Host-Guest Doping Modulated Afterglow Emission of Fluoroquinolones for Their Separation-Free Detection and Discrimination.

Detection and discrimination of fluoroquinolones (FQs) are crucial for food safety but remain a formidable challenge due to their minor differences in molecular structures and the serious interferences from food matrices. Herein, we propose an afterglow assay for the detection and discrimination of FQs through modulating their room-temperature phosphorescence (RTP) and thermally activated delayed fluorescence (TADF) properties by a host-guest doping strategy. FQs were doped into the boric acid host, forming boronic anhydride structures and hydrogen bonds, which prompted the RTP and TADF performance of FQs by stabilizing their excited states, preventing triplet exciton quenching, and reducing the energy gap between singlet and triplet states. The FQs can be quantitatively detected through monitoring the afterglow intensity of host-guest systems, as low as 0.25 µg/mL. The differences in the afterglow intensity and emission lifetime allowed accurate discrimination of 11 types of FQs through pattern recognition methods. Aided by the delayed signal detection model of afterglow emission, the background signal and the interferences from food matrices were effectively eliminated, which endow the detection and discrimination of mixed FQs in commercial meat samples, without multiple-step separation processes.

Nanomaterial-Enabled Photothermal Heating and Its Use for Cancer Therapy via Localized Hyperthermia.

Photothermal therapy (PTT), which employs nanoscale transducers delivered into a tumor to locally generate heat upon irradiation with near-infrared light, shows great potential in killing cancer cells through hyperthermia. The efficacy of such a treatment is determined by a number of factors, including the amount, distribution, and dissipation of the generated heat, as well as the type of cancer cell involved. The amount of heat generated is largely controlled by the number of transducers accumulated inside the tumor, the absorption coefficient and photothermal conversion efficiency of the transducer, and the irradiance of the light. The efficacy of treatment depends on the distribution of the transducers in the tumor and the penetration depth of the light. The vascularity and tissue thermal conduction both affect the dissipation of heat and thereby the distribution of temperature. The successful implementation of PTT in the clinic setting critically depends on techniques for real-time monitoring and management of temperature.

Efficacy of a mouthwash containing ε-poly-L-lysine, funme peptides and domiphen in reducing halitosis and supragingival plaque: a randomized clinical trial.

OBJECTIVE: To evaluate the antibacterial effectiveness of a combination of ε-poly-L-lysine (ε-PL), funme peptide (FP) as well as domiphen against oral pathogens, and assess the efficacy of a BOP® mouthwash supplemented with this combination in reducing halitosis and supragingival plaque in a clinical trial. MATERIALS AND METHODS: The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of the compound against Fusobacterium nucleatum, Porphyromonas gingivalis, Streptococcus mutans, and Aggregatibacter actinomycetemcomitans were determined by the gradient dilution method. Subsequently, the CCK-8 assay was used to detect the toxicity of mouthwash on human gingival fibroblastst, and the effectiveness in reducing halitosis and supragingival plaque of the mouthwash supplemented with the combination was analyzed by a randomized, double-blind, parallel-controlled clinical trial. RESULTS: The combination exhibited significant inhibitory effects on tested oral pathogens with the MIC < 1.56% (v/v) and the MBC < 3.13% (v/v), and the mouthwash containing this combination did not inhibit the viability of human gingival fibroblasts at the test concentrations. The clinical trial showed that the test group displayed notably lower volatile sulfur compounds (VSCs) at 0, 10, 24 h, and 7 d post-mouthwash (P < 0.05), compared with the baseline. After 7 days, the VSC levels of the and control groups were reduced by 50.27% and 32.12%, respectively, and notably cutting severe halitosis by 57.03% in the test group. Additionally, the Plaque Index (PLI) of the test and control group decreased by 54.55% and 8.38%, respectively, and there was a significant difference in PLI between the two groups after 7 days (P < 0.01). CONCLUSIONS: The combination of ε-PL, FP and domiphen demonstrated potent inhibitory and bactericidal effects against the tested oral pathogens, and the newly formulated mouthwash added with the combination exhibited anti-dental plaque and anti-halitosis properties in a clinical trial and was safe. TRIAL REGISTRATION: The randomized controlled clinical trial was registered on Chinese Clinical Trial Registry (No. ChiCTR2300073816, Date: 21/07/2023).

