The Critical Role of Erythrolysis and Microglia/Macrophages in Clot Resolution After Intracerebral Hemorrhage: A Review of the Mechanisms and Potential Therapeutic Targets.

Intracerebral hemorrhage (ICH) is a common cerebrovascular disorder with high morbidity and mortality. Secondary brain injury after ICH, which is initiated by multiple hemolytic products during erythrolysis, has been identified as a critical factor accounting for the poor prognosis of ICH patients. Clot resolution and hematoma clearance occur immediately after ICH via erythrolysis and erythrophagocytosis. During this process, erythrolysis after ICH results in the release of hemoglobin and products of degradation along with rapid morphological changes in red blood cells (RBCs). Phagocytosis of deformed erythrocytes and products of degradation by microglia/macrophages accelerates hematoma clearance, which turns out to be neuroprotective. Thus, a better understanding of the mechanism of erythrolysis and the role of microglia/macrophages after ICH is urgently needed. In this review, the current research progresses on the underlying mechanism of erythrolysis and erythrophagocytosis, as well as several useful tools for the quantification of erythrolysis-induced brain injury, are summarized, providing potential intervention targets and possible treatment strategies for ICH patients.

Inhibition of Mer exacerbates early brain injury by regulating microglia/macrophage phenotype after subarachnoid hemorrhage in mice.

BACKGROUND: Polarization of microglia/macrophages toward the pro-inflammatory phenotype is a crucial contributor to neuroinflammation after subarachnoid hemorrhage (SAH). Mer belongs to the TAM receptor tyrosine kinases family, which is known to play a significant role in the resolution of inflammation. However, the effect and mechanism of Mer after SAH remain unclear. In this study, we explored the effect of Mer on modulating the microglia/macrophage phenotype and neuroinflammation and possible potential mechanism after SAH. METHOD: Endovascular perforation model of SAH was performed. There are 3 parts in this study. Firstly, the time course of Mer expression was determined within 72 hours after SAH. Secondly, the effect of Mer downregulation on brain water content, neurological function, and microglial polarization was evaluated at 24 h after SAH. Thirdly, the neuroprotective effects of pharmacological Mer agonist were assessed. RESULT: The expression of Mer increased after SAH, and was prominently localized in microglia/macrophages. Treatment with Mer siRNA increased pro-inflammatory phenotype and decreased anti-inflammatory phenotype of microglia/macrophage, thus resulted in exacerbation of neurological deficits and brain edema after SAH. Mechanistically, the downregulation of Mer inhibited the downstream anti-inflammatory signals, SOCS1/SOCS3, by decreasing phosphorylated STATs. CONCLUSION: Mer is involved in the microglia/macrophage polarization and inflammation resolution after SAH, and that mechanism, at least in part, may contribute to the involvement of the STATs/SOCSs pathway.

Prx2 (Peroxiredoxin 2) as a Cause of Hydrocephalus After Intraventricular Hemorrhage.

Background and Purpose- Our recent study demonstrated that release of Prx2 (peroxiredoxin 2) from red blood cells (RBCs) is involved in the inflammatory response and brain injury after intracerebral hemorrhage. The current study investigated the role of extracellular Prx2 in hydrocephalus development after experimental intraventricular hemorrhage. Methods- There were 4 parts in this study. First, Sprague-Dawley rats received an intraventricular injection of lysed RBC or saline and were euthanized at 1 hour for Prx2 measurements. Second, rats received an intraventricular injection of Prx2, deactivated Prx2, or saline. Third, lysed RBC was coinjected with conoidin A, a Prx2 inhibitor, or vehicle. Fourth, rats received Prx2 injection and were treated with minocycline or saline (i.p.). The effects of Prx2 and the inhibitors were examined using magnetic resonance imaging assessing ventriculomegaly, histology assessing ventricular wall damage, and immunohistochemistry to assess inflammation, particularly at the choroid plexus. Results- Intraventricular injection of lysed RBC resulted in increased brain Prx2 and hydrocephalus. Intraventricular injection of Prx2 alone caused hydrocephalus, ventricular wall damage, activation of choroid plexus epiplexus cells (macrophages), and an accumulation of neutrophils. Conoidin A attenuated lysed RBC-induced injury. Systemic minocycline treatment reduced the epiplexus cell activation and hydrocephalus induced by Prx2. Conclusions- Prx2 contributed to the intraventricular hemorrhage-induced hydrocephalus, probably by inducing inflammatory responses in choroid plexus and ventricular wall damage.

