Nitric oxide nano-reactor DNMF/PLGA enables tumor vascular microenvironment and chemo-hyperthermia synergetic therapy.

BACKGROUND: Breast cancer ranks first among malignant tumors, of which triple-negative breast cancer (TNBC) is characterized by its highly invasive behavior and the worst prognosis. Timely diagnosis and precise treatment of TNBC are substantially challenging. Abnormal tumor vessels play a crucial role in TNBC progression and treatment. Nitric oxide (NO) regulates angiogenesis and maintains vascular homeostasis, while effective NO delivery can normalize the tumor vasculature. Accordingly, we have proposed here a tumor vascular microenvironment remodeling strategy based on NO-induced vessel normalization and extracellular matrix collagen degradation with multimodality imaging-guided nanoparticles against TNBC called DNMF/PLGA. RESULTS: Nanoparticles were synthesized using a chemotherapeutic agent doxorubicin (DOX), a NO donor L-arginine (L-Arg), ultrasmall spinel ferrites (MnFe2O4), and a poly (lactic-co-glycolic acid) (PLGA) shell. Nanoparticle distribution in the tumor was accurately monitored in real-time through highly enhanced magnetic resonance imaging and photoacoustic imaging. Near-infrared irradiation of tumor cells revealed that MnFe2O4 catalyzes the production of a large amount of reactive oxygen species (ROS) from H2O2, resulting in a cascade catalysis of L-Arg to trigger NO production in the presence of ROS. In addition, DOX activates niacinamide adenine dinucleotide phosphate oxidase to generate and supply H2O2. The generated NO improves the vascular endothelial cell integrity and pericellular contractility to promote vessel normalization and induces the activation of endogenous matrix metalloproteinases (mainly MMP-1 and MMP-2) so as to promote extravascular collagen degradation, thereby providing an auxiliary mechanism for efficient nanoparticle delivery and DOX penetration. Moreover, the chemotherapeutic effect of DOX and the photothermal effect of MnFe2O4 served as a chemo-hyperthermia synergistic therapy against TNBC. CONCLUSION: The two therapeutic mechanisms, along with an auxiliary mechanism, were perfectly combined to enhance the therapeutic effects. Briefly, multimodality image-guided nanoparticles provide a reliable strategy for the potential application in the fight against TNBC.

Potentiating dual-directional immunometabolic regulation with nanomedicine to enhance anti-tumor immunotherapy following incomplete photothermal ablation.

Photothermal therapy (PTT) is a promising cancer treatment method due to its ability to induce tumor-specific T cell responses and enhance therapeutic outcomes. However, incomplete PTT can leave residual tumors that often lead to new metastases and decreased patient survival in clinical scenarios. This is primarily due to the release of ATP, a damage-associated molecular pattern that quickly transforms into the immunosuppressive metabolite adenosine by CD39, prevalent in the tumor microenvironment, thus promoting tumor immune evasion. This study presents a photothermal nanomedicine fabricated by electrostatic adsorption among the Fe-doped polydiaminopyridine (Fe-PDAP), indocyanine green (ICG), and CD39 inhibitor sodium polyoxotungstate (POM-1). The constructed Fe-PDAP@ICG@POM-1 (FIP) can induce tumor PTT and immunogenic cell death when exposed to a near-infrared laser. Significantly, it can inhibit the ATP-adenosine pathway by dual-directional immunometabolic regulation, resulting in increased ATP levels and decreased adenosine synthesis, which ultimately reverses the immunosuppressive microenvironment and increases the susceptibility of immune checkpoint blockade (aPD-1) therapy. With the aid of aPD-1, the dual-directional immunometabolic regulation strategy mediated by FIP can effectively suppress/eradicate primary and distant tumors and evoke long-term solid immunological memory. This study presents an immunometabolic control strategy to offer a salvage option for treating residual tumors following incomplete PTT.

Smart responsive Fe/Mn nanovaccine triggers liver cancer immunotherapy via pyroptosis and pyroptosis-boosted cGAS-STING activation.

