Tea polyphenol-derived nanomedicine for targeted photothermal thrombolysis and inflammation suppression.

Thrombotic diseases impose a significant global health burden, and conventional drug-based thrombolytic therapies are encumbered by the risk of bleeding complications. In this study, we introduce a novel drug-free nanomedicine founded on tea polyphenols nanoparticles (TPNs), which exhibits multifaceted capabilities for localized photothermal thrombolysis. TPNs were synthesized through a one-pot process under mild conditions, deriving from the monomeric epigallocatechin-3-gallate (EGCG). Within this process, indocyanine green (ICG) was effectively encapsulated, exploiting multiple intermolecular interactions between EGCG and ICG. While both TPNs and ICG inherently possessed photothermal potential, their synergy significantly enhanced photothermal conversion and stability. Furthermore, the nanomedicine was functionalized with cRGD for targeted delivery to activated platelets within thrombus sites, eliciting robust thrombolysis upon laser irradiation across diverse thrombus types. Importantly, the nanomedicine's potent free radical scavenging abilities concurrently mitigated vascular inflammation, thus diminishing the risk of disease recurrence. In summary, this highly biocompatible multifunctional nanomaterial holds promise as a comprehensive approach that combines thrombolysis with anti-inflammatory actions, offering precision in thrombosis treatment.

Amino acid-based metallo-supramolecular nanoassemblies capable of regulating cellular redox homeostasis for tumoricidal chemo-/photo-/catalytic combination therapy.

Nanozymes, as nanomaterials with natural enzyme activities, have been widely applied to deliver various therapeutic agents to synergistically combat the progression of malignant tumors. However, currently common inorganic nanozyme-based drug delivery systems still face challenges such as suboptimal biosafety, inadequate stability, and inferior tumor selectivity. Herein, a super-stable amino acid-based metallo-supramolecular nanoassembly (FPIC NPs) with peroxidase (POD)- and glutathione oxidase (GSHOx)-like activities was fabricated via Pt4+-driven coordination co-assembly of l-cysteine derivatives, the chemotherapeutic drug curcumin (Cur), and the photosensitizer indocyanine green (ICG). The superior POD- and GSHOx-like activities could not only catalyze the decomposition of endogenous hydrogen peroxide into massive hydroxyl radicals, but also deplete the overproduced glutathione (GSH) in cancer cells to weaken intracellular antioxidant defenses. Meanwhile, FPIC NPs would undergo degradation in response to GSH to specifically release Cur, causing efficient mitochondrial damage. In addition, FPIC NPs intrinsically enable fluorescence/photoacoustic imaging to visualize tumor accumulation of encapsulated ICG in real time, thereby determining an appropriate treatment time point for tumoricidal photothermal (PTT)/photodynamic therapy (PDT). In vitro and in vivo findings demonstrated the quadruple orchestration of catalytic therapy, chemotherapeutics, PTT, and PDT offers conspicuous antineoplastic effects with minimal side reactions. This work may provide novel ideas for designing supramolecular nanoassemblies with multiple enzymatic activities and therapeutic functions, allowing for wider applications of nanozymes and nanoassemblies in biomedicine.