Nanoliposomes Encapsulated Rapamycin/Resveratrol to Induce Apoptosis and Ferroptosis for Enhanced Colorectal Cancer Therapy.

OBJECTIVES: Monotherapy is often ineffective for treating colorectal cancer. In this study, we developed PEG-modified liposomes loaded with rapamycin (Rapa) and resveratrol (Res) (Rapa/Res liposomes, or RRL) to investigate their therapeutic potential in colorectal cancer. METHODS: RRL were constructed using the reversed-phase evaporation method. We assessed the cytotoxicity, apoptosis, and ferroptotic effects of RRL on colorectal cancer HCT116 cells. The anti-tumor efficacy of RRL was evaluated in HCT116 xenograft mice. RESULTS: RRL had a particle size of 86.67 ± 1.10 nm and a zeta potential of -33.13 ± 0.49 mV. The coloaded formulation demonstrated satisfactory performance both in vitro and in vivo, resulting in increased cytotoxicity to HCT116 cells and significant suppression of HCT116 xenografts tumor growth. Mechanically, RRL significantly increased the apoptosis rate of HCT116 cells, induced ROS accumulation in tumor cells, and effectively downregulated the expression of the ferroptosis-associated proteins GPX4 and SLC7A11, demonstrating its superior efficacy compared to that of Rapa liposomes (Rapa/Lps) or Res liposomes (Res/Lps) alone. CONCLUSION: Coloading Rapa and Res into liposomes to promote apoptosis and ferroptosis in tumor cells represents a promising strategy for the treatment of colorectal cancer.

Preparation and characterization of slow-release urea fertilizer encapsulated by a blend of starch derivative and polyvinyl alcohol with desirable biodegradability and availability.

In this study, a novel double-layer slow-release fertilizer (SRF) was developed utilizing stearic acid (SA) as a hydrophobic inner coating and a blend of starch phosphate carbamate (abbreviated as SPC) and polyvinyl alcohol (PVA) as a hydrophilic outer coating (designated as SPCP). The mass ratios of SPC and PVA in the SPCP matrices were systematically optimized by comprehensively checking the water absorbency, water contact angle (WCA), water retention property (WR), and mechanical properties such as percentage elongation at break and tensile strength with FTIR, XRD, EDS, and XPS techniques, etc. Moreover, the optimal SPCP/5:5 demonstrated superior water absorbency with an 80.2 % increase for the total mass compared to natural starch/PVA(NSP), along with desirable water retention capacity in the soil, exhibiting a weight loss of only 48 % over 13 d. Relative to pure urea and SA/NSPU/5:5, SA/SPCPU/5:5 released 50.3 % of its nutrient within 15 h, leading to nearly complete release over 25 h in the aqueous phase, while only 46.6 % of urea was released within 20 d in soil, extending to approximately 30 d. The slow release performance of urea reveals that the diffusion rate of urea release shows a significant decrease with an increase in coating layers. Consequently, this work demonstrated a prospective technology for the exploration of environmentally friendly SRF by integrating biodegradable starch derivatives with other polymers.

Preparation and characterization of starch carbamate modified natural sodium alginate composite hydrogel blend formulation and its application for slow-release fertilizer.

The exploration of environmentally friendly slow-release fertilizer (SRF) based on natural bio-polymers is of great importance in the development of modern agriculture and horticulture. Herein, a novel starch carbamate (SC) modified sodium alginate (SA) hydrogel (SC/SAH) was prepared utilizing as-synthesized SC and natural SA through the cationic ions crosslinking method and ultimately the corresponding slow-release fertilizer (SC/SAH-SRF) was successfully developed by immersing the dried SC/SAH matrix into saturated urea solution. Due to the low gelation temperature and high viscosity of the synthesized SC, the formed SC/SAH exhibits significantly enhanced properties including excellent water absorbency up to 8.02 g/g with considerable repeatability, abundant pore structure and high hydrophilicity compared with the neat SAH and natural starch based hydrogel (NS/SAH). Accordingly, the SC/SAH leads to higher urea loading amount âˆ¼ 1.28 g/g. Importantly, the resultant SC/SAH-SRF also shows superior slow-release performance, yielding a cumulative urea release of only 61.6 % within 10 h and almost completely release >16 h in water, what's more, only 58.5 % of the urea releases within 25 days and exceeding 50 days for complete release in soil column assays. The slow-release of urea from SC/SAH-SRF well complies for the first-order kinetics and accomplishes via a non-Fickian diffusion process. Moreover, the pot experiment demonstrates that the SC/SAH-SRF has higher growth promotion role for the maize seedlings than those of others. Consequently, this work provides a novel strategy for preparing environmentally friendly SRF by blending modified starch and hydrogel.

