Efferocytosis and Respiratory Disease.

Cells are the smallest units that make up living organisms, which constantly undergo the processes of proliferation, differentiation, senescence and death. Dead cells need to be removed in time to maintain the homeostasis of the organism and keep it healthy. This process is called efferocytosis. If the process fails, this may cause different types of diseases. More and more evidence suggests that a faulty efferocytosis process is closely related to the pathological processes of respiratory diseases. In this review, we will first introduce the process and the related mechanisms of efferocytosis of the macrophage. Secondly, we will propose some methods that can regulate the function of efferocytosis at different stages of the process. Next, we will discuss the role of efferocytosis in different lung diseases and the related treatment approaches. Finally, we will summarize the drugs that have been applied in clinical practice that can act upon efferocytosis, in order to provide new ideas for the treatment of lung diseases.

PLGA-Based Micro/Nanoparticles: An Overview of Their Applications in Respiratory Diseases.

Respiratory diseases, such as asthma and chronic obstructive pulmonary disease (COPD), are critical areas of medical research, as millions of people are affected worldwide. In fact, more than 9 million deaths worldwide were associated with respiratory diseases in 2016, equivalent to 15% of global deaths, and the prevalence is increasing every year as the population ages. Due to inadequate treatment options, the treatments for many respiratory diseases are limited to relieving symptoms rather than curing the disease. Therefore, new therapeutic strategies for respiratory diseases are urgently needed. Poly (lactic-co-glycolic acid) micro/nanoparticles (PLGA M/NPs) have good biocompatibility, biodegradability and unique physical and chemical properties, making them one of the most popular and effective drug delivery polymers. In this review, we summarized the synthesis and modification methods of PLGA M/NPs and their applications in the treatment of respiratory diseases (asthma, COPD, cystic fibrosis (CF), etc.) and also discussed the research progress and current research status of PLGA M/NPs in respiratory diseases. It was concluded that PLGA M/NPs are the promising drug delivery vehicles for the treatment of respiratory diseases due to their advantages of low toxicity, high bioavailability, high drug loading capacity, plasticity and modifiability. And at the end, we presented an outlook on future research directions, aiming to provide some new ideas for future research directions and hopefully to promote their widespread application in clinical treatment.

Chronic exposure to low-level lipopolysaccharide dampens influenza-mediated inflammatory response via A20 and PPAR network.

Influenza A virus (IAV) infection leads to severe inflammation, and while epithelial-driven inflammatory responses occur via activation of NF-κB, the factors that modulate inflammation, particularly the negative regulators are less well-defined. In this study we show that A20 is a crucial molecular switch that dampens IAV-induced inflammatory responses. Chronic exposure to low-dose LPS environment can restrict this excessive inflammation. The mechanisms that this environment provides to suppress inflammation remain elusive. Here, our evidences show that chronic exposure to low-dose LPS suppressed IAV infection or LPS stimulation-induced inflammation in vitro and in vivo. Chronic low-dose LPS environment increases A20 expression, which in turn positively regulates PPAR-α and -γ, thus dampens the NF-κB signaling pathway and NLRP3 inflammasome activation. Knockout of A20 abolished the inhibitory effect on inflammation. Thus, A20 and its induced PPAR-α and -γ play a key role in suppressing excessive inflammatory responses in the chronic low-dose LPS environment.

The Abundance and Function of Neutrophils in the Endometriosis Systemic and Pelvic Microenvironment.

Endometriosis is a common inflammatory illness in which endometrial tissue grows outside the uterine cavity. Immune dysfunction is now widely acknowledged as the primary cause of endometriosis. The immune cell population represented by neutrophils is thought to play an essential role in the etiology, pathophysiology, and associated clinical outcome. There is growing evidence that neutrophils have a role in chronic and aseptic inflammatory diseases, and endometriosis patients have increased levels of neutrophils in plasma, peritoneal fluid, and ectopic endometrium. Here, we sought to review the function of neutrophils in the pathogenesis of endometriosis, with an emphasis on the role of neutrophils in regulating endometrial angiogenesis and the local inflammatory microenvironment.

Effects of Electrical Stimulation on Articular Cartilage Regeneration with a Focus on Piezoelectric Biomaterials for Articular Cartilage Tissue Repair and Engineering.

There is increasing evidence that chondrocytes within articular cartilage are affected by endogenous force-related electrical potentials. Furthermore, electrical stimulation (ES) promotes the proliferation of chondrocytes and the synthesis of extracellular matrix (ECM) molecules, which accelerate the healing of cartilage defects. These findings suggest the potential application of ES in cartilage repair. In this review, we summarize the pathogenesis of articular cartilage injuries and the current clinical strategies for the treatment of articular cartilage injuries. We then focus on the application of ES in the repair of articular cartilage in vivo. The ES-induced chondrogenic differentiation of mesenchymal stem cells (MSCs) and its potential regulatory mechanism are discussed in detail. In addition, we discuss the potential of applying piezoelectric materials in the process of constructing engineering articular cartilage, highlighting the important advances in the unique field of tissue engineering.