BACKGROUND: The prognosis for hepatocellular carcinoma (HCC) remains suboptimal, characterized by high recurrence and metastasis rates. Although metalloimmunotherapy has shown potential in combating tumor proliferation, recurrence and metastasis, current apoptosis-based metalloimmunotherapy fails to elicit sufficient immune response for HCC. RESULTS: A smart responsive bimetallic nanovaccine was constructed to induce immunogenic cell death (ICD) through pyroptosis and enhance the efficacy of the cGAS-STING pathway. The nanovaccine was composed of manganese-doped mesoporous silica as a carrier, loaded with sorafenib (SOR) and modified with MIL-100 (Fe), where Fe3+, SOR, and Mn2+ were synchronized and released into the tumor with the help of the tumor microenvironment (TME). Afterward, Fe3+ worked synergistically with SOR-induced immunogenic pyroptosis (via both the classical and nonclassical signaling pathways), causing the outflow of abundant immunogenic factors, which contributes to dendritic cell (DC) maturation, and the exposure of double-stranded DNA (dsDNA). Subsequently, the exposed dsDNA and Mn2+ jointly activated the cGAS-STING pathway and induced the release of type I interferons, which further led to DC maturation. Moreover, Mn2+-related T1 magnetic resonance imaging (MRI) was used to visually evaluate the smart response functionality of the nanovaccine. CONCLUSION: The utilization of metallic nanovaccines to induce pyroptosis-mediated immune activation provides a promising paradigm for HCC treatment.

Advances in imaging of the lacrimal gland in Sjögren's syndrome: A narrative review.

Due to lymphocytic infiltration of the salivary and lacrimal glands, Sjogren's syndrome (SS), a systemic autoimmune illness that mostly affects the exocrine glands, causes dry mouth (xerostomia) and dry eyes (xerophthalmia). Additionally, SS is associated with various comorbidities such as cardiovascular diseases, infections, musculoskeletal diseases, and cancers. Among patients with SS, xerophthalmia frequently arises as a complication, leading to insufficient tear production or rapid tear evaporation, thereby causing discomfort, irritation, and a gritty sensation in the eyes. This article aims to examine recent advancements in the imaging of the lacrimal gland in Sjögren's syndrome and briefly discusses the utilization of various imaging examinations for the lacrimal gland in this particular disease.

Bi-DTPA, a potential CT-guided radiation sensitizer.

The therapeutic effects and application of radiotherapy are restricted to some extent due to low radiosensitivity of tumor tissues and adverse effects by excess dosage. Current radiosensitizers are confronted with problems in clinical translation because of complicated manufacture technique and high cost. In this research, we have synthesized a radiosensitizer with advantages in low cost and mass production, which could be applied to CT imaging and enhanced radiotherapy in breast cancer, namely Bi-DTPA. It not only enhanced tumor CT imaging which resulted in better therapeutic accuracy, but also realized radiotherapy sensitization by producing massive ROS and inhibit tumor proliferation, providing a sound perspective in the clinical translation of the radiosensitizer.

NIR Activated Multimodal Therapeutics Based on Metal-Phenolic Networks-Functionalized Nanoplatform for Combating against Multidrug Resistance and Metastasis.

Multidrug resistance (MDR) and metastasis in cancer have become increasingly serious problems since antitumor efficiency is greatly restricted by a single therapeutic modality and the insensitive tumor microenvironment (TME). Herein, metal-phenolic network-functionalized nanoparticles (t-P@TFP NPs) are designed to realize multiple therapeutic modalities and reshape the TME from insensitive to sensitive under multimodal imaging monitoring. After a single irradiation, a near-infrared laser-activated multistage reaction occurs. t-P@TFP NPs trigger the phase transition of perfluoropentane (PFP) to release tannic acid (TA)/ferric ion (Fe3+ )-coated paclitaxel (PTX) and cause hyperthermia in the tumor region to efficiently kill cancer cells. Additionally, PTX is released after the disassembly of the TA-Fe3+ film by the abundant adenosine triphosphate (ATP) in the malignant tumor, which concurrently inhibits ATP-dependent drug efflux to improve sensitivity to chemotherapeutic agents. Furthermore, hyperthermia-induced immunogenic cell death (ICD) transforms "cold" tumors into "hot" tumors with the assistance of PD-1/PD-L1 blockade to evoke antitumor immunogenicity. This work carefully reveals the mechanisms underlying the abilities of these multifunctional NPs, providing new insights into combating the proliferation and metastasis of multidrug-resistant tumors.