Rapamycin circumvents anti PD-1 therapy resistance in colorectal cancer by reducing PD-L1 expression and optimizing the tumor microenvironment.

The unresectable or postoperative recurrence of advanced metastatic colorectal cancer (CRC) is the difficulty of its clinical management, and pharmacological therapy is the main source of benefit. Immune checkpoint inhibitors are therapeutic options but are effective in approximately 5 % of patients with deficient mismatch repair (MMR)/microsatellite instability CRC and are ineffective in patients with MMR-proficient (pMMR)/microsatellite stable (MSS) CRCs, which may be associated with the tumor microenvironment (TME). Here, we propose a new combination strategy and evaluate the efficacy of rapamycin (Rapa) combined with anti-PD-1 (αPD-1) in CT26 tumor-bearing mice, azoxymethane (AOM)/dextran sodium sulfate (DSS) inflammation-associated CRC mice, CT26-Luc tumor-bearing mice with postoperative recurrence, and CT26 liver metastasis mice. The results revealed that Rapa improved the therapeutic effect of αPD-1 and effectively inhibited colorectal carcinogenesis, postoperative recurrence, and liver metastasis. Mechanistically, Rapa improved the anticancer effect of αPD-1, associated with Rapa reprograming of the immunosuppressive TME. Rapa effectively depleted α-SMA+ cancer-associated fibroblasts and degraded collagen in the tumor tissue, increasing T lymphocyte infiltration into the tumor tissue. Rapa induced the downregulation of programed cell death 1 ligand 1 (PD-L1) protein and transcript levels in CT26 cells, which may be associated with the inhibition of the mTOR/P70S6K signaling axis. Furthermore, co-culture of tumor cells and CD8+ T lymphocytes demonstrated that Rapa-induced PD-L1 downregulation in tumor cells increased spleen-derived CD8+ T lymphocyte activation. Therefore, Rapa improves the anti-tumor effect of αPD-1 in CRCs, providing new ideas for its use to improve combinatorial strategies for anti-PD-1 immunotherapy.

SLC45A3 Serves as a Potential Therapeutic Biomarker to Attenuate White Matter Injury After Intracerebral Hemorrhage.

Intracerebral hemorrhage (ICH) is a severe cerebrovascular disease, which impairs patients' white matter even after timely clinical interventions. Indicated by studies in the past decade, ICH-induced white matter injury (WMI) is closely related to neurological deficits; however, its underlying mechanism and pertinent treatment are yet insufficient. We gathered two datasets (GSE24265 and GSE125512), and by taking an intersection among interesting genes identified by weighted gene co-expression networks analysis, we determined target genes after differentially expressing genes in two datasets. Additional single-cell RNA-seq analysis (GSE167593) helped locate the gene in cell types. Furthermore, we established ICH mice models induced by autologous blood or collagenase. Basic medical experiments and diffusion tensor imaging were applied to verify the function of target genes in WMI after ICH. Through intersection and enrichment analysis, gene SLC45A3 was identified as the target one, which plays a key role in the regulation of oligodendrocyte differentiation involving in fatty acid metabolic process, etc. after ICH, and single-cell RNA-seq analysis also shows that it mainly locates in oligodendrocytes. Further experiments verified overexpression of SLC45A3 ameliorated brain injury after ICH. Therefore, SLC45A3 might serve as a candidate therapeutic biomarker for ICH-induced WMI, and overexpression of it may be a potential approach for injury attenuation.

Multi-targeting liposomal codelivery of cisplatin and rapamycin inhibits pancreatic cancer growth and metastasis through stromal modulation.

