"Yin-Yang philosophy" for the design of anticancer drug delivery nanoparticles.

Understanding the in vivo transport process provides guidelines for designing ideal nanoparticles (NPs) with higher efficacy and fewer off-target effects. Many factors, such as particle size, morphology, surface potential, structural stability, and etc., may influence the delivering process of NPs due to the existence of various physiological barriers within the body. Herein, we summarise the distinct influences of NP physicochemical properties on the four consecutive in vivo transport steps: (1) navigating with bloodstream within blood vessels, (2) transport across vasculature walls into tumour tissues, (3) intratumoural transport through the interstitial space, and (4) cellular uptake & intracellular delivery by cancerous cells. We found that the philosophy behind the current consensus for NP design has certain similarities to the "Yin-Yang" theory in traditional Chinese culture. Almost all physicochemical properties, regardless of big or small sizes, long or short length, positive or negative zeta potentials, are double-edged swords. The balance of potential benefits and side effects, drug selectivity and accessibility should be fully considered when optimising particle design, similar to the "Yin-Yang harmony". This paper presents a comprehensive review of the advancements in NPs research, focusing on their distinct features in tumour targeting, drug delivery, and cell uptake. Additionally, it deliberates on future developmental trends and potential obstacles, thereby aiming to uncover the ways these characteristics influence the NPs' biological activity and provide theoretical guidance for the targeted delivery of NPs.

The development of a human Brucella mucosal vaccine: What should be considered?

Brucellosis is a chronic infectious disease that is zoonotic in nature. Brucella can infect humans through interactions with livestock, primarily via the digestive tract, respiratory tract, and oral cavity. This bacterium has the potential to be utilized as a biological weapon and is classified as a Category B pathogen by the Centers for Disease Control and Prevention. Currently, there is no approved vaccine for humans against Brucella, highlighting an urgent need for the development of a vaccine to mitigate the risks posed by this pathogen. Brucella primarily infects its host by adhering to and penetrating mucosal surfaces. Mucosal immunity plays a vital role in preventing local infections, clearing microorganisms from mucosal surfaces, and inhibiting the spread of pathogens. As mucosal vaccine strategies continue to evolve, the development of a safe and effective mucosal vaccine against Brucella appears promising.This paper reviews the immune mechanism of mucosal vaccines, the infection mechanism of Brucella, successful Brucella mucosal vaccines in animals, and mucosal adjuvants. Additionally, it elucidates targeting and optimization strategies for mucosal vaccines to facilitate the development of human vaccines against Brucella.

Using construction procurement strategy to achieve socioeconomic development objectives.

The procurement strategy for a construction project should provide the framework to achieve secondary procurement and socio-economic development objectives [2]. However, little attention has been focused on this in theory and practice. This paper addresses that gap by presenting a case study of the innovative targeting strategy developed and successfully implemented on a New Universities Project in South Africa to promote specified socioeconomic development objectives. Document analysis was used to examine how four socioeconomic development targets or key performance indicators, namely: local employment, skills development, local expenditure, and B-BBEE, were contractually integrated into the main works contracts. Four out of five framework contractors achieved the development targets, with low-performance damages applied in one case where the contractor failed to achieve all the development targets. The findings demonstrate how an appropriate construction procurement strategy that effectively integrates the packaging, targeting, and contracting strategies with effective systems for monitoring performance-based specifications, can play an essential role in promoting and realising socio-economic development objectives and social value through infrastructure projects.

The pharmacological role of Ginsenoside Rg3 in liver diseases: A review on molecular mechanisms.

Liver diseases are a significant global health burden and are among the most common diseases. Ginssennoside Rg3 (Rg3), which is one of the most abundant ginsenosides, has been found to have significant preventive and therapeutic effects against various types of diseases with minimal side effects. Numerous studies have demonstrated the significant preventive and therapeutic effects of Rg3 on various liver diseases such as viral hepatitis, acute liver injury, nonalcoholic liver diseases (NAFLD), liver fibrosis and hepatocellular carcinoma (HCC). The underlying molecular mechanism behind these effects is attributed to apoptosis, autophagy, antioxidant, anti-inflammatory activities, and the regulation of multiple signaling pathways. This review provides a comprehensive description of the potential molecular mechanisms of Rg3 in the development of liver diseases. The article focuses on the regulation of apoptosis, oxidative stress, autophagy, inflammation, and other related factors. Additionally, the review discusses combination therapy and liver targeting strategy, which can accelerate the translation of Rg3 from bench to bedside. Overall, this article serves as a valuable reference for researchers and clinicians alike.