Ultrasound-based deep learning in the establishment of a breast lesion risk stratification system: a multicenter study.

OBJECTIVES: To establish a breast lesion risk stratification system using ultrasound images to predict breast malignancy and assess Breast Imaging Reporting and Data System (BI-RADS) categories simultaneously. METHODS: This multicenter study prospectively collected a dataset of ultrasound images for 5012 patients at thirty-two hospitals from December 2018 to December 2020. A deep learning (DL) model was developed to conduct binary categorization (benign and malignant) and BI-RADS categories (2, 3, 4a, 4b, 4c, and 5) simultaneously. The training set of 4212 patients and the internal test set of 416 patients were from thirty hospitals. The remaining two hospitals with 384 patients were used as an external test set. Three experienced radiologists performed a reader study on 324 patients randomly selected from the test sets. We compared the performance of the DL model with that of three radiologists and the consensus of the three radiologists. RESULTS: In the external test set, the DL model achieved areas under the receiver operating characteristic curve (AUCs) of 0.980 and 0.945 for the binary categorization and six-way categorizations, respectively. In the reader study set, the DL BI-RADS categories achieved a similar AUC (0.901 vs. 0.933, p = 0.0632), sensitivity (90.98% vs. 95.90%, p = 0.1094), and accuracy (83.33% vs. 79.01%, p = 0.0541), but higher specificity (78.71% vs. 68.81%, p = 0.0012) than those of the consensus of the three radiologists. CONCLUSIONS: The DL model performed well in distinguishing benign from malignant breast lesions and yielded outcomes similar to experienced radiologists. This indicates the potential applicability of the DL model in clinical diagnosis. KEY POINTS: • The DL model can achieve binary categorization for benign and malignant breast lesions and six-way BI-RADS categorizations for categories 2, 3, 4a, 4b, 4c, and 5, simultaneously. • The DL model showed acceptable agreement with radiologists for the classification of breast lesions. • The DL model performed well in distinguishing benign from malignant breast lesions and had promise in helping reduce unnecessary biopsies of BI-RADS 4a lesions.

Piezoelectric enhanced sulfur doped graphdiyne nanozymes for synergistic ferroptosis-apoptosis anticancer therapy.

Graphdiyne has excellent potential due to its enzymatic properties. Metal-free sulfur-doped Graphdiyne (S-GDY) has piezoelectric characteristics, and ultrasonic excitation of S-GDY enhances peroxidase activity. It can turn hydrogen peroxide into toxic hydroxyl radicals and induce apoptosis in 4T1 cells. More importantly, the ultrasound (US) enhanced nanozyme induced 4T1 cell ferroptosis by promoting an imbalanced redox reaction due to glutathione depletion and glutathione peroxidase 4 inactivation. S-GDY exhibited enhanced nanozyme activity in vitro and in vivo that may directly trigger apoptosis-ferroptosis for effective tumor therapy. Altogether, this study was expected to provide new insights into the design of piezoelectric catalytic nanozyme and expand their application in the catalytic therapy of tumors.

Photochemically-driven highly efficient intracellular delivery and light/hypoxia programmable triggered cancer photo-chemotherapy.