Pancreatic cancer treatment faces challenges due to drug resistance as well as liver metastasis. As a new strategy for treating pancreatic cancer, combination therapy is now available, but the dense mesenchymal barrier in the tumor tissue blocks drug delivery and impairs its therapeutic efficacy. To address this issue, we prepared an ATF peptide-decorated liposomal co-loaded with cisplatin and rapamycin (ATF@Pt/Rapa Lps), which targets both tumor cells and cancer-associated fibroblasts that express uPAR receptors. In tumor sphere penetration experiments, ATF peptide modified liposomes significantly enhanced deep penetration. More importantly, the ATF@Pt/Rapa Lps disrupted the stroma, as demonstrated by the downregulation of ɑ-SMA, I collagen, and fibronectin protein in vivo and in vitro. In this way, highly effective drug delivery to tumor cells can be achieved. As expected, there was a stronger inhibition of cell proliferation and migration by ATF@Pt/Rapa Lps in vitro compared to free Pt/Rapa and Pt/Rapa Lps. Furthermore, ATF@Pt/Rapa Lps showed greater therapeutic effects in PANC02 transplanted tumor mice and liver metastasis mice models. Ultimately, multi-targeting nanomedicines co-loaded with Rapa and cisplatin may provide a new approach to treating metastatic pancreatic cancer.

Stromal and tumor immune microenvironment reprogramming through multifunctional cisplatin-based liposomes boosts the efficacy of anti-PD-1 immunotherapy in pancreatic cancer.

The dense stromal barrier in pancreatic cancer tissues blocks intratumoral delivery and distribution of chemotherapeutics and therapeutic antibodies, causing poor chemoimmunotherapy responses. We designed a multi-targeted pH-sensitive liposome which encapsulates cisplatin (Pt) in its water core (denoted as ATF@Pt Lps) and shows high affinity for uPAR receptors in pancreatic cancer cells, tumor-associated macrophages, and cancer-associated fibroblasts. Systemic administration of ATF@Pt Lps enabled overcoming the central stromal cellular barrier and effective drug delivery into tumor cells, resulting in a strong therapeutic response in a Panc02 cell derived transplanted tumor mouse model. More importantly, ATF@Pt Lps degradation of collagen contributes to the infiltration of CD8+ T cells into tumors as well as an enhanced accumulation of anti PD-1 monoclonal antibodies. Furthermore, the killing of tumor cells by Pt also leads to the release of tumor antigens, which promote the proliferation of immune cells, especially CD83+ cells, Th1 CD4+ cells, and CD8+ cytotoxic T cells, that converted an immunoscore "cold" pancreatic cancer into a pro-immune "hot" tumor. A further combination with an immune checkpoint agent, anti PD-1 antibodies that inhibit PD-1, can enhance tumor specific cytotoxic T cell response. Accordingly, ATF@Pt Lps displays multi-targeting, controlled drug release, stromal disruption, enhanced penetration, killing of cancer cells, modification of the immunosuppressive microenvironment, and enhancement of immunity. This study provides important mechanistic information for the further development of a combination of ATF@Pt Lps and anti PD-1 antibodies for the effective treatment of pancreatic cancer.

DJ-1 Alleviates Neuroinflammation and the Related Blood-Spinal Cord Barrier Destruction by Suppressing NLRP3 Inflammasome Activation via SOCS1/Rac1/ROS Pathway in a Rat Model of Traumatic Spinal Cord Injury.

DJ-1 has been shown to play essential roles in neuronal protection and anti-inflammation in nervous system diseases. This study aimed to explore how DJ-1 regulates neuroinflammation after traumatic spinal cord injury (t-SCI). The rat model of spinal cord injury was established by the clamping method. The Basso, Beattie, Bresnahan (BBB) score and the inclined plane test (IPT) were used to evaluate neurological function. Western blot was then applied to test the levels of DJ-1, NLRP3, SOCS1, and related proinflammatory factors (cleaved caspase 1, IL-1ß and IL-18); ROS level was also examined. The distribution of DJ-1 was assessed by immunofluorescence staining (IF). BSCB integrity was assessed by the level of MMP-9 and tight junction proteins (Claudin-5, Occludin and ZO-1). We found that DJ-1 became significantly elevated after t-SCI and was mainly located in neurons. Knockdown of DJ-1 with specific siRNA aggravated NLRP3 inflammasome-related neuroinflammation and strengthened the disruption of BSCB integrity. However, the upregulation of DJ-1 by Sodium benzoate (SB) reversed these effects and improved neurological function. Furthermore, SOCS1-siRNA attenuated the neuroprotective effects of DJ-1 and increased the ROS, Rac1 and NLRP3. In conclusion, DJ-1 may alleviate neuroinflammation and the related BSCB destruction after t-SCI by suppressing NLRP3 inflammasome activation by SOCS1/Rac1/ROS pathways. DJ-1 shows potential as a feasible target for mediating neuroinflammation after t-SCI.

