojan-Horse Diameter-Reducible Nanotheranostics for Macroscopic/Microscopic Imaging-Monitored Chemo-Antiangiogenic Therapy.

Although nanotheranostics have displayed striking potential toward precise nanomedicine, their targeting delivery and tumor penetration capacities are still impeded by several biological barriers. Besides, the current antitumor strategies mainly focus on killing tumor cells rather than antiangiogenesis. Enlightened by the fact that the smart transformable self-targeting nanotheranostics can enhance their targeting efficiency, tumor penetration, and cellular uptake, we herein report carrier-free Trojan-horse diameter-reducible metal-organic nanotheranostics by the coordination-driven supramolecular sequential co-assembly of the chemo-drug pemetrexed (PEM), transition-metal ions (FeIII), and antiangiogenesis pseudolaric acid B. Such nanotheranostics with both a high dual-drug payload efficiency and outstanding physiological stability are responsively decomposed into numerous ultra-small-diameter nanotheranostics under stimuli of the moderate acidic tumor microenvironment and then internalized into tumor cells through tumor-receptor-mediated self-targeting, synergistically enhancing tumor penetration and cellular uptake. Besides, such nanotheranostics enable visualization of self-targeting capacity under the macroscopic monitor of computed tomography/magnetic resonance imaging, thereby realizing efficient oncotherapy. Moreover, tumor microvessels are precisely monitored by optical coherence tomography angiography/laser speckle imaging during chemo-antiangiogenic therapy in vivo, visually verifying that such nanotheranostics possess an excellent antiangiogenic effect. Our work will provide a promising strategy for further tumor diagnosis and targeted therapy.

Metabolizable pH/H2O2 dual-responsive conductive polymer nanoparticles for safe and precise chemo-photothermal therapy.

Conductive polymers with high near-infrared absorbance, have attracted considerable attention in the design of intelligent nanomedicines for cancer therapy, especially chemo-photothermal therapy. However, the unknown long-term biosafety of conductive polymers in vivo due to non-degradability hinders their clinic application. Herein, a H2O2-triggered degradable conductive polymer, polyacrylic acid (PAA) stabilized poly(pyrrole-3-COOH) (PAA@PPyCOOH), is fabricated to form nanoparticles with doxorubicin (DOX) for safe and precise chemo-phototherapy. The PAA@PPyCOOH was found to be an ideal photothermal nano-agent with good dispersity, excellent biocompatibility and high photothermal conversion efficiency (56%). After further loading of doxorubicin (DOX), PAA@PPyCOOH@DOX demonstrates outstanding photothermal performance, as well as pH/H2O2 dual-responsive release of DOX in tumors with an acidic and overexpressed H2O2 microenvironment, resulting in superior chemo-photothermal therapeutic effects. The degradation mechanism of PAA@PPyCOOH is proposed to be the ring-opening reaction between the pyrrole-3-COOH unit and H2O2. More importantly, the nanoparticles can be specifically degraded by excess H2O2 in tumor, and the degradation products were confirmed to be excreted via urine and feces. In vivo therapeutic evaluation of chemo-photothermal therapy reveals tumor growth of 4T1 breast cancer model is drastically inhibited and no apparent side-effect is detected, thus indicating substantial potential in clinic application.

The role and mechanism of polydopamine and cuttlefish ink melanin carrying copper ion nanoparticles in antibacterial properties and promoting wound healing.