BACKGROUND: Using nanotechnology to improve the efficiency of tumor treatment represents a major research interest in recent years. However, there are paradoxes and obstacles in using a single nanoparticle to fulfill all the requirements of complex tumor treatment. RESULTS: In this paper, a programmed-triggered nanoplatform (APP NPs), which is sequentially responsive to light and hypoxia, is rationally integrated for photoacoustic (PA) imaging-guided synergistic cancer photo-chemotherapy. The nanoplatform is constructed by in situ hybridization of dopamine monomer in the skeleton of PCN-224 and loading prodrug banoxantrone (AQ4N). Upon first-stage irradiation with a 660 nm laser, cellular internalization was effectively promoted by a photosensitizer-mediated photochemical effect. Furthermore, under second-stage irradiation, APP NPs exhibit a notably high photothermal conversion efficiency and sufficient reactive oxygen species (ROS) production for photothermal therapy (PTT) and photodynamic therapy (PDT), respectively, which not only triggers rapid intercellular drug release but also consequently aggravates tumor hypoxia levels, and aggravated hypoxia can further active the cytotoxicity of AQ4N for chemotherapy. Both in vitro and in vivo studies confirm that the dual-stage light guided photo-chemotherapy strategy exhibits a greatly enhanced anticancer effects and superior therapeutic safety. CONCLUSION: This work represents a versatile strategy to construct a dual-stage light induced PDT/PTT and hypoxia-activated chemotherapy nanoplatform and will be promising for the development of multistimuli-responsive nanosystems with programmable functions for precise cancer therapy.

A hybrid nanopharmaceutical for specific-amplifying oxidative stress to initiate a cascade of catalytic therapy for pancreatic cancer.

BACKGROUND: Oxidative stress (OS) induced by an imbalance of oxidants and antioxidants is an important aspect in anticancer therapy, however, as an adaptive response, excessive glutathione (GSH) in the tumor microenvironment (TME) acts as an antioxidant against high reactive oxygen species (ROS) levels and prevents OS damage to maintain redox homoeostasis, suppressing the clinical efficacy of OS-induced anticancer therapies. RESULTS: A naturally occurring ROS-activating drug, galangin (GAL), is introduced into a Fenton-like catalyst (SiO2@MnO2) to form a TME stimulus-responsive hybrid nanopharmaceutical (SiO2-GAL@MnO2, denoted SG@M) for enhancing oxidative stress. Once exposed to TME, as MnO2 responds and consumes GSH, the released Mn2+ converts endogenous hydrogen peroxide (H2O2) into hydroxyl radicals (·OH), which together with the subsequent release of GAL from SiO2 increases ROS. The "overwhelming" ROS cause OS-mediated mitochondrial malfunction with a decrease in mitochondrial membrane potential (MMP), which releases cytochrome c from mitochondria, activates the Caspase 9/Caspase 3 apoptotic cascade pathway. Downregulation of JAK2 and STAT3 phosphorylation levels blocks the JAK2/STAT3 cell proliferation pathway, whereas downregulation of Cyclin B1 protein levels arrest the cell cycle in the G2/M phase. During 18 days of in vivo treatment observation, tumor growth inhibition was found to be 62.7%, inhibiting the progression of pancreatic cancer. Additionally, the O2 and Mn2+ released during this cascade catalytic effect improve ultrasound imaging (USI) and magnetic resonance imaging (MRI), respectively. CONCLUSION: This hybrid nanopharmaceutical based on oxidative stress amplification provides a strategy for multifunctional integrated therapy of malignant tumors and image-visualized pharmaceutical delivery.

Tumor-penetrating nanoplatform with ultrasound "unlocking" for cascade synergistic therapy and visual feedback under hypoxia.