The Role of the Blood Neutrophil-to-Lymphocyte Ratio in Aneurysmal Subarachnoid Hemorrhage.

Aneurysmal subarachnoid hemorrhage (aSAH) is an important type of stroke with the highest rates of mortality and disability. Recent evidence indicates that neuroinflammation plays a critical role in both early brain injury and delayed neural deterioration after aSAH, contributing to unfavorable outcomes. The neutrophil-to-lymphocyte ratio (NLR) is a peripheral biomarker that conveys information about the inflammatory burden in terms of both innate and adaptive immunity. This review summarizes relevant studies that associate the NLR with aSAH to evaluate whether the NLR can predict outcomes and serve as an effective biomarker for clinical management. We found that increased NLR is valuable in predicting the clinical outcome of aSAH patients and is related to the risk of complications such as delayed cerebral ischemia (DCI) or rebleeding. Combined with other indicators, the NLR provides improved accuracy for predicting prognosis to stratify patients into different risk categories. The underlying pathophysiology is highlighted to identify new potential targets for neuroprotection and to develop novel therapeutic strategies.

Hydrocephalus Induced by Intraventricular Peroxiredoxin-2: The Role of Macrophages in the Choroid Plexus.

The choroid plexus (CP) is the primary source of cerebrospinal fluid in the central nervous system. Recent evidence indicates that inflammatory pathways at the CP may be involved in hydrocephalus development. Peroxiredoxin 2 (Prx2) is a major component of red blood cells. Extracellular Prx2 is proinflammatory, and its release after red blood cell lysis may contribute to hydrocephalus after intraventricular hemorrhage. This study aimed to identify alterations in CP macrophages and dendritic cells following intracerebroventricular Prx2 injection and investigate the relationship between macrophages/dendritic cells and hydrocephalus. There were two parts to this study. In the first part, adult male Sprague-Dawley rats received an intracerebroventricular injection of Prx2 or saline. In the second part, Prx2 was co-injected with clodronate liposomes or control liposomes. All animals were euthanized at 24 h after magnetic resonance imaging. Immunohistochemistry was used to evaluate macrophages in CP, magnetic resonance imaging to quantify hydrocephalus, and histology to assess ventricular wall damage. The intracerebroventricular injection of Prx2 not only increased the OX-6 positive cells, but it also altered their location in the CP and immunophenotype. Co-injecting clodronate liposomes with Prx2 decreased the number of macrophages and simultaneously attenuated Prx2-induced hydrocephalus and ventricular wall damage. These results suggest that CP macrophages play an essential role in CP inflammation-induced hydrocephalus. These macrophages may be a potential therapeutic target in post-hemorrhagic hydrocephalus.

Comparison of Operative and Conservative Treatment for Asymptomatic Moyamoya Disease: Preliminary Experience in Small Retrospective Series.

OBJECTIVE: The best management of asymptomatic moyamoya disease (MMD) remains controversial. In this study, the authors aimed to explore an experience for treatment modality for asymptomatic MMD. METHODS: The authors retrospectively reviewed a total of 23 patients (age range 30-58 years) with asymptomatic MMD during the past 5 years at their institutions. The patients were divided into 2 groups: The surgical group included 11 patients, and the conservative group included 12 patients. The demographic, radiologic, and clinical findings of the patients were evaluated. At follow-up over 13-65 months, the future clinical and radiologic progression events were evaluated. RESULTS: During the follow-up period, 3 patients suffered from future clinical progression events in the conservative group: 1 experienced stroke, and 2 experienced transient ischemic attack. Among the patients in the surgical group, only 1 experienced transient ischemic attack. Kaplan-Meier analysis showed that patients undergoing surgeries had longer clinical progression-free survival times compared with patients in the conservative group (P = 0.002). CONCLUSIONS: Surgical treatment may be an alternative choice for patients with asymptomatic MMD. However, the best strategy for asymptomatic MMD in order to reduce future cerebrovascular risks still needs to be further explored.

Phosphorylation of UT-A1 on serine 486 correlates with membrane accumulation and urea transport activity in both rat IMCDs and cultured cells.