Melanin-like nanoparticles loaded with an angiotensin antagonist for an improved photothermal cancer therapy.

An abnormal tumor growth induces solid stress in tumors, thus reducing blood perfusion. As a result, the impaired blood perfusion, with dense interstitial matrix in tumors significantly reduces the penetration and efficacy of nanotherapeutics. In this study, we have developed a losartan-loaded polydopamine nanoparticle (PLST) for the enhanced delivery of nanoparticles to tumors and improved photothermal cancer therapy. Losartan, an angiotensin inhibitor, is also able to alleviate the solid stress in tumors. It was laden on polydopamine nanoparticles via π-π stacking and was released upon tumor extracellular acidity. PLST reduced collagen production in vitro along with the lowered expression of profibrotic factors of TGF-ß1, CCN2, and TIMP-1. The in vivo studies reveal that PLST reduced solid stress in tumors, and the amount of PLST accumulated in tumors was enhanced. The efficiency of the photothermal ablation of tumors was significantly enhanced by using PLST.

Melanin-like nanoparticles decorated with an autophagy-inducing peptide for efficient targeted photothermal therapy.

Photothermal therapy efficiently ablates tumors via hyperthermia but inevitably induces serious side effects including thermal damage to normal tissues, inflammations and enhanced risk of tumor metastasis. In this study, we fabricated a dual peptide decorated melanin-like nanoparticle for tumor-targeted and autophagy-promoted photothermal therapy in pursuit of improved cancer treatment. The multifunctional nanoparticle was composed of dual peptide RGD- and beclin 1-modified and PEGylated melanin-like polydopamine nanoparticles. Beclin 1-derived peptide modified on the nanoparticle up-regulated autophagy in cancer cells and further sensitized the tumors to photothermal ablation. RGD decorated on the particle surface enhanced the selectivity and cellular uptake of polydopamine nanoparticles by breast cancer cells. In vivo therapeutic experiments revealed that the tumor-targeted and autophagy promotion-associated photothermal therapy efficiently regressed tumors at a low temperature around 43 °C. The study provides a novel and efficient strategy to improve the efficiency of photothermal therapy via the up-regulation of autophagy in tumor cells.

A Carboxyl-Terminated Dendrimer Enables Osteolytic Lesion Targeting and Photothermal Ablation of Malignant Bone Tumors.

Malignant bone tumor accompanied by tumor-associated osteolysis remains a challenging task in clinical practice. Nanomedicines engineered with bone-targeting ligands, such as alendronate and pamidronate, are developed for targeted delivery of therapeutic agents to bone tumors. However, these targeting strategies usually show relatively poor selectivity toward the healthy skeletons and the osteolytic lesions because of the high binding affinity of bisphosphonates with all the bone tissues. Here, we reported a carboxyl-terminated dendrimer as the candidate to preferentially deliver therapeutic nanoparticles to the osteolytic lesions in a malignant bone tumor model. The high density of carboxyl groups on dendrimer surface endow the polymer with natural bone-binding capability. The dendrimer encapsulated with platinum nanoparticle predominantly accumulates at the osteolytic lesions around bone tumors rather than at healthy bone tissues in vivo. The therapeutic experiments reveal that the dendrimer-mediated photothermal therapy efficiently suppresses bone tumors and osteolysis, and the anionic polymer exhibits minimal cytotoxicity and hematologic toxicity. The results suggest that the carboxyl-terminated dendrimer is a promising candidate for selective delivery of therapeutics to the osteolytic lesions and photothermal treatment of malignant bone tumors.

One stone with two birds: Phytic acid-capped platinum nanoparticles for targeted combination therapy of bone tumors.

Targeted drug delivery to malignant bone lesions remains a challenging task in the treatment of bone tumors. In this article, we reported a naturally occurring phytic acid (PA) with both bone-targeting capability and anticancer activity. The PA-capped platinum nanoparticles showed high affinity to hydroxyapatite in vitro and in vivo, and maintained both the inherent anticancer ability of PA and photothermal effect of platinum nanoparticles. PA-capped nanoparticles displayed a 4-fold higher accumulation in the osteolytic lesions than sodium citrate-templated ones, and efficiently inhibited bone tumor growth and the tumor associated-osteolysis upon exposure to a near-infrared light. This study provides a novel and efficient strategy to prepare bone-targeted nanoparticles with inherent anticancer activity for combination therapy of malignant bone tumors.

Autophagy inhibition enabled efficient photothermal therapy at a mild temperature.

The heterogeneously-distributed hyperthermia in nanomaterial-mediated photothermal therapy commonly results in incomplete tumor eradication and serious damage of health tissue. Here, we found autophagy was activated in cancer cells underwent photothermal therapy and the inhibition of autophagy significantly enhanced the efficacy of photothermal killing of cancer cells. A formulation of chloroquine-loaded polydopamine nanoparticles was developed for sensitized photothermal cancer therapy, and the in vitro and in vivo study demonstrated that inhibition of autophagy remarkably augmented the efficacy of photothermal therapy, leading to efficient tumor suppression at a mild temperature. The regulation of autophagy provides a new route to increase the efficacy of photothermal cancer therapy.