BACKGROUND: Combined therapy based on the effects of cascade reactions of nanoplatforms to combat specific solid tumor microenvironments is considered a cancer treatment strategy with transformative clinical value. Unfortunately, an insufficient O2 supply and the lack of a visual indication hinder further applications of most nanoplatforms for solid tumor therapy. RESULTS: A visualizable nanoplatform of liposome nanoparticles loaded with GOD, H(Gd), and PFP and grafted with the peptide tLyP-1, named tLyP-1H(Gd)-GOD@PFP, was constructed. The double-domain peptide tLyP-1 was used to specifically target and penetrate the tumor cells; then, US imaging, starvation therapy and sonodynamic therapy (SDT) were then achieved by the ultrasound (US)-activated cavitation effect under the guidance of MR/PA imaging. GOD not only deprived the glucose for starvation therapy but also produced H2O2, which in coordination with 1O2 produced by H(Gd), enable the effects of SDT to achieve a synergistic therapeutic effect. Moreover, the synergistic therapy was enhanced by O2 from PFP and low-intensity focused ultrasound (LIFU)-accelerated redox effects of the GOD. The present study demonstrated that the nanoplatform could generate a 3.3-fold increase in ROS, produce a 1.5-fold increase in the maximum rate of redox reactions and a 2.3-fold increase in the O2 supply in vitro, and achieve significant tumor inhibition in vivo. CONCLUSION: We present a visualizable nanoplatform with tumor-penetrating ability that can be unlocked by US to overcome the current treatment problems by improving the controllability of the O2 supply, which ultimately synergistically enhanced cascade therapy.

Targeted Degradation of PD-L1 and Activation of the STING Pathway by Carbon-Dot-Based PROTACs for Cancer Immunotherapy.

Proteolysis targeting chimeras (PROTACs) technology is an emerging approach to degrade disease-associated proteins. Here, we report carbon-dot (CD)-based PROTACs (CDTACs) that degrade membrane proteins via the ubiquitin-proteasome system. CDTACs can bind to programmed cell death ligand 1 (PD-L1), recruit cereblon (CRBN) to induce PD-L1 ubiquitination, and degrade them with proteasomes. Fasting-mimicking diet (FMD) is also used to enhance the cellular uptake and proteasome activity. More than 99 % or 90 % of PD-L1 in CT26 or B16-F10 tumor cells can be degraded by CDTACs, respectively. Furthermore, CDTACs can activate the stimulator of interferon genes (STING) pathway to trigger immune responses. Thus, CDTACs with FMD treatment effectively inhibit the growth of CT26 and B16-F10 tumors. Compared with small-molecule-based PROTACs, CDTACs offer several advantages, such as efficient membrane protein degradation, targeted tumor accumulation, immune system activation, and in vivo detection.

Near-Infrared II Nanoadjuvant-Mediated Chemodynamic, Photodynamic, and Photothermal Therapy Combines Immunogenic Cell Death with PD-L1 Blockade to Enhance Antitumor Immunity.

The efficacy of immune checkpoint inhibition in inducing death of cancer cells is affected by the immunosuppressive "cold" tumor microenvironment, which results in a poor response by the patient's antitumor immune system. However, the immunomodulatory effects of immunogenic cell death in response to irritation by heat energy and reactive oxygen species (ROS) can switch the tumor microenvironment from "cold" to "hot." This study has developed a nanoadjuvant for immune therapy using iron tungsten oxide (FeWOx)-based nanosheets with surface PEGylation (FeWOx-PEG). This FeWOx-PEG nanoadjuvant serves as a chemodynamic reagent via the Fenton reaction and acts as a photosensitizer for photodynamic and photothermal therapy under near-infrared II laser irradiation; however, it could also be used to augment tumor-infiltrating T-cells and provoke a systemic antitumor immune response by combining the immunogenic cell death triggered by ROS and photothermal therapy with the immune checkpoint blockade. This research demonstrates that application of the FeWOx-PEG nanoadjuvant under the guidance of magnetic resonance/computed tomography/photoacoustic imaging can eliminate the primary tumor and suppress the growth of distant tumors.

Antithrombotic Therapy by Regulating the ROS-Mediated Thrombosis Microenvironment and Specific Nonpharmaceutical Thrombolysis Using Prussian Blue Nanodroplets.