Vasopressin is the primary hormone regulating urine-concentrating ability. Vasopressin phosphorylates the UT-A1 urea transporter in rat inner medullary collecting ducts (IMCDs). To assess the effect of UT-A1 phosphorylation at S486, we developed a phospho-specific antibody to S486-UT-A1 using an 11 amino acid peptide antigen starting from amino acid 482 that bracketed S486 in roughly the center of the sequence. We also developed two stably transfected mIMCD3 cell lines: one expressing wild-type UT-A1 and one expressing a mutated form of UT-A1, S486A/S499A, that is unresponsive to protein kinase A. Forskolin stimulates urea flux in the wild-type UT-A1-mIMCD3 cells but not in the S486A/S499A-UT-A1-mIMCD3 cells. The phospho-S486-UT-A1 antibody identified UT-A1 protein in the wild-type UT-A1-mIMCD3 cells but not in the S486A/S499A-UT-A1-mIMCD3 cells. In rat IMCDs, forskolin increased the abundance of phospho-S486-UT-A1 (measured using the phospho-S486 antibody) and of total UT-A1 phosphorylation (measured by (32)P incorporation). Forskolin also increased the plasma membrane accumulation of phospho-S486-UT-A1 in rat IMCD suspensions, as measured by biotinylation. In rats treated with vasopressin in vivo, the majority of the phospho-S486-UT-A1 appears in the apical plasma membrane. In summary, we developed stably transfected mIMCD3 cell lines expressing UT-A1 and an S486-UT-A1 phospho-specific antibody. We confirmed that vasopressin increases UT-A1 accumulation in the apical plasma membrane and showed that vasopressin phosphorylates UT-A1 at S486 in rat IMCDs and that the S486-phospho-UT-A1 form is primarily detected in the apical plasma membrane.

Design and synthesis of a new series of low toxic naphthalimide platinum(IV) antitumor complexes with dual DNA damage mechanism.

Naphthalimide platinum(IV) antitumor complexes with potential dual DNA damage mechanism were designed, synthesized and evaluated for antitumor activities. The incorporation of DNA targeted naphthalimide group to the platinum(IV) system exerts much positive impacts on their antitumor efficacy. The mechanism research reveals that the title compounds could interact with dsDNA in platinum(IV) form via the naphthalimide group and cause DNA lesion. The further reduction would release platinum(II) complexes and naphthalimide acids which would induce remarkable secondary damage to DNA. Furthermore, the naphthalimide platinum(IV) compounds could combine with human serum albumin via electrostatic force, which are favourable for their storage and transport in blood. Moreover, the title compounds exhibit higher accumulation in tumor cells, and exert lower toxic and higher safe properties than oxaliplatin in vivo.

Polymer-based gadolinium oxide nanocomposites for FL/MR/PA imaging guided and photothermal/photodynamic combined anti-tumor therapy.

Recently, ultrasmall gadolinium oxide (Gd2O3) nanoparticles with high longitudinal relaxation rate have received enormous attention. However, it can't be concentrated in tumor site through intravenous administration due to its ultrasmall size. In this project, we coated ultrasmall Gd2O3 nanoparticles with a near-infrared (NIR) light-absorbing polymer polypyrrole (PPy), modifying with hyaluronic acid (HA) and loaded aluminum phthalocyanine (AlPc), the Gd2O3@PPy/AlPc-HA nanoparticles could be used for fluorescence (FL)/magnetic resonance (MR)/photoacoustic (PA) imaging guided as well as remotely controlled PTT/PDT combined anti-tumor therapy. Polymerized PPy with high photothermal conversion efficiency was introduced to assemble the ultrasmall Gd2O3 nanoparticles which have high longitudinal relaxation rate and signal-to-noise ratio, thus obtaining Gd2O3@PPy nanoparticles which possess a larger particle size and can be more suitable for tumor targeting based on the EPR effect. HA and AlPc were adsorbed on PPy for HA-mediated tumor targeting and photodynamic therapy respectively. The in vivo triple-modal imaging revealed that Gd2O3@PPy/AlPc-HA nanoparticles possess enhanced tumor uptake effect after intravenous injection. More importantly, the nanoparticles exhibited an obvious photothermal effect, which can trigger the release and de-quench of AlPc. The anti-tumor efficiency further corroborated that the combined therapy achieved an excellent tumor inhibition therapeutic effect which was much better than any other mono-therapy. Consequently, our work encouraged further exploration of polymer-based multifunctional theranostic nanoparticles for cancer combination therapy under remote near-infrared (NIR) light controls.