Injectable Alginate Complex Hydrogel Loaded with Dual-Drug Nanovectors Offers Effective Photochemotherapy against Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC), accounting for approximately 20% of breast cancer cases, is a particular subtype that lacks tumor-specific targets and is difficult to treat due to its high aggressiveness and poor prognosis. Chemotherapy remains the major systemic treatment for TNBC. However, its applicability and efficacy in the clinic are usually concerning due to a lack of targeting, adverse side effects, and occurrence of multidrug resistance, suggesting that the development of effective therapeutics is still highly demanded nowadays. In this study, an injectable alginate complex hydrogel loaded with indocyanine green (ICG)-entrapped perfluorocarbon nanoemulsions (IPNEs) and camptothecin (CPT)-doped chitosan nanoparticles (CCNPs), named IPECCNAHG, was developed for photochemotherapy against TNBC. IPNEs with perfluorocarbon can induce hyperthermia and generate more singlet oxygen than an equal dose of free ICG upon near-infrared (NIR) irradiation to achieve photothermal and photodynamic therapy. CCNPs with positive charge may facilitate cellular internalization and provide sustained release of CPT to carry out chemotherapy. Both nanovectors can stabilize agents in the same hydrogel system without interactions. IPECCNAHG integrating IPNEs and CCNPs enables stage-wise combinational therapeutics that may overcome the issues described above. With 60 s of NIR irradiation, IPECCNAHG significantly inhibited the growth of MDA-MB-231 tumors in the mice without systemic toxicity within the 21 day treatment. We speculate that such anticancer efficacy was accomplished by phototherapy followed by chemotherapy, where cancer cells were first destroyed by IPNE-derived hyperthermia and singlet oxygen, followed by sustained damage with CPT after internalization of CCNPs; a two-stage tumoricidal process. Taken together, the developed IPECCNAHG is anticipated to be a feasible tool for TNBC treatment in the clinic.

Morusin-Cu(II)-indocyanine green nanoassembly ignites mitochondrial dysfunction for chemo-photothermal tumor therapy.

Nanoscale drug delivery systems derived from natural bioactive materials accelerate the innovation and evolution of cancer treatment modalities. Morusin (Mor) is a prenylated flavonoid compound with high cancer chemoprevention activity, however, the poor water solubility, low active pharmaceutical ingredient (API) loading content, and instability compromise its bioavailability and therapeutic effectiveness. Herein, a full-API carrier-free nanoparticle is developed based on the self-assembly of indocyanine green (ICG), copper ions (Cu2+) and Mor, termed as IMCNs, via coordination-driven and π-π stacking for synergistic tumor therapy. The IMCNs exhibits a desirable loading content of Mor (58.7 %) and pH/glutathione (GSH)-responsive motif. Moreover, the photothermal stability and photo-heat conversion efficiency (42.8 %) of IMCNs are improved after coordination with Cu2+ and help to achieve photothermal therapy. Afterward, the released Cu2+ depletes intracellular overexpressed GSH and mediates Fenton-like reactions, and further synergizes with ICG at high temperatures to expand oxidative damage. Furthermore, the released Mor elicits cytoplasmic vacuolation, expedites mitochondrial dysfunction, and exerts chemo-photothermal therapy after being combined with ICG to suppress the migration of residual live tumor cells. In vivo experiments demonstrate that IMCNs under laser irradiation could excellently inhibit tumor growth (89.6 %) through the multi-modal therapeutic performance of self-enhanced chemotherapy/coordinated-drugs/ photothermal therapy (PTT), presenting a great potential for cancer therapy.

NIR-Triggered Thermosensitive Nanoreactors for Dual-Guard Mechanism-Mediated Precise and Controllable Cancer Chemo-Phototherapy.

Thermosensitive nanoparticles can be activated by externally applying heat, either through laser irradiation or magnetic fields, to trigger the release of drug payloads. This controlled release mechanism ensures that drugs are specifically released at the tumor site, maximizing their effectiveness while minimizing systemic toxicity and adverse effects. However, its efficacy is limited by the low concentration of drugs at action sites, which is caused by no specific target to tumor sties. Herein, hyaluronic acid (HA), a gooey, slippery substance with CD44-targeting ability, was conjugated with a thermosensitive polymer poly(acrylamide-co-acrylonitrile) to produce tumor-targeting and thermosensitive polymeric nanocarrier (HA-P) with an upper critical solution temperature (UCST) at 45 °C, which further coloaded chemo-drug doxorubicin (DOX) and photosensitizer Indocyanine green (ICG) to prepare thermosensitive nanoreactors HA-P/DOX&ICG. With photosensitizer ICG acting as the "temperature control element", HA-P/DOX&ICG nanoparticles can respond to temperature changes when receiving near-infrared irradiation and realize subsequent structure depolymerization for burst drug release when the ambient temperature was above 45 °C, achieving programmable and on-demand drug release for effective antitumor therapy. Tumor inhibition rate increased from 61.8 to 95.9% after laser irradiation. Furthermore, the prepared HA-P/DOX&ICG nanoparticles possess imaging properties, with ICG acting as a probe, enabling real-time monitoring of drug distribution and therapeutic response, facilitating precise treatment evaluation. These results provide enlightenment for the design of active tumor targeting and NIR-triggered programmable and on-demand drug release of thermosensitive nanoreactors for tumor therapy.