Melanin and its analogue polydopamine (PDA) have attracted considerable attention in biomedical science due to their surface-rich metal binding sites, excellent adhesion and good biocompatibility. Bacterial infections at the wound site and uncontrolled bleeding are associated with a high risk of death, and the prevention of wound infections remains a major challenge. On this basis, the four nanoparticles (NPs) of melanin, PDA, copper ion-loaded melanin (Cu(ii) loaded melanin) and copper ion-loaded PDA (Cu(ii) loaded PDA) were studied in terms of antibacterial and wound healing capabilities. The in vitro experiments showed that Cu(ii) loaded PDA NPs had good blood compatibility and low cytotoxicity, showing the best antibacterial effect in comparison with other samples. Not only could the slow release of copper ions from the nanoparticles kill bacteria, but also the phenolic hydroxyl group and amine groups of PDA NPs played a synergistic role in bacterial death. In wound healing experiments, the Cu(ii) loaded PDA NPs could easily and tightly bind with biological tissue, demonstrating excellent hemostasis, antibacterial and wound healing capabilities. In summary, the excellent properties of Cu(ii) loaded PDA NPs made them a safe and effective drug for preventing wound infection and promoting healing.

Self-targeting nanotherapy based on functionalized graphene oxide for synergistic thermochemotherapy.

Nanotherapy based on thermochemotherapy has boomed as a promising alternative for oncotherapy due to the enhanced permeability and retention (EPR) effect. However, a lack of self-targeting capacity prevents nanotherapy from efficiently accumulating in tumor tissue and internalizing into tumor cells, resulting in a suboptimal therapeutic effect. To overcome these bottlenecks, a kind of methotrexate (MTX)-soybean phospholipid (SPC) inclusion complex (MTX-SPC)-modified graphene oxide (CGO) nanotherapy (CGO-MTX-SPC) is constructed by CGO nanosheets as a supporter for MTX-SPC, thereby realizing active-targeting and synergistic thermochemotherapy. As an FDA-approved chemotherapeutic drug, MTX can be regarded as a tumor-targeting enhancer against the folate receptor on account of its similar structure to folic acid (FA). The fabricated CGO-MTX-SPC has a sheet shape with a size of ca. 109 nm and tumor microenvironment-responsive on-demand drug release. It is worth noting that the physiological stability of CGO-MTX-SPC is better than that of CGO while displaying an improved photothermal effect. In addition, CGO-MTX-SPC can specifically recognize tumor cells and then achieve on-demand drug burst release by dual stimuli of internal lysosomal acidity and an external laser. Moreover, in vivo experimental results further demonstrate that CGO-MTX-SPC displays significant enrichment at the tumor location by active targeting mechanisms due to the introduction of MTX-SPC, endowing the synergistic thermochemotherapy effect upon 808 nm laser irradiation and almost thorough tumor elimination while significantly erasing undesirable side effects. Taken together, the design idea of our nanotherapy not only provides a potential tumor-targeting therapeutic strategy but also broadens the drug payload method of two-dimensional nanomaterials.

A novel self-targeting theranostic nanoplatform for photoacoustic imaging-monitored and enhanced chemo-sonodynamic therapy.

Sonodynamic therapy has attracted wide attention as a noninvasive therapy due to deep tissue penetration. However, majority sonosensitizers often suffer from poor physiological stability, rapid blood clearance and nonspecific targeting, which seriously hinders their further practical applications. Inspired by the concept of active targeting drug delivery, both dual-functional chemo-drug pemetrexed (PEM, emerges an innate affinity toward the folate receptor) and amphiphilic d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) were selected to be covalently linked by an esterase-responsive ester linkage. The synthesized self-targeting TPGS-PEM prodrug and indocyanine green (ICG) as functional motifs can be self-assembled into a TPGS-PEM-ICG nanoplatform within an aqueous medium. The TPGS-PEM-ICG nanoplatform with outstanding structural and physiological stability not only protects the sonosensitizer from reticular endothelial system clearance but also achieves active targeting drug delivery and efficient tumor enrichment. Moreover, TPGS-PEM-ICG nanoplatform can selectively recognize tumor cells and then realize on-demand drug burst release by multiple stimuli of internal lysosomal acidity, esterase and external ultrasound, which guarantee low side effects toward normal tissues and organs. It is also worth noting that our nanoplatform exhibits protruding tumor enrichment under the precise guidance of photoacoustic/fluorescence imaging. Further in vitro and in vivo experimental results well confirmed that the TPGS-PEM-ICG nanoplatform possesses enhanced chemo-sonodynamic effects. Interestingly, the highly toxic reactive oxygen species can remarkably reduce the blood oxygen saturation signal of the tumor microenvironment via precise, multifunctional and high-resolution photoacoustic imaging. Taken together, the TPGS-PEM-ICG nanoplatform can be expected to hold enormous potential for diagnosis, prognosis and targeted therapy for tumor.