Photosensitizer loaded PEG-MoS2-Au hybrids for CT/NIRF imaging-guided stepwise photothermal and photodynamic therapy.

In this study, we developed X-ray computed tomography (CT)/near-infrared fluorescence (NIRF) imaging for visually guiding the photothermal therapy (PTT)/photodynamic therapy (PDT) of antitumor nanocomposites (PEG-MoS2-Au-Ce6), by adsorbing chlorin e6 (Ce6) to the gold nanoparticle (AuNPs)-decorated molybdenum disulfide (PEG-MoS2) nanosheets. The NIR photosensitizer Ce6 was adsorbed onto the PEG-MoS2-Au hybrids viaπ-π stacking and hydrophobic interactions, where Ce6 remained in its quenched state due to the surface plasmon resonance (SPR) capacity of AuNPs, as well as the coupling interaction with PEG-MoS2 nanosheets. However, Ce6 was dequenched and boosted strong NIR fluorescence signals after being released from the surface of PEG-MoS2-Au hybrids upon heat generation, thus producing the PDT effect for anti-tumor therapy. Moreover, the PEG-MoS2 nanosheets and Ce6 in the PEG-MoS2-Au-Ce6 nanocomposites could be further used for CT and NIRF dual-modal imaging, respectively. In vitro NIR-triggered drug release studies indicated that the PEG-MoS2-Au-Ce6 nanocomposites rapidly release the drug around the tumor site under the photothermal effect. Therefore, this dual-modality nanosystem simultaneously enables precise cancer diagnosis and therapy.

A photoresponsive and rod-shape nanocarrier: Single wavelength of light triggered photothermal and photodynamic therapy based on AuNRs-capped & Ce6-doped mesoporous silica nanorods.

Rod-shape nanocarriers have attracted great interest because of their better cell internalization capacity and higher drug loading properties. Besides, the combination of photodynamic therapy (PDT) and photothermal therapy (PTT) holds great promise to overcome respective limitations of the anti-cancer treatment. In this work, we first report Au nanorods-capped and Ce6-doped mesoporous silica nanorods (AuNRs-Ce6-MSNRs) for the single wavelength of near infrared (NIR) light triggered combined phototherapy. AuNRs-Ce6-MSNRs are not only able to generate hyperthermia to perform PTT effect based on the AuNRs, but also can produce singlet oxygen (1O2) for PDT effect based on Ce6 after uncapping of AuNRs under the single NIR wavelength irradiation. In addition, the combined therapy can be dual-imaging guided by taking the photoacoustic (PA) and NIR fluorescence (NIRF) imaging of AuNRs and Ce6, respectively. What's more, by utilizing the special structure of MSNRs, this nanocarrier can serve as a drug delivery platform with high drug loading capacity and enhanced cellular uptake efficiency. The multi-functional nanocomposite is designed to integrate photothermal and photodynamic therapy, in vivo dual-imaging into one system, achieving synergistic anti-tumor effects both in vitro and in vivo.

A single-light triggered and dual-imaging guided multifunctional platform for combined photothermal and photodynamic therapy based on TD-controlled and ICG-loaded CuS@mSiO2.

Near-infrared (NIR)-responsive drug delivery systems have received enormous attention because of their good biocompatibility and high biological penetration. In this work, we report a novel 1-tetradecanol (TD)-controlled and indocyanine green (ICG)-loaded CuS@mSiO2 phototherapy nanoplatform (CuS@mSiO2-TD/ICG). The CuS@mSiO2 nanoparticles prepared by a facile one-pot approach can serve as drug-delivery vehicles to transport the NIR absorbing phototherapeutic agent (ICG) within the mesoporous cavities. Meanwhile a phase-change molecule (PCM), TD, is introduced as a thermosensitive gatekeeper to avoid the premature release of loaded ICG. Noticeably, the combined therapy is irradiated at an 808 nm single-light wavelength, thus performing the photothermal therapy (PTT) based on CuS@mSiO2 as well as simultaneously triggering the photodynamic (PDT)/PTT effect based on ICG. Furthermore, ICG also has the function of dual in vivo fluorescence imaging and photoacoustic (PA) imaging. This dual imaging-guided and gatekeeper-controlled nanoplatform for the single-light triggered PTT/PDT treatment holds significant promise for future cancer therapy due to their markedly improved therapeutic efficacy and decreased systemic toxicity.