Influence of photoactivation on tissue response to different dyes used in photodynamic therapy and laser ablation therapy.

Laser ablation therapy (LA) uses Indocyanine Green dye (ICG) which efficiently absorbs laser energy and the increased temperature results in an instantaneous flame that chars tissue and microbes. Photodynamic therapy (PDT) uses different dyes that are activated by light to kill bacteria. This study evaluated the biocompatibility of the dye Curcumin (CUR), Methylene Blue (MB), and Indocyanine Green (ICG) before and after laser activation (ACT). Polyethylene tubes containing one of the dyes were implanted in the subcutaneous tissue of 32 rats (4 tubes per rat) which were divided into 8 groups: C - control (saline solution); C + ACT (Red Laser 660 nm); CUR; CUR + ACT (480 nm blue LED); MB; MB + ACT (Red Laser 660 nm); ICG; ICG + ACT (810 nm Infrared Laser). After 7 and 30 days (n = 8/time), the rats were euthanized and the tubes with the surrounding tissue were removed and processed for histological analysis of inflammation using H&E stain, and collagen fiber maturation using picrosirius red (PSR). A two-way analysis of variance statistical test was applied (p < 0.05). At 7 days, regardless of laser activation, the CUR group showed a greater inflammatory infiltrate compared to the ICG and control groups, and the MB group had a greater inflammation only in relation to the control (p < 0.05). At 30 days, CUR and MB groups showed a greater inflammatory infiltrate than the control (p < 0.05). ICG group was equal to the control in both periods, regardless of the laser activation (p > 0.05). Laser activation induced the proliferation of collagen immature fibers at 7 days, regardless of the dye (p < 0.05). The CUR group showed a lower percentage of immature and mature fibers at 7 days, compared to ICG and control (p < 0.05) and, at 30 days, compared to control (p < 0.05). Regardless of laser activation, the ICG showed the results of collagen maturation closest to the control (p > 0.05). It was concluded that all dyes are biocompatible and that laser activation did not interfere with biocompatibility. In addition, the maturity of collagen was adequate before and after the laser activation. These results demonstrate that the clinical use of dyes is safe even when activated with a laser.

Calcium-enriched carbon nanoparticles loaded with indocyanine green for near-infrared fluorescence imaging-guided synergistic calcium overload, photothermal therapy, and glutathione-depletion-enhanced photodynamic therapy.

Combining phototherapy with other treatments has significantly advanced cancer therapy. Here, we designed and fabricated calcium-enriched carbon nanoparticles (Ca-CNPs) that could effectively deplete glutathione (GSH) and release calcium ions in tumors, thereby enhancing the efficacy of photodynamic therapy (PDT) and the calcium overload effect that leads to mitochondrial dysfunction. Due to the electrostatic interaction, π-π stacking interaction, multiple hydrogen bonds, and microporous structures, indocyanine green (ICG) was loaded onto the surface of Ca-CNPs with a high loading efficiency of 44.7 wt%. The obtained Ca-CNPs@ICG can effectively improve the photostability of ICG while retaining its ability to generate singlet oxygen (1O2) and undergo photothermal conversion (Ca-CNPs@ICG vs. ICG, 45.1% vs. 39.5%). In vitro and in vivo experiments demonstrated that Ca-CNPs@ICG could be used for near-infrared fluorescence imaging-guided synergistic calcium overload, photothermal therapy, and GSH depletion-enhanced PDT. This study sheds light on the improvement of 1O2 utilization efficiency and calcium overload-induced mitochondrial membrane potential imbalance in tumor cells.