Continuous and Patterned Conducting Polymer Coatings on Diverse Substrates: Rapid Fabrication by Oxidant-Intermediated Surface Polymerization and Application in Flexible Devices.

Conducting polymer coatings and patterns are the most important forms of these materials for many practical applications, but a simple and efficient approach to these forms remains challenging. Herein, we report a universal oxidant-intermediated surface polymerization (OISP) for the fabrication of conducting polymer coatings and patterns on various substrates. A coating or pattern composed of densely packed colloidal V2O5·nH2O nanowires is deposited on the substrate via spin coating, dip coating, or printing, which is converted into a conducting polymer one after in situ oxidation polymerization. The polymerization occurs selectively on the V2O5·nH2O coatings, and high-quality polypyrrole, polyaniline, and poly(3,4-ethylenedioxythiophene) coatings and patterns on planar and curved polymeric, metallic, and ceramic substrates are obtained in a fast reaction rate similar to the electrochemical polymerization. The mechanistic study reveals that the method relies on the excellent processability and formability of V2O5·nH2O nanowires, which is further explained by their large aspect ratio and surface activity. A flexible gas sensor array comprising three individual sensors made of different conducting polymers is fabricated using oxidant-intermediated surface polymerization, and it is successfully used to distinguish various analyte vapors. The method developed here will provide a powerful tool for the fabrication of conducting polymer-based devices.

Tumor-Specific Endogenous FeII-Activated, MRI-Guided Self-Targeting Gadolinium-Coordinated Theranostic Nanoplatforms for Amplification of ROS and Enhanced Chemodynamic Chemotherapy.

Low drug payload and lack of tumor-targeting for chemodynamic therapy (CDT) result in an insufficient reactive oxygen species (ROS) generation, which seriously hinders its further clinical application. Therefore, how to improve the drug payload and tumor targeting for amplification of ROS and combine it with chemotherapy has been a huge challenge in CDT. Herein, methotrexate (MTX), gadolinium (Gd), and artesunate (ASA) were used as theranostic building blocks to be coordinately assembled into tumor-specific endogenous FeII-activated and magnetic resonance imaging (MRI)-guided self-targeting carrier-free nanoplatforms (NPs) for amplification of ROS and enhanced chemodynamic chemotherapy. The obtained ASA-MTX-GdIII NPs exhibited extremely high drug payload (∼96 wt %), excellent physiological stability, long circulating ability (half-time: ∼12 h), and outstanding tumor accumulation. Moreover, ASA-MTX-GdIII NPs could be specifically uptaken by tumor cells via folate (FA) receptors and subsequently be disassembled via lysosomal acidity-induced coordination breakage, resulting in drug burst release. Most strikingly, the produced ASA could be catalyzed by tumor-specific overexpressed endogenous FeII ions to generate sufficient ROS for enhancing the main chemodynamic efficacy, which could exert a synergistic effect with the assistant chemotherapy of MTX. Interestingly, ASA-MTX-GdIII NPs caused a lower ROS generation and toxicity on normal cell lines that seldom expressed endogenous FeII ions. Under MRI guidance with assistance of self-targeting, significantly superior synergistic tumor therapy was performed on FA receptor-overexpressed tumor-bearing mice with a higher ROS generation and an almost complete elimination of tumor. This work highlights ASA-MTX-GdIII NPs as an efficient chemodynamic-chemotherapeutic agent for MRI imaging and tumor theranostics.