Pan-cancer spatially resolved single-cell analysis reveals the crosstalk between cancer-associated fibroblasts and tumor microenvironment.

Cancer-associated fibroblasts (CAFs) are a heterogeneous cell population that plays a crucial role in remodeling the tumor microenvironment (TME). Here, through the integrated analysis of spatial and single-cell transcriptomics data across six common cancer types, we identified four distinct functional subgroups of CAFs and described their spatial distribution characteristics. Additionally, the analysis of single-cell RNA sequencing (scRNA-seq) data from three additional common cancer types and two newly generated scRNA-seq datasets of rare cancer types, namely epithelial-myoepithelial carcinoma (EMC) and mucoepidermoid carcinoma (MEC), expanded our understanding of CAF heterogeneity. Cell-cell interaction analysis conducted within the spatial context highlighted the pivotal roles of matrix CAFs (mCAFs) in tumor angiogenesis and inflammatory CAFs (iCAFs) in shaping the immunosuppressive microenvironment. In patients with breast cancer (BRCA) undergoing anti-PD-1 immunotherapy, iCAFs demonstrated heightened capacity in facilitating cancer cell proliferation, promoting epithelial-mesenchymal transition (EMT), and contributing to the establishment of an immunosuppressive microenvironment. Furthermore, a scoring system based on iCAFs showed a significant correlation with immune therapy response in melanoma patients. Lastly, we provided a web interface ( https://chenxisd.shinyapps.io/pancaf/ ) for the research community to investigate CAFs in the context of pan-cancer.

[Pathways and Mechanisms of Periodontitis Contributing to Adverse Pregnancy Outcomes].

Periodontitis is a chronic oral inflammatory disease with a high incidence in the global population. Periodontal pathogens can colonize and infect multiple human tissues and organs through blood transmission, which is an important risk factor of many systemic diseases. Recently, the correlation between periodontitis and adverse pregnancy outcomes (APOs) has attracted growing research interest. Herein, we systematically reviewed the research progress in the relationship between periodontitis and APOs and summarized reported findings on the pathways and mechanisms by which periodontitis contributes to APOs. We also clarified that intrauterine infection caused by oral pathogens transmitted through blood is an important pathway by which periodontitis interferes with pregnancy. In addition, further research focused on the discovery of more APOs-related oral pathogenic bacteria and their virulence factors, analysis of the interaction between pathogenic bacteria and placental tissue, and pathogenic pathways of oral bacterial invasion of the fetus will promote thorough analysis of the specific molecular mechanism of how periodontitis affects APOs. Furthermore, the validation of the results of human population-based studies through animal/cell experiments and the translation into effective intervention strategies are of great clinical significance to the prevention and control of the occurrence and development of APOs.

Ultrasmall iron oxide nanoparticles cause significant toxicity by specifically inducing acute oxidative stress to multiple organs.