In thrombotic diseases, the effects of reactive oxygen species (ROS)-mediated oxidative stress as a "perpetrator" in thrombosis must be resolved. Accordingly, an insufficient understanding of thrombus therapy prompted the authors to pursue a more comprehensive and efficient antithrombotic treatment strategy. A Prussian blue (PB)-based nanodroplet system (PB-PFP@PC) is designed using PB and perfluorinated pentane (PFP) in the core, and a targeting peptide (CREKA, Cys-Arg-Glu-Lys-Ala) is attached to poly(lactic-coglycolic acid) (PLGA) as the delivery carrier shell. Upon near-infrared (NIR) laser irradiation, PB and PFP jointly achieve an unprecedented dual strategy for drug-free thrombolysis: photothermal therapy (PTT) combined with optical droplet vaporization (ODV). PB, a nanoenzyme, also regulates the vascular microenvironment via its antioxidant activity to continuously scavenge abnormally elevated ROS and correspondingly reduce inflammatory factors in the thrombus site. This study provides a demonstration of not only the potential of ODV in thrombus therapy but also the mechanism underlying PTT thrombolysis due to thermal ablation-induced fibrin network structural damage. Moreover, PB catalyzes ROS to generate oxygen (O2 ), which combines with the ODV effect, enhancing the ultrasound signal. Thus, regulation of the thrombosis microenvironment combined with specific nonpharmaceutical thrombolysis by PB nanodroplets provides a more comprehensive and efficient antithrombotic therapeutic strategy.

ROS-responsive liposomes as an inhaled drug delivery nanoplatform for idiopathic pulmonary fibrosis treatment via Nrf2 signaling.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic disease with pathophysiological characteristics of transforming growth factor-ß (TGF-ß), and reactive oxygen species (ROS)-induced excessive fibroblast-to-myofibroblast transition and extracellular matrix deposition. Macrophages are closely involved in the development of fibrosis. Nuclear factor erythroid 2 related factor 2 (Nrf2) is a key molecule regulating ROS and TGF-ß expression. Therefore, Nrf2 signaling modulation might be a promising therapy for fibrosis. The inhalation-based drug delivery can reduce systemic side effects and improve therapeutic effects, and is currently receiving increasing attention, but direct inhaled drugs are easily cleared and difficult to exert their efficacy. Therefore, we aimed to design a ROS-responsive liposome for the Nrf2 agonist dimethyl fumarate (DMF) delivery in the fibrotic lung. Moreover, we explored its therapeutic effect on pulmonary fibrosis and macrophage activation. RESULTS: We synthesized DMF-loaded ROS-responsive DSPE-TK-PEG@DMF liposomes (DTP@DMF NPs). DTP@DMF NPs had suitable size and negative zeta potential and excellent capability to rapidly release DMF in a high-ROS environment. We found that macrophage accumulation and polarization were closely related to fibrosis development, while DTP@DMF NPs could attenuate macrophage activity and fibrosis in mice. RAW264.7 and NIH-3T3 cells coculture revealed that DTP@DMF NPs could promote Nrf2 and downstream heme oxygenase-1 (HO-1) expression and suppress TGF-ß and ROS production in macrophages, thereby reducing fibroblast-to-myofibroblast transition and collagen production by NIH-3T3 cells. In vivo experiments confirmed the above findings. Compared with direct DMF instillation, DTP@DMF NPs treatment presented enhanced antifibrotic effect. DTP@DMF NPs also had a prolonged residence time in the lung as well as excellent biocompatibility. CONCLUSIONS: DTP@DMF NPs can reduce macrophage-mediated fibroblast-to-myofibroblast transition and extracellular matrix deposition to attenuate lung fibrosis by upregulating Nrf2 signaling. This ROS-responsive liposome is clinically promising as an ideal delivery system for inhaled drug delivery.

A non-invasive nanoparticles for multimodal imaging of ischemic myocardium in rats.