Polynorepinephrine Nanoparticles: A Novel Photothermal Nanoagent for Chemo-Photothermal Cancer Therapy.

Novel photothermal nanoagents (PTNAs) with excellent photothermal performance, smart-responsive property, and biocompatibility are in urgent need for precise chemo-photothermal cancer therapy. Herein, polynorepinephrine nanoparticles (PNE NPs) with a high photothermal conversion efficiency (η) of 808 nm laser (67%), pH/thermal responsibility, and little to no long-term toxicity were synthesized from an endogenic neurotransmitter norepinephrine. Compared to their analogues, polydopamine NPs, a widely used PTNA, PNE NPs exhibited a higher η value (enhanced 1.63-fold) and better cellular uptake efficiency (enhanced 2.57-fold). After modifying with polyethylene glycol (PEG) and loading with doxorubicin (DOX), PNE-PEG@DOX could realize responsive release of DOX under either a cytolysosome pH microenvironment (pH 5.0) or an 808 nm laser irradiation, resulting in an enhanced chemotherapeutic efficacy of DOX. Besides, in vivo combination therapy leads to nearly complete ablation of tumor tissues, while no significant side effects were found in normal tissues. Hence, this intelligent and biocompatible nanoplatform based on PNE NPs holds great potential in promoting the clinic transformation of precise chemo-photothermal cancer therapy.

A glucose biosensor based on the immobilization of glucose oxidase and Au nanocomposites with polynorepinephrine.

A glucose biosensor based on Au nanoparticles (AuNPs), glucose oxidase (GOD) and polynorepinephrine (PNE) was fabricated by a simple and green approach. PNE-functionalized AuNPs (AuNPs@PNE) were synthetized by the polymerization of norepinephrine (NE) onto the surfaces of AuNPs and casted on an Au electrode. After dropping a solution containing NE and GOD on the AuNPs@PNE-modified Au electrode and oxidizing the monomer NE by cyclic voltammetry, a PNE, GOD and AuNP-modified Au electrode (PNE/GOD/AuNPs@PNE/Au) was obtained. The biosensor presented high sensitivity of 35.4 µA mM-1 cm-2 to glucose in the range from 0.003 mM to 3.43 mM with a response time of less than 3 s, a detection limit of 1.34 µM at a signal/noise ratio of 3, a low Michaelis-Menten constant (6.8 mM) and outstanding selectivity as well as stability. Moreover, the sensitivity and linear detection range of the as-prepared biosensor were further enhanced by the addition of the redox mediator p-benzoquinone.

Poly(norepinephrine)-coated FeOOH nanoparticles as carriers of artemisinin for cancer photothermal-chemical combination therapy.

The photothermal-chemical combination therapy is a promising approach for cancer treatment, however, chemotherapy often causes severe toxic and side effects on normal tissues. Herein, tumor-specific FeOOH@PNE-Art nanoparticles were fabricated via coating poly(norepinephrine) (PNE) on FeOOH nanoparticles, followed by loading of artemisinin (Art). The as-prepared nanoparticles exhibited excellent biocompatibility, strong near-infrared (NIR) absorbance and pH-responsive synchronous release of Art and iron ions. The released iron ions could not only supply iron ions in cancer cells which mediate endoperoxide bridge cleavage of Art and generate reactive oxygen species (ROS), but also react with H2O2 at tumour sites via the Fenton reaction and produce hydroxyl radicals, inducing a tumour-specific killing. Moreover, owing to the synchronous release of Art and iron ions as well as the low leakage of iron ions, FeOOH@PNE-Art nanoparticles showed extremely low toxicity to normal tissue. Under NIR light irradiation, the tumours in FeOOH@PNE-Art injected mice were thoroughly eliminated after 7 days of treatment and no tumour recurrence was found 30 days after treatment, manifesting very high efficacy of combination therapy.