BACKGROUND: Iron oxide nanoparticles have been approved by food and drug administration for clinical application as magnetic resonance imaging (MRI) and are considered to be a biocompatible material. Large iron oxide nanoparticles are usually used as transversal (T2) contrast agents to exhibit dark contrast in MRI. In contrast, ultrasmall iron oxide nanoparticles (USPIONs) (several nanometers) showed remarkable advantage in longitudinal (T1)-weighted MRI due to the brighten effect. The study of the toxicity mainly focuses on particles with size of tens to hundreds of nanometers, while little is known about the toxicity of USPIONs. RESULTS: We fabricated Fe3O4 nanoparticles with diameters of 2.3, 4.2, and 9.3 nm and evaluated their toxicity in mice by intravenous injection. The results indicate that ultrasmall iron oxide nanoparticles with small size (2.3 and 4.2 nm) were highly toxic and were lethal at a dosage of 100 mg/kg. In contrast, no obvious toxicity was observed for iron oxide nanoparticles with size of 9.3 nm. The toxicity of small nanoparticles (2.3 and 4.2 nm) could be reduced when the total dose was split into 4 doses with each interval for 5 min. To study the toxicology, we synthesized different-sized SiO2 and gold nanoparticles. No significant toxicity was observed for ultrasmall SiO2 and gold nanoparticles in the mice. Hence, the toxicity of the ultrasmall Fe3O4 nanoparticles should be attributed to both the iron element and size. In the in vitro experiments, all the ultrasmall nanoparticles (< 5 nm) of Fe3O4, SiO2, and gold induced the generation of the reactive oxygen species (ROS) efficiently, while no obvious ROS was observed in larger nanoparticles groups. However, the ·OH was only detected in Fe3O4 group instead of SiO2 and gold groups. After intravenous injection, significantly elevated ·OH level was observed in heart, serum, and multiple organs. Among these organs, heart showed highest ·OH level due to the high distribution of ultrasmall Fe3O4 nanoparticles, leading to the acute cardiac failure and death. CONCLUSION: Ultrasmall Fe3O4 nanoparticles (2.3 and 4.2 nm) showed high toxicity in vivo due to the distinctive capability in inducing the generation of ·OH in multiple organs, especially in heart. The toxicity was related to both the iron element and size. These findings provide novel insight into the toxicology of ultrasmall Fe3O4 nanoparticles, and also highlight the need of comprehensive evaluation for their clinic application.

The blood urea nitrogen/creatinine (BUN/cre) ratio was U-shaped associated with all-cause mortality in general population.

OBJECTIVES: This study aimed to explore the relationship between the blood urea nitrogen/creatinine (BUN/Cre) ratio and all-cause or cause-specific mortality in the general population. METHODS: Participants were enrolled from the National Health and Nutrition Examination Survey (NHANES) during 1999 to 2014. Baseline variables were acquired from questionnaires and examinations. Death status were ascertained from National Death Index records. Cox proportional hazards models with cubic spines were used to estimate hazard ratios (HRs) and 95% confidence interval (CI) of all-cause mortality, cardiovascular and cancer mortality. RESULTS: A total of 42038 participants were enrolled in the study with a median 8.13 years of follow-up. Older people and women tend to have a higher BUN/Cre ratio. After multivariable adjustment, BUN/Cre ratio between 11.43 and 14.64 was associated with the lowest all-cause mortality compared with the participants with the lowest quartile (HR 0.83 [0.76, 0.91]; p < 0.001). The highest quartile of BUN/Cre ratio was associated with the lowest risk of cancer mortality (HR 0.64 [0.53, 0.78]; p < 0.001). Restricted cubic splines showed BUN/Cre was nonlinearly associated with all-cause mortality and linearly associated with cancer mortality. CONCLUSIONS: This study confirmed a U-shape relationship between BUN/Cre ratio and all-cause mortality in the general population.

A Tumor-Penetrating Nanomedicine Improves the Chemoimmunotherapy of Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant tumors with a low survival rate. The therapeutic effect of chemotherapy and immunotherapy for PDAC is disappointing due to the presence of dense tumor stroma and immunosuppressive cells in the tumor microenvironment (TME). Herein, a tumor-penetrating nanoparticle is reported to modulate the deep microenvironment of PDAC for improved chemoimmunotherapy. The tumor pH-sensitive polymer is synthesized by conjugating N,N-dipentylethyl moieties and monomethoxylpoly(ethylene glycol) onto PAMAM dendrimer, into whose cavity a hydrophobic gemcitabine (Gem) prodrug is accommodated. They self-assemble into nanoparticles (denoted as SPN@Pro-Gem) with the size around 120 nm at neutral pH, but switch into small particles (≈8 nm) at tumor site to facilitate deep delivery of Gem into the tumor parenchyma. In addition to killing cancer cells that resided deeply in the tumor tissue, SPN@Pro-Gem could modulate the TME by reducing the abundance of tumor-associated macrophages and myeloid-derived suppressor cells as well as upregulating the expression level of PD-L1 of tumor cells. This collectively facilitates the infiltration of cytotoxic T cells into the tumors and renders checkpoint inhibitors more effective in previously unresponsive PDAC models. This study reveals a promising strategy for improving the chemoimmunotherapy of pancreatic cancer.