BACKGROUND: Ischemic heart disease (IHD) is the leading cause of morbidity and mortality worldwide, and imposes a serious economic load. Thus, it is crucial to perform a timely and accurate diagnosis and monitoring in the early stage of myocardial ischemia. Currently, nanoparticles (NPs) have emerged as promising tools for multimodal imaging, because of their advantages of non-invasion, high-safety, and real-time dynamic imaging, providing valuable information for the diagnosis of heart diseases. RESULTS: In this study, we prepared a targeted nanoprobe (termed IMTP-Fe3O4-PFH NPs) with enhanced ultrasound (US), photoacoustic (PA), and magnetic resonance (MR) performance for direct and non-invasive visual imaging of ischemic myocardium in a rat model. This successfully designed nanoprobe had excellent properties such as nanoscale size, good stability, phase transformation by acoustic droplet vaporization (ADV), and favorable safety profile. Besides, it realized obvious targeting performance toward hypoxia-injured cells as well as model rat hearts. After injection of NPs through the tail vein of model rats, in vivo imaging results showed a significantly enhanced US/PA/MR signal, well indicating the remarkable feasibility of nanoprobe to distinguish the ischemic myocardium. CONCLUSIONS: IMTP-Fe3O4-PFH NPs may be a promising nanoplatform for early detection of ischemic myocardium and targeted treatment under visualization for the future.

A novel targeted multifunctional nanoplatform for visual chemo-hyperthermia synergy therapy on metastatic lymph nodes via lymphatic delivery.

BACKGROUND: Distant metastasis to vital organs is the major contributor to breast cancer mortality, and regional lymph node metastasis is an important facilitator of distant metastasis and recurrence in this cancer. The early diagnosis and precise treatment of lymph node metastasis are crucial for staging and prognosis in breast cancer. Herein, we report a visualized precision medicine nanoplatform of metastatic lymph nodes for ultrasonic/photoacoustic (US/PA) dual modal imaging-guided in situ targeted hyperthermia-combined chemotherapy. RESULTS: Carbon nanoparticles (CNs), approved by the China Food and Drug Administration, were loaded with docetaxel and rationally combined with anti-hypoxia-inducible factor 1α antibody-modified poly (lactic-co-glycolic acid) (PLGA) nanoparticles to achieve the combination of passive targeting at the lymph nodes and intracellular targeting at HIF 1α factor. The accumulation and retention of nanoparticles in metastatic lymph nodes via lymphatic delivery were enhanced. Docetaxel could be effectively offloaded by CNs that have active carbon nanoparticles, and the PLGA membrane prevented drug leakage. The nanoparticles exhibited excellent photothermal performance with a photothermal conversion efficiency of 28.9%, killing tumor cells in metastatic lymph nodes through hyperthermia. In vitro and in vivo systematic evaluations revealed that hyperpyrexia triggered the rupture of nanoparticles caused by the phase transition of perfluorohexane, resulting in docetaxel release for achieving in situ hyperthermia-combined chemotherapy. CONCLUSIONS: The laser-triggered highly efficient in situ chemotherapy nanosystem achieves targeted synergistic chemo-hyperthermia treatment of metastatic lymph nodes, and lymphatic delivery represents a strategy to avoid additional injury caused by drugs entering the blood circulation.

Amplified antitumor efficacy by a targeted drug retention and chemosensitization strategy-based "combo" nanoagent together with PD-L1 blockade in reversing multidrug resistance.

BACKGROUND: Recent studies have demonstrated that multidrug resistance (MDR) is a critical factor in the low efficacy of cancer chemotherapy. The main mechanism of MDR arises from the overexpression of P-glycoprotein (P-gp), which actively enhances drug efflux and limits the effectiveness of chemotherapeutic agents. RESULTS: In this study, we fabricated a "combo" nanoagent equipping with triple synergistic strategies for enhancing antitumor efficacy against MDR cells. Tumor homing-penetrating peptide endows the nanosystem with targeting and penetrating capabilities in the first stage of tumor internalization. The abundant amine groups of polyethylenimine (PEI)-modified nanoparticles then trigger a proton sponge effect to promote endo/lysosomal escape, which enhances the intracellular accumulation and retention of anticancer drugs. Furthermore, copper tetrakis(4-carboxyphenyl)porphyrin (CuTCPP) encapsulated in the nanosystem, effectively scavenges endogenous glutathione (GSH) to reduce the detoxification mediated by GSH and sensitize the cancer cells to drugs, while simultaneously serving as a photoacoustic imaging (PAI) contrast agent for image visualization. Moreover, we also verify that these versatile nanoparticles in combination with PD-1/PD-L1 blockade therapy can not only activate immunological responses but also inhibit P-gp expression to obliterate primary and metastatic tumors. CONCLUSION: This work shows a significant enhancement in therapeutic efficacy against MDR cells and syngeneic tumors by using multiple MDR reversing strategies compared to an equivalent dose of free paclitaxel.