Dbl family RhoGEFs in cancer: different roles and targeting strategies.

Small Ras homologous guanosine triphosphatase (Rho GTPase) family proteins are highly associated with tumorigenesis and development. As intrinsic exchange activity regulators of Rho GTPases, Rho guanine nucleotide exchange factors (RhoGEFs) have been demonstrated to be closely involved in tumor development and received increasing attention. They mainly contain two families: the diffuse B-cell lymphoma (Dbl) family and the dedicator of cytokinesis (Dock) family. More and more emphasis has been paid to the Dbl family members for their abnormally high expression in various cancers and their correlation to poor prognosis. In this review, the common and distinctive structures of Dbl family members are discussed, and their roles in cancer are summarized with a focus on Ect2, Tiam1/2, P-Rex1/2, Vav1/2/3, Trio, KALRN, and LARG. Significantly, the strategies targeting Dbl family RhoGEFs are highlighted as novel therapeutic opportunities for cancer.

Pathogen-Activated Macrophage Membrane Encapsulated CeO2 -TCPP Nanozyme with Targeted and Photo-Enhanced Antibacterial Therapy.

Nanozymes with peroxidase-mimic activity have recently emerged as effective strategies for eliminating infections. However, challenges in enhancing catalytic activities and the ability to target bacteria have hindered the broader application of nanozymes in bacterial infections. Herein, a novel nanozyme based on mesoporous CeO2 nanosphere and meso-tetra(4-carboxyphenyl)porphine (TCPP) encapsulated within pathogen-activated macrophage membranes, demonstrates photodynamic capability coupled with photo-enhanced chemodynamic therapy for selective and efficient antibacterial application against infected wounds. Interestingly, the expression of Toll-like receptors accordingly upregulates when macrophages are co-cultured with specific bacteria, thereby facilitating to recognition of the pathogen-associated molecular patterns originating from bacteria. The CeO2 not only serve as carriers for TCPP, but also exhibit intrinsic peroxidase-like catalytic activity. Consequently, Staphylococcus aureus (S. aureus)-activated macrophage membrane-coated CeO2 -TCPP (S-MM@CeO2 -TCPP) generated singlet oxygen, and simultaneously promoted photo-enhanced chemodynamic therapy, significantly boosting reactive oxygen species (ROS) to effectively eliminate bacteria. S-MM@CeO2 -TCPP specifically targeted S. aureus via Toll-like receptor, thereby directly disrupting bacterial structural integrity to eradicate S. aureus in vitro and relieve bacteria-induced inflammation to accelerate infected wound healing in vivo. By selectively targeting specific bacteria and effectively killing pathogens, such strategy provides a more efficient and reliable alternative for precise elimination of pathogens and inflammation alleviation in microorganism-infected wounds.

Potential role of Chinese medicine nanoparticles to treat coronary artery disease.

Coronary artery disease (CAD) is a leading cause of death worldwide, while conventional treatments such as percutaneous coronary intervention (PCI) have limitations. This review aims to explore the potential of nanoparticles loaded with Chinese medicine in the treatment of CAD. We conducted a comprehensive literature search to summarize the characteristics of nanovehicle systems, targeting strategies, and administration methods of various nanoparticles containing Chinese medicine for CAD treatment. Nanoparticle-based drug delivery systems, capable of delivering Chinese medicine, offer several advantages, including high targeting efficiency, prolonged half-life, and low systemic toxicity, making them promising for CAD treatment. Overall, nanoparticles containing Chinese medicine present a promising approach for the treatment of CAD.

An integrated overview of the immunosuppression features in the tumor microenvironment of pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies. It is characterized by a complex and immunosuppressive tumor microenvironment (TME), which is primarily composed of tumor cells, stromal cells, immune cells, and acellular components. The cross-interactions and -regulations among various cell types in the TME have been recognized to profoundly shape the immunosuppression features that meaningfully affect PDAC biology and treatment outcomes. In this review, we first summarize five cellular composition modules by integrating the cellular (sub)types, phenotypes, and functions in PDAC TME. Then we discuss an integrated overview of the cross-module regulations as a determinant of the immunosuppressive TME in PDAC. We also briefly highlight TME-targeted strategies that potentially improve PDAC therapy.