Fe3O4-Based Multifunctional Nanospheres for Amplified Magnetic Targeting Photothermal Therapy and Fenton Reaction.

Multifunctional nanoplatforms have attracted the interests of many scientists because they can achieve better therapeutic effect in the combined treatment of cancer. A novel cancer therapeutic strategy which combines an Fe3O4-based in vivo Fenton reaction with polypyrrole (PPy)-based photothermal therapy (PTT) was proposed. The multifunctional nanocomposite was comprised of Fe3O4 as the core, PPy as the shell, and polyethylene glycol. PPy could absorb near-infrared (NIR) light strongly and convert it into heat for tumor photothermal ablation, and Fe3O4 NPs were used as a target component to guide the nanoparticles to the tumor site under an external magnetic field. It was found that the PPy coating could be used not only for inducing PTT to ablate tumor cells but also for promoting Fe2+/3+ release from Fe3O4 nanoparticles. In vitro cell experiments confirmed that the increased Fe2+/3+ release could effectively enhance the Fe3O4-based Fenton reaction, which catalyzed the conversion of H2O2 into a highly toxic hydroxyl radical (•OH), thus inducing tumor cell apoptosis. Furthermore, our experiments also showed that the PPy coating could generate a photothermal effect to kill 4T1 tumor cells under NIR light exposure but did no harm to normal cells in the dark. Under the guidance of the magnet, we found Fe3O4@PPy-PEG (Fe3O4@P-P) nanoparticles could effectively enrich in the tumor site, and the therapeutic effect from PTT and the photothermal strengthened Fenton reaction was also verified in vivo. It is confirmed for the first time that the photothermal effect could promote the release of iron ions from Fe3O4 under acid conditions and enhance the Fenton reaction. Therefore, the Fe3O4@P-P nanoparticles, combined with the Fenton reaction and photothermal effect, and obviously the magnetic targeting and magnetic resonance imaging ability, are able to be a candidate for novel tumor theranostic agents.

Fe2+/Fe3+ Ions Chelated with Ultrasmall Polydopamine Nanoparticles Induce Ferroptosis for Cancer Therapy.

Ferroptosis, a promising mechanism of killing cancer cells, has become a research hotspot in cancer therapy. Besides, advantages of polymeric nanomaterials in improving anticancer efficacy and reducing side effect are widely accepted. In this work, based on the property of polypodamine to chelate metal ions, ultrasmall poly(ethylene glycol)-modified polydopamine nanoparticles, (UPDA-PEG)@Fe2+/3+ nanoparticles, a novel ferroptosis agent, was rationally designed by chelating iron ions on ultrasmall polydopamine nanoparticles modified by PEG. This treatment led to a bigger specific surface area, which could support more reactive sites to chelate large number of iron ions, which is beneficial for exploring the detailed mechanism of ferroptosis-induced tumor cell death by iron ions. Also, the pH-dependent release of iron ions can reach approximately 70% at pH 5.0, providing the advantage of application in tumor microenvironment. The in vitro tests showed that the as-prepared NPs exhibit an effective anticancer effect on tumor cells including 4T1 and U87MG cells, yet ferric ions show a stronger ability of killing cancer cells than ferrous ions. Differences between ferrous ions and ferric ions in the ferroptosis pathway were monitored by the change of marker, including reactive oxygen species (ROS), glutathione peroxidase 4, and lipid peroxide (LPO), as well as the promoter and inhibitor of ferroptosis pathway. UPDA-PEG@Fe2+ nanoparticles induce ferroptosis that depends more on ROS; however, a more LPO-dependent ferroptosis is induced by UPDA-PEG@Fe3+ nanoparticles. Additionally, the in vivo studies using tumor-bearing Balb/c mice demonstrated that the as-prepared NPs could significantly inhibit tumor progression. UPDA-PEG@Fe2+/3+ nanoparticles reported herein represent the nanoparticles related to iron ions for chemotherapy against cancer through the ferroptosis pathway.