Multilayer nanodrug delivery system with spatiotemporal drug release improves tumor microenvironment for synergistic anticancer therapy.

The inflammatory response is one of the general symptoms that accompany tumorigenesis, the pro-inflammatory factors cyclooxygenase-2 (COX-2) and COX-2-derived prostaglandin-2 (PGE-2) in the inflammatory environment surrounding tumors possess promoting tumor development, metastasis and angiogenesis effects. In addition, the hypoxic environment of tumors severely limits the effectiveness of photodynamic therapy (PDT). In this study, a universal extracellular-intracellular 'on-demand' release nanomedicine DOX@PDA-ICG@MnO2@GN-CEL was developed for the combined fight against malignant tumors using a spatiotemporal controlled gelatin coated polydopamine (PDA@GN) as the carrier and loaded with the chemotherapeutic drug doxorubicin (DOX), the photosensitizer indocyanine green (ICG), the PDT enhancer MnO2and the anti-inflammatory drug celecoxib (CEL) individually. Our results showed that DOX@PDA-ICG@MnO2@GN-CEL could release CEL extracellularly by matrix metalloproteinase-2 response and inhibit the COX-2/PGE-2 pathway, reduce chemotherapy resistance and attenuate the concurrent inflammation. After entering the tumor cells, the remaining DOX@PDA-ICG@MnO2released DOX, ICG and MnO2intracellularly through PDA acid response. MnO2promoted the degradation of endogenous H2O2to generate oxygen under acidic conditions to alleviate the tumor hypoxic environment, enhance PDT triggered by ICG. PDA and ICG exhibited photothermal therapy synergistically, and DOX exerted chemotherapy with reduced chemotherapy resistance. The dual responsive drug release switch enabled the chemotherapeutic, photothermal, photodynamic and anti-inflammatory drugs precisely acted on different sites of tumor tissues and realized a promising multimodal combination therapy.

Cell Membrane Coated pH-Responsive Intelligent Bionic Delivery Nanoplatform for Active Targeting in Photothermal Therapy.

Aim: To produce pH-responsive bionic high photothermal conversion nanoparticles actively targeting tumors for sensitizing photothermal therapy (PTT). Materials and Methods: The bionic nanoparticles (ICG-PEI@HM NPs) were prepared by electrostatic adsorption of indocyanine green (ICG) coupled to polyethyleneimine (PEI) and modified with tumor cell membranes. In vitro and in vivo experiments were conducted to investigate the efficacy of ICG-PEI@HM-mediated PTT. Results: The intelligent responsiveness of ICG-PEI@HM to pH promoted the accumulation of ICG and enhanced the PTT performance of ICG-PEI@HM NPs. Compared with free ICG, NPs exhibited great photothermal stability, cellular uptake, and active tumor targeting for PTT. Conclusion: ICG-PEI@HM NPs can enhance the efficacy of PTT and can be used as a new strategy for the construction of photothermal agents.

GSH/pH dual response drug delivery system for photothermal enhanced gene-immunotherapy.