AGGF1 inhibits the expression of inflammatory mediators and promotes angiogenesis in dental pulp cells.

OBJECTIVES: To determine the role of angiogenic factor with G-patch and FHA domain 1 (AGGF1) in inflammatory response of human dental pulp cells (DPCs) and the underneath mechanism and to explore its role in angiogenesis. MATERIALS AND METHODS: The expression of AGGF-1 in human healthy and inflammatory pulp tissues was detected by immunohistochemistry. RT-qPCR and Western blot were used to evaluate the expression of AGGF1 in DPCs stimulated by lipopolysaccharide (LPS). After AGGF1 was knocked down, the expression of LPS-induced inflammatory cytokines in DPCs was quantified by RT-qPCR and ELISA. Immunofluorescence and Western blot were used to assess the activation of NF-κB signaling. Inflammatory cytokines were detected by RT-qPCR and ELISA in DPCs pretreated with NF-κB pathway inhibitors before LPS stimulation, and then the effect of AGGF1 on angiogenesis was also evaluated. RESULTS: AGGF1 expression increased in inflammatory dental pulp tissues. In DPCs stimulated by LPS, AGGF1 was upregulated in a dose-dependent manner (P < 0.05). In AGGF1 knockdown cells, the expression of IL-6, IL-8, and monocyte chemoattractant protein-1 (MCP-1/CCL-2) increased by LPS stimulation (P < 0.001). Nuclear translocation of p65 was promoted, and the addition of NF-κB inhibitors inhibited the expression of inflammatory factors. Meanwhile, knockdown of AGGF1 inhibited vascularization. CONCLUSIONS: AGGF1 inhibited the synthesis of inflammatory cytokines through NF-κB signaling pathway and promoted the angiogenesis of DPCs. CLINICAL RELEVANCE: This study might shed light in the treatment of pulpitis and regeneration of dental pulp tissues; however, more clinical trials are required to validate these findings.

Reversible Thermochromic Nanoparticles Composed of a Eutectic Mixture for Temperature-Controlled Photothermal Therapy.

Photothermal therapy (PTT) is an effective approach to cancer therapy. However, the high temperature during the therapy increases the damage to surrounding normal tissues. Thermochromic material, which exhibits temperature-activated color change and optical absorption, is a promising photothermal agent for precisely temperature-controlled PTT. Nevertheless, the construction of nanosized thermochromic particles with an appropriate transition temperature (44-47 °C) is still a great challenge. Here, thermochromic nanoparticles with the transition temperature at 45 °C based on a leuco dye-developer-solvent system are developed for thermostatic photothermal tumor therapy. Below the temperature, the nanoparticles take a dark green color to absorb light and convert it into heat efficiently. Once the temperature reaches the transition point, the colored nanoparticles switch to a colorless state, maintaining the temperature at the predefined level and allowing deeper light penetration. The autoregulated nanoparticles exhibit a prominent therapeutic effect for the tumor without destroying normal tissues.

Nanoparticle-Enabled Dual Modulation of Phagocytic Signals to Improve Macrophage-Mediated Cancer Immunotherapy.