Engineering nanoparticle toolkits for mRNA delivery.

The concept of using mRNA to produce its own medicine in situ in the body makes it an ideal drug candidate, holding great potential to revolutionize the way we approach medicine. The unique characteristics of mRNA, as well as its customizable biomedical functions, call for the rational design of delivery systems to protect and transport mRNA molecules. In this review, a nanoparticle toolkit is presented for the development of mRNA-based therapeutics from a drug delivery perspective. Nano-delivery systems derived from either natural systems or chemical synthesis, in the nature of organic or inorganic materials, are summarised. Delivery strategies in controlling the tissue targeting and mRNA release, as well as the role of nanoparticles in building and boosting the activity of mRNA drugs, have also been introduced. In the end, our insights into the clinical and translational development of mRNA nano-drugs are presented.

Alcohol reshapes a liver premetastatic niche for cancer by extra- and intrahepatic crosstalk-mediated immune evasion.

Cancer metastatic organotropism is still a mystery. The liver is known to be susceptible to cancer metastasis and alcoholic injury. However, it is unclear whether and how alcohol facilitates liver metastasis and how to intervene. Here, we show that alcohol preferentially promotes liver metastasis in colon-cancer-bearing mice and post-surgery pancreatic cancer patients. The mechanism is that alcohol triggers an extra- and intrahepatic crosstalk to reshape an immunosuppressive liver microenvironment. In detail, alcohol upregulates extrahepatic IL-6 and hepatocellular IL-6 receptor expression, resulting in hepatocyte STAT3 signaling activation and downstream lipocalin-2 (Lcn2) upregulation. Furthermore, LCN2 promotes T cell-exhaustion neutrophil recruitment and cancer cell epithelial plasticity. In contrast, knocking out hepatocellular Stat3 or systemic Il6 in alcohol-treated mice preserves the liver microenvironment and suppresses liver metastasis. This mechanism is reflected in hepatocellular carcinoma patients, in that alcohol-associated signaling elevation in noncancerous liver tissue indicates adverse prognosis. Accordingly, we discover a novel application for BBI608, a small molecular STAT3 inhibitor that can prevent liver metastasis. BBI608 pretreatment protects the liver and suppresses alcohol-triggered premetastatic niche formation. In conclusion, under extra- and intrahepatic crosstalk, the alcoholic injured liver forms a favorable niche for cancer cell metastasis, while BBI608 is a promising anti-metastatic agent targeting such microenvironments.

Influence of lung cancer model characteristics on tumor targeting behavior of nanodrugs.

Evidence is mounting that there is a significant gap between the antitumor efficacy of nanodrugs in preclinical mouse tumor models and in clinical human tumors, and that differences in tumor models are likely to be responsible for this gap. Herein, we investigated the enhanced permeability and retention (EPR) effect in mouse lung cancer models with different tumor growth rates, volumes and locations, and analyzed the nanodrug tumor targeting behaviors limited by tumor vascular pathophysiological characteristics in various tumor models. The results showed that the fast-growing tumors were characterized by lower vascular tight junctions, leading to higher vascular paracellular transport activity and nanodrug tumor accumulation. The paracellular transport activity increased with the growth of tumor, but the vascular density and transcellular transport activity decreased, and as a result, the average tumor accumulation of passive targeting nanodrugs decreased. Orthotopic tumors were rich in blood vessels, but had low vascular transcellular and paracellular transport activities, making it difficult for nanodrug accumulation in orthotopic tumors via passive targeting strategies. The antitumor efficacy of passive targeting nanodrugs in various lung cancer-bearing mice validated the aforementioned nanodrug accumulation behavior, and nanodrugs based on the angiogenesis-tumor sequential targeting strategy achieved obviously improved efficacy in orthotopic lung cancer-bearing mice. These results suggest that the EPR effect varies in different tumor models and should not be used as a universal targeting strategy for antitumor nanodrugs. Besides, attention should be paid to the animal tumor models in the evaluation of nanodrugs so as to avoid exaggerating the antitumor efficacy.

Advances in lipid-based nanocarriers for breast cancer metastasis treatment.