Breast cancer has emerged as a leading cause of mortality among women. Photothermal therapy represents a recent therapeutic modality for eradicating localized tumors, albeit hindered by its limited penetration into tumor tissues. Recognizing the potential of photothermal therapy to induce immunogenic cell death in tumor cells, we explored a gene delivery approach utilizing small interfering RNA targeting programmed death ligand 1 (PD-L1), abbreviated as siPD-L1, to bolster the anti-tumor immune response elicited by this therapy. Nonetheless, the suboptimal release efficiency and inherent instability of RNA molecules have posed challenges to their therapeutic efficacy. In this study, we designed a glutathione (GSH)/pH-responsive micelle system, employing biocompatible and low-toxicity polyethyleneimine in conjunction with structurally robust pluronic P123, to encapsulate both indocyanine green (ICG) and siPD-L1 for precise targeting in breast cancer treatment. The resulting PSP/ICG/siPD-L1 nanocarrier demonstrated admirable biocompatibility and stability. Upon internalization into tumor cells, this nanocarrier exhibited rapid release of both ICG and siPD-L1, responding to the acidic tumor microenvironment and GSH conditions. The inclusion of siPD-L1 effectively downregulated the expression of PD-L1 on the tumor cell surface, thereby impeding tumor growth. Additionally, ICG demonstrated a photothermal effect when exposed to near-infrared light. Both in vitro and in vivo investigations substantiated the nanocarrier's efficacy against tumor cells, culminating in the complete ablation of 4T1 tumors in situ. Consequently, PSP/ICG/siPD-L1 emerges as a promising nanocarrier candidate for augmenting anti-tumor immunity through the synergistic combination of photothermal therapy and gene-based intervention.

Mn2+ /Ir3+ -Doped and CaCO3 -Covered Prussian Blue Nanoparticles with Indocyanine Green Encapsulation for Tumor Microenvironment Modulation and Image-Guided Synergistic Cancer Therapy.

The development of smart theranostic nanoplatforms has gained great interest in effective cancer treatment against the complex tumor microenvironment (TME), including weak acidity, hypoxia, and glutathione (GSH) overexpression. Herein, a TME-responsive nanoplatform named PMICApt /ICG, based on PB:Mn&Ir@CaCO3 Aptamer /ICG, is designed for the competent synergistic photothermal therapy and photodynamic therapy (PDT) under the guidance of photothermal and magnetic resonance imaging. The nanoplatform's aptamer modification targeting the transferrin receptor and the epithelial cell adhesion molecule on breast cancer cells, and the acid degradable CaCO3 shell allow for effective tumor accumulation and TME-responsive payload release in situ. The nanoplatform also exhibits excellent PDT properties due to its ability to generate O2 and consume antioxidant GSH in tumors. Additionally, the synergistic therapy is achieved by a single wavelength of near-infrared laser. RNA sequencing is performed to identify differentially expressed genes, which show that the expressions of proliferation and migration-associated genes are inhibited, while the apoptosis and immune response gene expressions are upregulated after the synergistic treatments. This multifunctional nanoplatform that responds to the TME to realize the on-demand payload release and enhance PDT induced by TME modulation holds great promise for clinical applications in tumor therapy.

Medical Applications and Advancement of Near Infrared Photosensitive Indocyanine Green Molecules.

Indocyanine green (ICG) is an important kind of near infrared (NIR) photosensitive molecules for PTT/PDT therapy as well as imaging. When exposed to NIR light, ICG can produce reactive oxygen species (ROS), which can kill cancer cells and pathogenic bacteria. Moreover, the absorbed light can also be converted into heat by ICG molecules to eliminate cancer cells. In addition, it performs exceptionally well in optical imaging-guided tumor therapy and antimicrobial therapy due to its deeper tissue penetration and low photobleaching properties in the near-infrared region compared to other dyes. In order to solve the problems of water and optical stability and multi-function problem of ICG molecules, composite nanomaterials based on ICG have been designed and widely used, especially in the fields of tumors and sterilization. So far, ICG molecules and their composite materials have become one of the most famous infrared sensitive materials. However, there have been no corresponding review articles focused on ICG molecules. In this review, the molecular structure and properties of ICG, composite material design, and near-infrared light- triggered anti-tumor, and antibacterial, and clinical applications are reviewed in detail, which of great significance for related research.

Hyperthermia-triggered biomimetic bubble nanomachines.