Activation of the phagocytosis of macrophages to tumor cells is an attractive strategy for cancer immunotherapy, but the effectiveness is limited by the fact that many tumor cells express an increased level of anti-phagocytic signals (e.g., CD47 molecules) on their surface. To promote phagocytosis of macrophages, a pro-phagocytic nanoparticle (SNPACALR&aCD47 ) that concurrently carries CD47 antibody (aCD47) and a pro-phagocytic molecule calreticulin (CALR) is constructed to simultaneously modulate the phagocytic signals of macrophages. SNPACALR&aCD47 can achieve targeted delivery to tumor cells by specifically binding to the cell-surface CD47 and block the CD47-SIRPα pathway to inhibit the "don't eat me" signal. Tumor cell-targeted delivery increases the exposure of recombinant CALR on the cell surface and stimulates an "eat me" signal. Simultaneous modulation of the two signals enhances the phagocytosis of 4T1 tumor cells by macrophages, which leads to significantly improved anti-tumor efficacy in vivo. The findings demonstrate that the concurrent blockade of anti-phagocytic signals and activation of pro-phagocytic signals can be effective in macrophage-mediated cancer immunotherapy.

Hyaluronic acid-coated polymeric micelles with hydrogen peroxide scavenging to encapsulate statins for alleviating atherosclerosis.

Inflammation and oxidative stress are two major factors that are involved in the pathogenesis of atherosclerosis. A smart drug delivery system that responds to the oxidative microenvironment of atherosclerotic plaques was constructed in the present study. Simvastatin (SIM)-loaded biodegradable polymeric micelles were constructed from hyaluronic acid (HA)-coated poly(ethylene glycol)-poly(tyrosine-ethyl oxalyl) (PEG-Ptyr-EO) for the purpose of simultaneously inhibiting macrophages and decreasing the level of reactive oxygen species (ROS) to treat atherosclerosis. HA coating endows the micelle system the ability of targeting CD44-positive inflammatory macrophages. Owing to the ROS-responsive nature of PEG-Ptyr-EO, the micelles can not only be degraded by enzymes, but also consumes ROS by itself at the pathologic sites, upon which the accumulation of pro-inflammatory macrophages is effectively suppressed and oxidative stress is alleviated. Consequently, the cellular uptake experiment demonstrated that SIM-loaded HA-coated micelles can be effectively internalized by LPS-induced RAW264.7 cells and showed high cytotoxicity against the cells, but low cytotoxicity against LO2 cells. In mouse models of atherosclerosis, intravenously SIM-loaded HA-coated micelles can effectively reduce plaque content of cholesterol, resulting in remarkable therapeutic effects. In conclusion, the SIM-loaded micelle system provides a promising and innovative option against atherosclerosis.

Enhanced antitumor efficacy and attenuated cardiotoxicity of doxorubicin in combination with lycopene liposomes.

The aim of this study was to evaluate whether lycopene-loaded liposomes (L-LYC) could interfere with the antitumor efficacy and cardiotoxicity of doxorubicin (DOX). L-LYC were prepared by a thin-film hydration method to overcome the instability, insolubility, and low bioavailability of lycopene. The mean diameter and morphology of the liposomes were determined by dynamic light scattering and transmission electron microscopy, respectively, and then, in vitro cytotoxicity and in vivo antitumor activity were determined to evaluate the effects of L-LYC and their combination with DOX. Finally, we evaluated whether L-LYC could decrease the DOX-induced cardiotoxicity in vivo. The results showed that the particle size of L-LYC appeared uniform, and the average diameter was approximately 160.4 nm. Compared with DOX treatment alone, the combination of L-LYC and DOX showed significantly increased cytotoxicity in vitro and decreased the tumor size in B16 melanoma-bearing mice in vivo. Furthermore, the DOX-induced cardiotoxicity was clearly relieved in combination with L-LYC. The overall findings indicated that L-LYC have a great potential for improving the therapeutic efficacy and attenuating the cardiotoxicity of the chemotherapy drug DOX.

Nanoenabled Reversal of IDO1-Mediated Immunosuppression Synergizes with Immunogenic Chemotherapy for Improved Cancer Therapy.