Breast cancer (BC) is the most common cancer affecting women worldwide, with over 2 million women diagnosed every year, and close to 8 million women currently alive following a diagnosis of BC in the last 5-years. The side effects such as chemodrug toxicity to healthy tissues and drug resistance severely affect the quality of life of BC patients. To overcome these limitations, many efforts have been made to develop nanomaterial-based drug delivery systems. Among these nanocarriers, lipid-based delivery platforms represented one of the most successful candidates for cancer therapy, improving the safety profile and therapeutic efficacy of encapsulated drugs. In this review we will mainly discuss and summarize the recent advances in such delivery systems for BC metastasis treatment, with a particular focus on targeting the common metastatic sites in bone, brain and lung. We will also provide our perspectives on lipid-based nanocarrier development for future clinical translation.

The persistent-predation strategy of the red lionfish (Pterois volitans).

The pursuit of prey is vital to the biology of a predator and many aspects of predatory behaviour are well-studied. However, it is unclear how a pursuit can be effective when the prey is faster than a non-cryptic predator. Using kinematic measurements, we considered the strategy of red lionfish (Pterois volitans) as they pursued a faster prey fish (Chromis viridis) under laboratory conditions. Despite swimming about half as fast as C. viridis, lionfish succeeded in capturing prey in 61% of our experiments. This successful pursuit behaviour was defined by three critical characteristics. First, lionfish targeted C. viridis with pure pursuit by adjusting their heading towards the prey's position and not the anticipated point of interception. Second, lionfish pursued prey with uninterrupted motion. By contrast, C. viridis moved intermittently with variation in speed that included slow swimming. Such periods allowed lionfish to close the distance to a prey and initiate a suction-feeding strike at a relatively close distance (less than 9 cm). Finally, lionfish exhibited a high rate of strike success, capturing prey in 74% of all strikes. These characteristics comprise a behaviour that we call the 'persistent-predation strategy', which may be exhibited by a diversity of predators with relatively slow locomotion.

In vivo computation with sensor fusion and search acceleration for smart tumor homing.

BACKGROUND AND OBJECTIVE: Motivated by the advancements on bioresorbable nanoswimmers, this paper considers the advantages of direct targeting over systemic targeting for smart tumor homing under the general framework of computational nanobiosensing. Nanoswimmers assembled by magnetic nanoparticles can be used as contrast agents to estimate the locations of tumors inside the human body. METHODS: Closely observing the response of nanoswimmers (which act as in vivo biosensors) to the tumor-triggered biological gradients and then guiding them through external manipulation, can result in a higher accumulation at the diseased location. Sensor informatics along with data fusion can play a crucial role in such a knowledge-aided targeting process. Specifically, built upon our previous work on direct targeting inspired by the gradient descent optimization, this work is focused on resolving the real-life constraints of in vivo natural computation such as uniformity of the magnetic field and finite life span of the nanoswimmers. To overcome these challenges, we propose a multi-estimate-fusion strategy to obtain a common steering direction for the swarm of nanoswimmers. RESULTS: We show through computational experiments (1) that the mean of individual gradient estimations provides the best choice for symmetrical conditions (tumor location in line with the direction of blood flow) while leader-based swarm steering gives the best results for non-symmetrical search space, and (2) that the iterative memory-driven gradient descent optimization detects the target faster compared to the classical memory-less gradient descent and knowledge-less systemic targeting. CONCLUSION: Our proposed strategies demonstrate that a clear demarcation between malignant tumors and healthy tissues can be visualized before nanoswimmers are consumed in human vasculature. We believe that our work will help in overcoming the challenges posed by natural in vivo computation for tumor diagnosis at its early stage.

Regulation of in vivo fate of exosomes for therapeutic applications: New frontier in nanomedicines.

The significance of exosomes as intercellular messengers in a range of biological phenomena has hugely inspired many researchers to use them for disease diagnosis and treatment. Likewise, since the adoption of exosomes as new tools for our research, I aspired to address relevant delivery challenges with my expertise in the field of nanomedicine to develop better exosome-related therapies. In particular, innately therapeutic and exogenous drug-loaded exosomes should be located at the target site, whereas pathological exosomes or their biogenesis pathways should be targeted to control them. Reflecting recent preclinical efforts in my research group to meet such needs, the related previous work history, and initial accomplishments for regulating the in vivo fate of exosomes are covered in this contribution to the Orations-New Horizons of the Journal of Controlled Release, along with our ambitions for future developments in the field.

Curcumin encapsulation in functional PLGA nanoparticles: A promising strategy for cancer therapies.