Nanoparticle-based drug delivery systems have gained much attention in the treatment of various malignant tumors during the past decades. However, limited tumor penetration of nanodrugs remains a significant hurdle for effective tumor therapy due to the existing biological barriers of tumoral microenvironment. Inspired by bubble machines, here we report the successful fabrication of biomimetic nanodevices capable of in-situ secreting cell-membrane-derived nanovesicles with smaller sizes under near infrared (NIR) laser irradiation for synergistic photothermal/photodynamic therapy. Porous Au nanocages (AuNC) are loaded with phase transitable perfluorohexane (PFO) and hemoglobin (Hb), followed by oxygen pre-saturation and indocyanine green (ICG) anchored 4T1 tumor cell membrane camouflage. Upon slight laser treatment, the loaded PFO undergoes phase transition due to surface plasmon resonance effect produced by AuNC framework, thus inducing the budding of outer cell membrane coating into small-scale nanovesicles based on the pore size of AuNC. Therefore, the hyperthermia-triggered generation of nanovesicles with smaller size, sufficient oxygen supply and anchored ICG results in enhanced tumor penetration for further self-sufficient oxygen-augmented photodynamic therapy and photothermal therapy. The as-developed biomimetic bubble nanomachines with temperature responsiveness show great promise as a potential nanoplatform for cancer treatment.

Multifunctional Covalent Organic Framework-Based Microneedle Patch for Melanoma Treatment.

Melanoma is resistant to conventional chemotherapy and radiotherapy. Therefore, it is essential to develop a targeted, low-toxic, and minimally invasive treatment. Here, DTIC/ICG-Fe3O4@TpBD BSP/HA microneedles (MNs) were designed and fabricated, which can enhance targeting to melanoma and perform photothermal therapy (PTT) and chemotherapy simultaneously to synergistically exert anticancer effects. The system consisted of magnetic nanoparticles (DTIC/ICG-Fe3O4@TpBD), dissoluble matrix (Bletilla polysaccharide (BSP)/hyaluronic acid (HA)), and a polyvinyl alcohol backing layer. Due to the good magnetic responsiveness of Fe3O4@TpBD, dacarbazine (DTIC) and indocyanine green (ICG) can be better targeted to the tumor tissue and improve the therapeutic effect. BSP and HA have good biocompatibility and transdermal ability, so that the MNs can completely penetrate the tumor tissue, be dissolved by the interstitial fluid, and release DTIC and ICG. Under near-infrared (NIR) light irradiation, ICG converts light energy into thermal energy and induces ablation of B16-OVA melanoma cells. In vivo results showed that DTIC/ICG-Fe3O4@TpBD BSP/HA MNs combined with chemotherapy and PTT could effectively inhibit the growth of melanoma without tumor recurrence or significant weight loss in mice. Therefore, DTIC/ICG-Fe3O4@TpBD BSP/HA MNs are expected to provide new ideas and therapeutic approaches for the clinical treatment of melanoma.

Dual-targeted delivery of paclitaxel and indocyanine green with aptamer-modified ferritin for synergetic chemo-phototherapy.

The combination of phototherapy and chemotherapy has become attractive and effective cancer treatment. However, the accurate delivery of both chemo-phototherapy drugs to the target site as well as the development of high-efficient phototherapy and chemotherapy drugs remain major challenges. In this study, indocyanine green (ICG) and paclitaxel (PTX)-loaded aptamer ferritin (HAS1411-PTX-ICG) was developed as a biocompatible nanoplatform for combined chemo/photothermal/photodynamic (PTT/PDT) therapy that was safe and highly effective against tumors. HAS1411 was prepared by coupling aptamer AS1411 to the surface of human H chain ferritin (HFtn) by the carbon diimide method to further enhance the targeting of HFtn. Both ICG and PTX were effectively encapsulated in the HAS1411 by incubation at 60 â„ƒ. Moreover, under near-infrared (NIR) light irradiation, HAS1411 enhanced the photothermal effect and cell internalization of ICG, as well as the production of reactive oxygen species in cancer cells. HAS1411-PTX-ICG displayed effective cytotoxicity and a significant tumor spheroids inhibitory effect owning to the improved internalization of PTX and ICG mediated by TfR1 and nucleolin dual receptors. Co-loaded PTX combined with ICG can produce chemo/PTT/PDT under near-infrared (NIR) light irradiation, enhancing the anti-tumor effect. The dual-targeting HAS1411 nanocarrier developed in this study can be a promising delivery system for cancer therapy and the fabricated HAS1411-PTX-ICG possesses potential application in chemo-phototherapy.