Certain chemotherapeutics (e.g., oxaliplatin, OXA) can evoke effective antitumor immunity responses by inducing immunogenic cell death (ICD). Unfortunately, tumors always develop multiple immunosuppressive mechanisms, such as the upregulation of immunosuppressive factors, to counteract the effects of immunogenic chemotherapy. Indoleamine 2,3-dioxygenase-1 (IDO1), a tryptophan catabolic enzyme overexpressed in tumor-draining lymph nodes (TDLNs) and tumor tissues, plays a pivotal role in the generation of the immunosuppressive microenvironment. Reversing IDO1-mediated immunosuppression may strengthen the ICD-induced immune response. Herein, we developed a nanoenabled approach for IDO1 pathway interference, which is accomplished by delivering IDO1 siRNA to both TDLNs and tumor tissues with the help of cationic lipid-assisted nanoparticles (CLANs). We demonstrated that the contemporaneous administration of OXA and CLANsiIDO1 could achieve synergetic antitumor effects via promoting dendritic cell maturation, increasing tumor-infiltrating T lymphocytes and decreasing the number of regulatory T cells in a subcutaneous colorectal tumor model. We further proved that this therapeutic strategy is applicable for the treatment of orthotopic pancreatic tumors and offers a strong immunological memory effect, which can provide protection against tumor rechallenge.

Development of "CLAN" Nanomedicine for Nucleic Acid Therapeutics.

Nucleic acid-based macromolecules have paved new avenues for the development of therapeutic interventions against a spectrum of diseases; however, their clinical translation is limited by successful delivery to the target site and cells. Therefore, numerous systems have been developed to overcome delivery challenges to nucleic acids. From the viewpoint of clinical translation, it is highly desirable to develop systems with clinically validated materials and controllability in synthesis. With this in mind, a cationic lipid assisted PEG-b-PLA nanoparticle (CLAN) is designed that is capable of protecting nucleic acids via encapsulation inside the aqueous core, and delivers them to target cells, while maintaining or improving nucleic acid function. The system is formulated from clinically validated components (PEG-b-PLA and its derivatives) and can be scaled-up for large scale manufacturing, offering potential for its future use in clinical applications. Here, the development and working mechanisms of CLANs, the ways to improve its delivery efficacy, and its application in various disease treatments are summarized. Finally, a prospective for the further development of CLAN is also discussed.

Synthesis of CaO2 Nanocrystals and Their Spherical Aggregates with Uniform Sizes for Use as a Biodegradable Bacteriostatic Agent.

As a solid precursor to O2 and hydrogen peroxide (H2 O2 ), calcium peroxide (CaO2 ) has found widespread use in applications related to disinfection and contaminant degradation. The lack of uniform nanoparticles, however, greatly limits the potential use of this material in other applications related to medicine. Here, a new route to the facile synthesis of CaO2 nanocrystals and their spherical aggregates with uniform, controllable sizes is reported. The synthesis involves the reaction between CaCl2 and H2 O2 to generate CaO2 primary nanocrystals of 2-15 nm in size in ethanol, followed by their aggregation into uniform, spherical particles with the aid of poly(vinyl pyrrolidone) (PVP). The average diameter of the spherical aggregates can be easily tuned in the range of 15-100 nm by varying the concentrations of CaCl2 and/or PVP. For the spherical aggregates with a smaller size, they release H2 O2 and O2 more quickly when exposed to water, resulting in superior antimicrobial activity. This study not only demonstrates a new route to the synthesis of uniform CaO2 nanocrystals and their spherical aggregates but also offers a promising bacteriostatic agent with biodegradability.

Comparison of the INTERGROWTH-21st standard and a new reference for head circumference at birth among newborns in Southern China.