Cancer cell membrane-coated nanoparticles for bimodal imaging-guided photothermal therapy and docetaxel-enhanced immunotherapy against cancer.

BACKGROUND: Mono-therapeutic modality has limitations in combating metastatic lesions with complications. Although emerging immunotherapy exhibits preliminary success, solid tumors are usually immunosuppressive, leading to ineffective antitumor immune responses and immunotherapeutic resistance. The rational combination of several therapeutic modalities may potentially become a new therapeutic strategy to effectively combat cancer. RESULTS: Poly lactic-co-glycolic acid (PLGA, 50 mg) nanospheres were constructed with photothermal transduction agents (PTAs)-Prussian blue (PB, 2.98 mg) encapsulated in the core and chemotherapeutic docetaxel (DTX, 4.18 mg)/ immune adjuvant-imiquimod (R837, 1.57 mg) loaded in the shell. Tumor cell membranes were further coated outside PLGA nanospheres (designated "M@P-PDR"), which acted as "Nano-targeted cells" to actively accumulate in tumor sites, and were guided/monitored by photoacoustic (PA)/ magnetic resonance (MR) imaging. Upon laser irradiation, photothermal effects were triggered. Combined with DTX, PTT induced in situ tumor eradication. Assisted by the immune adjuvant R837, the maturation rate of DCs increased by 4.34-fold compared with that of the control. In addition, DTX polarized M2-phenotype tumor-associated macrophages (TAMs) to M1-phenotype, relieving the immunosuppressive TME. The proportion of M2-TAMs decreased from 68.57% to 32.80%, and the proportion of M1-TAMs increased from 37.02% to 70.81%. Integrating the above processes, the infiltration of cytotoxic T lymphocytes (CTLs) increased from 17.33% (control) to 35.5%. Primary tumors and metastasis were significantly inhibited when treated with "Nano-targeted cells"-based cocktail therapy. CONCLUSION: "Nano-targeted cells"-based therapeutic cocktail therapy is a promising approach to promote tumor regression and counter metastasis/recurrence.

Herceptin-decorated paclitaxel-loaded poly(lactide-co-glycolide) nanobubbles: ultrasound-facilitated release and targeted accumulation in breast cancers.

Ultrasound can promote the drug release from drug-loaded substances and alter the tumor local microenvironment to facilitate the transport of drug carriers into the tumor tissues. Based on the altered tumor microenvironment, nanobubbles (NBs) as drug carriers with surfaces functionalized with targeting ligands can reach the tumor sites, thereby increasing the efficacy of chemotherapy. Herein, paclitaxel (PTX)-loaded poly(lactide-co-glycolide) (PLGA) NBs are prepared as drug carriers with covalently conjugated herceptin (anti-HER2 monoclonal antibody) on the surface to guide the target. The effect of ultrasound on the drug release and targeting of the herceptin-conjugated drug-loaded nanobubbles (PTX-NBs-HER) on the cancerous cells is determined. The use of ultrasound significantly improves the cell targeting capability in vitro, and efficiency of enhanced permeability and retention in vivo. The combination of PTX-NBs-HER and ultrasound facilitates the release of PTX, as well as the uptake and cell apoptosis in vitro. The in vivo application of both PTX-NBs-HER and ultrasound enhances the PTX targeting and accumulation in breast cancers while reducing the transmission and distribution of PTX in healthy organs. The combination of ultrasound with PTX-NBs-HER as contrast agents and drug carriers affords an image-guided drug delivery system for the precise targeted therapy of tumors.