A multifunctional 'golden cicada' nanoplatform breaks the thermoresistance barrier to launch cascade augmented synergistic effects of photothermal/gene therapy.

BACKGROUND: Photothermal therapy (PTT) is taken as a promising strategy for cancer therapy, however, its applicability is hampered by cellular thermoresistance of heat shock response and insufficient accumulation of photothermal transduction agents in the tumor region. In consideration of those limitations, a multifunctional "Golden Cicada" nanoplatform (MGCN) with efficient gene delivery ability and excellent photothermal effects is constructed, overcoming the thermoresistance of tumor cells and improving the accumulation of indocyanine green (ICG). RESULTS: Down-regulation of heat shock protein 70 (HSP70) makes tumor cells more susceptible to PTT, and a better therapeutic effect is achieved through such cascade augmented synergistic effects. MGCN has attractive features with prolonged circulation in blood, dual-targeting capability of CD44 and sialic acid (SA) receptors, and agile responsiveness of enzyme achieving size and charge double-variable transformation. It proves that, on the one hand, MGCN performs excellent capability for HSP70-shRNA delivery, resulting in breaking the cellular thermoresistance mechanism, on the other hand, ICG enriches in tumor site specifically and possesses a great thermal property to promoted PTT. CONCLUSIONS: In short, MGCN breaks the protective mechanism of cellular heat stress response by downregulating the expression of HSP70 proteins and significantly augments synergistic effects of photothermal/gene therapy via cascade augmented synergistic effects.

A Dual Heat Shock Protein Down-Regulation Strategy Using PDA/Cu/ICG/R Controlled by NIR "Switch" Enhances Mild-Photothermal Therapy Effect.

The purpose of this study is to down-regulate heat shock proteins and improve the mild photothermal therapy (mild-PTT) effect of polydopamine (PDA) by preparing the nanosystem of Cu2+ and indocyanine green (ICG)-loaded PDA nanospheres with surface modification of integrin-targeted cyclic peptide (cRGD) (PDA/Cu/ICG/R), which can limit ATP synthesis through the double mitochondrial destruction pathway. In vitro and in vivo experiments using PDA/Cu/ICG/R irradiated with an NIR laser demonstrate that when NIR is "OFF," Cu2+ can undergo Fenton-like reaction in tumor cells, producing a large amount of hydroxyl radicals (·OH), which leads to oxidative stress in cells. This oxidative stress can cause mitochondrial oxidative phosphorylation dysfunction, resulting in limited ATP synthesis. When NIR is "ON," mild-PTT can accelerate Cu2+ to produce ·OH. Simultaneously, NIR can activate ICG to produce reactive oxygen species (ROS) storm, amplify intracellular oxidative stress, and continuously damage mitochondria. The biodegradability of PDA greatly reduces the risk of toxicity caused by long-term retention of PDA/Cu/ICG/R in organisms. Finally, the improvement of the mild-PTT effect of PDA is successfully achieved through the double mitochondrial destruction pathway of Cu2+ and ICG controlled by NIR "switch."

Mitochondria Targeted Nanoparticles Potentiate Tumor Chemo-Phototherapy by Toxic Oxidative Stress Mediated Oxeiptosis.