BACKGROUND: Previous studies proposed that there were racial or ethnic disparities in fetal growth, challenging the use of international standards in specific populations. This study was to evaluate the validity of applying the INTERGROWTH-21st standard to a Chinese population for identifying abnormal head circumference (HC), in comparison with a newly generated local reference. METHODS: There were 24,257 singletons delivered by low-risk mothers in four perinatal health-care centers in Southern China. New HC reference was constructed and comparison in distribution of HC categories was performed between the INTERGROWTH-21st standard and new reference after applying these two tools in study population. Logistic regression was used to examine the association between abnormal HC and adverse neonatal outcomes. RESULTS: There were 4.40% of the newborns identified with microcephaly (HC > 2 standard deviation below the mean) using the INTERGROWTH-21st standard, comparing to the proportion of 2.83% using new reference. The newborns identified with microcephaly only by the INTERGROWTH-21st standard were not at a higher risk of adverse neonatal outcome, compared with those identified as non-microcephaly by both tools (OR 0.73, 95% CI 0.47-1.13). CONCLUSION: The new HC reference may be more appropriate for newborn assessment in Chinese populations than the INTERGROWTH-21st standard.

Cationic Polymeric Nanoparticle Delivering CCR2 siRNA to Inflammatory Monocytes for Tumor Microenvironment Modification and Cancer Therapy.

Accumulating evidence has confirmed that malignant tumors have a complex microenvironment, which consists of a heterogeneous collection of tumor cells and other cell subsets (including the full gamut of immune cells). Tumor-associated macrophages (TAMs), derived from circulating Ly6Chi monocytes, constitute the most substantial fraction of tumor-infiltrating immune cells in nearly all cancer types and contribute to tumor progression, vascularization, metastasis, immunosuppression, and therapeutic resistance. Interrupting monocyte recruitment to tumor tissues by disturbing pivotal signaling pathways (such as CCL2-CCR2) is viewed as one of the most promising avenues for tumor microenvironment manipulation and cancer therapy. One critical issue for monocyte-based therapy is to deliver therapeutic agents into monocytes efficiently. In the present study, we systematically investigated the relationship between the surface potential and the biodistribution of polymeric nanoparticles in monocytes in vivo, aiming to screen and identify an appropriate delivery system for monocyte targeting, and we found that cationic nanoparticles have a higher propensity to accumulate in monocytes compared with their neutral counterparts. We further demonstrated that siCCR2-encapsulated cationic nanoparticle (CNP/siCCR2) could modify immunosuppressive tumor microenvironment more efficiently and exhibit superior antitumor effect in an orthotopic murine breast cancer model.

Enzyme Degradable Hyperbranched Polyphosphoester Micellar Nanomedicines for NIR Imaging-Guided Chemo-Photothermal Therapy of Drug-Resistant Cancers.

Multidrug resistance (MDR) is the major cause for chemotherapy failure, which constitutes a formidable challenge in the field of cancer therapy. The synergistic chemo-photothermal treatment has been reported to be a potential strategy to overcome MDR. In this work, rationally designed enzyme-degradable, hyperbranched polyphosphoester nanomedicines were developed for reversing MDR via the codelivery of doxorubicin and IR-780 (hPPEDOX&IR) as combined chemo-photothermal therapy. The amphiphilic hyperbranched polyphosphoesters with phosphate bond as the branching point were synthesized via a simple but robust one-step polycondensation reaction. The self-assembled hPPEDOX&IR exhibited good serum stability, sustained release, preferable tumor accumulation, and enhanced drug influx of doxorubicin in resistant MCF-7/ADR cells. Moreover, the degradation of hPPEDOX&IR was accelerated in the presence of alkaline phosphatase, which was overexpressed in various cancers, resulting in the fast release of encapsulated doxorubicin. The enzyme-degradable polymer generated synergistic chemo-photothermal cytotoxicity against MCF-7/ADR cells and, thus, the efficient ablation of DOX-resistant tumor without regrowth. This delivery system may open a new avenue for codelivery of chemo- and photothermal therapeutics for MDR tumor therapy.