Nanoparticles have emerged as promising drug delivery systems for the treatment of several diseases. Novel cancer therapies have exploited these particles as alternative adjuvant therapies to overcome the traditional limitations of radio and chemotherapy. Curcumin is a natural bioactive compound found in turmeric, that has been reported to show anticancer activity against several types of tumors. Despite some biological limitations regarding its absorption in the human body, curcumin encapsulation in poly(lactic-co-glycolic acid) (PLGA), a non-toxic, biodegradable and biocompatible polymer, represents an effective strategy to deliver a drug to a tumor site. Furthermore, PLGA nanoparticles can be engineered with targeting moieties to reach specific cancer cells, thus enhancing the antitumor effects of curcumin. We herein aim to bring an up-to-date summary of the recently developed strategies for curcumin delivery to different types of cancer cells through encapsulation in PLGA nanoparticles, correlating their effects with those of curcumin on the biological capabilities acquired by cancer cells (cancer hallmarks). We discuss the targeting strategies proposed for advanced curcumin delivery and the respective improvements achieved for each cancer cell analyzed, in addition to exploring the encapsulation techniques employed. The conjugation of correct encapsulation techniques with tumor-oriented targeting design can result in curcumin-loaded PLGA nanoparticles that can successfully integrate the elaborate network of development of alternative cancer treatments along with traditional ones. Finally, the current challenges and future demands to launch these nanoparticles in oncology are comprehensively examined.

Combination therapy and drug delivery strategies for treatment of non-alcoholic fatty liver disease / 中国药科大学学报

@#Non-alcoholic fatty liver disease (NAFLD) is a series of chronic liver diseases strongly associated with the metabolic disorder with an increasing rate of worldwide prevalence.Due to its complicated pathogenesis, only Saroglitazar has been approved by Indian Drug Controller General (DCGI) as a PPAR-α/γ dual agonist to treat non-cirrhotic non-alcoholic steatohepatitis.Combination therapy, which can target same or different signaling pathways of NAFLD pathogenesis, has been developed to achieve synergistic therapeutic efficacy.Currently, small-molecule drug combination, RNAi combination therapy, and chemogene therapy are proposed as promising strategies in NAFLD treatment.In addition, designing a smart, safe and effective drug delivery system is key to realizing the druggability, clinical translation and industrialization of small molecule drugs and gene drugs.This review summarizes the research status and delivery system of small-molecule drug combination, RNAi combination therapy, and chemogene therapy, in the hope of providing some novel insight for the treatment of NAFLD.

Development of a PROTAC-Based Targeting Strategy Provides a Mechanistically Unique Mode of Anti-Cytomegalovirus Activity.

Human cytomegalovirus (HCMV) is a major pathogenic herpesvirus that is prevalent worldwide and it is associated with a variety of clinical symptoms. Current antiviral therapy options do not fully satisfy the medical needs; thus, improved drug classes and drug-targeting strategies are required. In particular, host-directed antivirals, including pharmaceutical kinase inhibitors, might help improve the drug qualities. Here, we focused on utilizing PROteolysis TArgeting Chimeras (PROTACs), i.e., hetero-bifunctional molecules containing two elements, namely a target-binding molecule and a proteolysis-inducing element. Specifically, a PROTAC that was based on a cyclin-dependent kinase (CDK) inhibitor, i.e., CDK9-directed PROTAC THAL-SNS032, was analyzed and proved to possess strong anti-HCMV AD169-GFP activity, with values of EC50 of 0.030 µM and CC50 of 0.175 µM (SI of 5.8). Comparing the effect of THAL-SNS032 with its non-PROTAC counterpart SNS032, data indicated a 3.7-fold stronger anti-HCMV efficacy. This antiviral activity, as illustrated for further clinically relevant strains of human and murine CMVs, coincided with the mid-nanomolar concentration range necessary for a drug-induced degradation of the primary (CDK9) and secondary targets (CDK1, CDK2, CDK7). In addition, further antiviral activities were demonstrated, such as the inhibition of SARS-CoV-2 replication, whereas other investigated human viruses (i.e., varicella zoster virus, adenovirus type 2, and Zika virus) were found insensitive. Combined, the antiviral quality of this approach is seen in its (i) mechanistic uniqueness; (ii) future options of combinatorial drug treatment; (iii) potential broad-spectrum activity; and (iv) applicability in clinically relevant antiviral models. These novel data are discussed in light of the current achievements of anti-HCMV drug development.