Hyaluronic Acid-Encapsulated Platinum Nanoparticles for Targeted Photothermal Therapy of Breast Cancer.

Targeted photothermal therapy (PTT) can improve the therapeutic outcomes and reduce side effects in cancer treatment. However, additional functionality means additional synthetic steps, increased risk of toxicity and complex behavior and effects in vivo. Herein, we developed a one-pot method to prepare tumor-targeted photothermal nanoparticles. Hyaluronic acid (HA), an anionic glycosaminoglycan that targets tumors via overexpressed cluster determinant 44 (CD44), was used as a polymer stabilizer to synthesize HA-encapsulated platinum nanoparticles (HA/Pt). The in vitro experiments demonstrated that HA/Pt were more efficiently internalized by cancer cells overexpressing CD44 compared with the non-tumor targeting alginate acid-encapsulated Pt nanoparticles (AA/Pt). The in vivo studies revealed that HA/Pt accumulated more in CD44-overexpressing tumor than AA/Pt, and more efficiently inhibited tumor growth via PTT. Our study developed an innovative method for facile fabrication of tumor-targeting photothermal nanoparticles.

Osteotropic peptide-mediated bone targeting for photothermal treatment of bone tumors.

The treatment of bone tumors is a challenging problem due to the inefficient delivery of therapeutics to bone and the bone microenvironment-associated tumor resistance to chemo- and radiotherapy. Here, we developed a bone-targeted nanoparticle, aspartate octapeptide-modified dendritic platinum-copper alloy nanoparticle (Asp-DPCN), for photothermal therapy (PTT) of bone tumors. Asp-DPCN showed much higher affinity toward hydroxyapatite and bone fragments than the non-targeted DPCN in vitro. Furthermore, Asp-DPCN accumulated more efficiently around bone tumors in vivo, and resulted in a higher temperature in bone tumors during PTT. Finally, Asp-DPCN-mediated PTT not only efficiently depressed the tumor growth but also significantly reduced the osteoclastic bone destruction. Our study developed a promising therapeutic approach for the treatment of bone tumors.

A thermo-degradable hydrogel with light-tunable degradation and drug release.

The development of thermo-degradable hydrogels is of great importance in drug delivery. However, it still remains a huge challenge to prepare thermo-degradable hydrogels with inherent degradation, reproducible, repeated and tunable dosing. Here, we reported a thermo-degradable hydrogel that is rapidly degraded above 44 °C by a facile chemistry. Besides thermo-degradability, the hydrogel also undergoes rapid photolysis with ultraviolet light. By embedding photothermal nanoparticles or upconversion nanoparticles into the gel, it can release the entrapped cargoes such as dyes, enzymes and anticancer drugs in an on-demand and dose-tunable fashion upon near-infrared light exposure. The smart hydrogel works well both in vitro and in vivo without involving sophisticated syntheses, and is well suited for clinical cancer therapy due to the high transparency and non-invasiveness features of near-infrared light.

MDM2 knockdown mediated by a triazine-modified dendrimer in the treatment of non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and the five-year survival rate is lower in advanced NSCLC patients. Chemotherapy is a widely used strategy in NSCLC treatment, but is usually limited by poor therapeutic efficacy and adverse effects. Therefore, a new therapeutic regimen is needed for NSCLC treatment. Gene therapy is a new strategy in the treatment of NSCLC. However, the lack of efficient and low toxic vectors remains the major obstacle. Here, we developed a biocompatible dendrimer as a non-viral vector for the delivery of mouse double minute2 (MDM2) siRNA in vitro and in vivo to treat NSCLC. The triazine-modified dendrimer efficiently stimulates the down-regulation of MDM2 gene in NSCLC PC9 cells, which induces significant cell apoptosis through the activation of apoptosis markers such as caspase-8 and poly(ADP-ribose) polymerase (PARP) cleavage. Furthermore, the dendrimer/MDM2 siRNA polyplexes showed excellent activity in the inhibition of tumor growth in a PC9 xenograft tumor model. These results suggested that inhibition the expression of MDM2 might be a potential target in NSCLC treatment.

Dendrimer-Templated Ultrasmall and Multifunctional Photothermal Agents for Efficient Tumor Ablation.

Ultrasmall and multifunctional nanoparticles are highly desirable for photothermal cancer therapy, but the synthesis of these nanoparticles remains a huge challenge. Here, we used a dendrimer as a template to synthesize ultrasmall photothermal agents and further modified them with multifunctional groups. Dendrimer-encapsulated nanoparticles (DENPs) including copper sulfide, platinum, and palladium nanoparticles possessed a sub-5 nm size and exhibited an excellent photothermal effect. DENPs were further modified with TAT or RGD peptides to facilitate their cellular uptake and targeting delivery to tumors. They were also decorated with fluorescent probes for real-time imaging and tracking of the particles' distribution. The in vivo study revealed RGD-modified DENPs efficiently reduced the tumor growth upon near-infrared irradiation. In all, our study provides a facile and flexible scaffold to prepare ultrasmall and multifunctional photothermal agents.