Insufficient accumulation of drug at the tumor site and the low drug response are the main reason for the unsatisfactory effect of cancer therapy. Delivery drugs exquisitely to subcellular level can be employed to reduce side effects, and expand the therapeutic window. Herein, a triphenylphosphine (TPP) modified lipid nanoparticles is designed which are loaded with the photosensitizer indocyanine green (ICG) and chemotherapeutic paclitaxel (PTX) for mitochondria-targeted chemo-phototherapy. Owing to the movement of majority mitochondria along microtubules in cytoplasm, mitochondrial targeting may enable PTX to act more effectively. Meanwhile, the existence of chemo-drug potentiates the phototherapy to achieve synergistic anti-tumor activity. As expected, mitochondria targeting nanomedicine (M-ICG-PTX NPs) showed improved mitochondria targeted cellular distribution and enhanced cell cytotoxicity in vitro. Also, M-ICG-PTX NPs exhibited higher tumor growth inhibition ability by promoting cell apoptosis and oxeiptosis pathway, and high effective inhibition of primary tumor growth and tumor metastasis. Taken together, M-ICG-PTX NPs may be promising nanoplatforms to achieve potent therapeutic effect for the combination of chemo- and photo-therapy (PTT).

Development of superior nanotheranostic agents with indocyanine green-conjugated poly(styrene-alt-maleic acid) nanoparticles for tumor imaging and phototherapy.

Developing safe, high-quality theranostic agents for cancer treatment is of great clinical value. In this work, for the first time, the clinical indocyanine green (ICG) is coupled with the biocompatible poly(styrene-alt-maleic anhydride) (PSMAn) to obtain the PSMAn-ICG polymer. The self-assembly of its hydrolyzed product in water results in ICG-conjugated poly(styrene-alt-maleic acid) nanoparticles (PSMA-ICG NPs). Intriguingly, the NPs have many advantages, including good solubility and stability in aqueous solutions, high photostability and decreased hemolytic damage to red blood cells, highlighting the importance of PSMA coupling. More interestingly, PSMA-ICG NPs significantly promote tumor targeting and enable long-term imaging of tumors. Furthermore, the administration of PSMA-ICG NPs in combination with near-infrared laser irradiation provides superior potency in the photothermal therapy of tumors. Furthermore, 9-amino-sialic acid (Sia)-coated PSMA-ICG NPs are fabricated, further enhancing tumor imaging and phototherapy. This is the first report of PSMA-NIR conjugates achieving tumor reduction in mice. Overall, this study provides novel phototheranostic agents with broad clinical transformation prospects.

Thermosensitive nanocomposite components for combined photothermal-photodynamic therapy in liver cancer treatment.

Phototherapies, in the form of photodynamic therapy (PDT) and photothermal therapy (PTT), have great application prospects in the field of biomedical science due to high precision and non-invasiveness. Because of the limited therapeutic efficacy of single phototherapy, researchers start to focus on combined PTT-PDT. Here, we designed a composite nanomaterial for PTT-PDT. H-TiO2 mesoporous spheres were prepared by sol-gel method and hydrogenation treatment. After modification with polydopamine (PDA), they were combined with indocyanine green (ICG) and NPe6 photosensitizers and coated by thermosensitive liposomes to prepare H-TiO2 @PDA@ICG@NPe6 @Lipo nanocomposite component. The results indicated a substantial improvement of the component in the aspects of spectral response range, photothermal conversion efficiency and light absorption performance by modification and photosensitizers, in the absence of any toxicities on cells. Thermal induction and sequential irradiation with 808 nm and 664 nm lasers induced the aggregation of H-TiO2 @PDA@ICG@NPe6 @Lipo at the tumor site to generate hyperthermia and massive reactive oxygen species (ROS), resulting in decreased cell activity or even cell apoptosis and restrained growth of allograft tumors. These findings underscore the favorable effects of H-TiO2 @PDA@ICG@NPe6 @Lipo on the combined phototherapies and provide approaches for the development of nano-drugs in the context of liver cancer.