Aromaticity Tuning of Heavy-Atom-Free Photosensitizers for Singlet Fission-Enhanced Immunogenic Photodynamic Oncotherapy.

The quantum yield of reactive oxygen species is of central importance for the development of organic photosensitizers and photodynamic therapy (PDT). A common molecular design approach for optimizing organic photosensitizers involves the incorporation of heavy atoms into their backbones. However, this raises concerns regarding heightened dark cytotoxicity and a shortened triplet-state lifetime. Herein, we demonstrate a heavy-atom-free (HAF) photosensitizer design strategy founded on the singlet fission (SF) mechanism for cancer PDT. Through the "single-atom surgery" approach to deleting oxygen atoms in pyrazino[2,3-g]quinoxaline skeleton photosensitizers, photosensitizers PhPQ and TriPhPQ are produced with Huckel's aromaticity and Baird's aromaticity in the ground state and triplet state, respectively, enabling the generation of two triplet excitons through SF. The SF process endows photosensitizer PhPQ with an ultrahigh triplet-state quantum yield (186%) and an outstanding 1O2 quantum yield (177%). Notably, HAF photosensitizers PhPQ and TriPhPQ enhanced PDT efficacy and potentiated αPD-L1 immune check blockade therapy in vivo, which show their promise for translational oncology treatment.

Natural Polysaccharide Delivery Platforms with Multiscale Structure Used for Cancer Chemoimmunotherapy.

Chemoimmunotherapy is an effective cancer treatment method. Drugs are always combined and used in treating cancer. However, the characteristic of drugs varies, making it challenging to control their release kinetics utilizing delivery devices with a single microstructure. In this study, we attempted to uniformly size drugs of varying molecular weights and confine them in a compartment where immune cells may be recruited and moved freely. Dextran microgels were created as modular drug libraries to address the cryogel burst release of small molecule drugs. Then, modular drug libraries and granulocyte-macrophage colony-stimulating factor (GM-CSF) were integrated into cryogels for a combined treatment. Herein, alginate was zwitterion modified to avoid the immune reaction generated by the material. Because of its macroporous structure, the cryogel could be injected into the body, eliminating invasive surgical procedures. Results demonstrated that multiscale delivery platforms could improve the synergistic effect of various medications on tumor treatment.

Multifunctional nanocarriers for targeted drug delivery and diagnostic applications of lymph nodes metastasis: a review of recent trends and future perspectives.

Lymph node metastasis is a frequent occurrence in a variety of tumour forms and poses an enormous challenge to cancer treatment. This process is critical to the development of the disease and is frequently linked to a poor prognosis. Over 90% of cancerous cells move through lymph nodes, making them important entry routes for the spread of cancer cells. The prognosis of cancer patients is significantly impacted by lymph node metastases, which also affects treatment choices. Targeting lymph node metastases presents numerous difficulties for conventional medication delivery techniques. It is still very difficult to selectively target cancer cells in lymph nodes without risking injury to healthy organs and unforeseen consequences. Additionally, systemic delivery of drugs is hampered by the slow flow rate of lymphatic vessels. Chemotherapeutic medicines' poor solubility and stability further reduce their effectiveness when taken orally. Additionally, the extracellular matrix that surrounds lymph node tumours is extensive, which makes it difficult for conventional pharmaceutical delivery systems to reach cancer cells. The development of nanocarriers for precise drug delivery to LNs has attracted a lot of interest to overcome these obstacles. Most solid tumours first spread through the lymphatic system, hence effective drug administration to these tissues is essential for better therapeutic results. Nanocarriers have several benefits, including the capacity to pass through barriers like blood-brain barriers and membranes to reach the lymphatic system. High medication dosages can be enclosed thanks to the physicochemical characteristics of nanocarriers, such as their higher surface-to-volume ratio. Additionally, ligands, antibodies, polymers, or biological molecules can be attached to nanocarrier surfaces to change their properties, allowing for the targeted delivery of lymph node epithelial cells. This use of nanocarriers for drug delivery maximizes on-target effects and related adverse effects while improving the effectiveness of medication delivery to target locations. More research and development in this field is needed to optimize nanocarrier design, increase targeting capabilities, and expand clinical applications for better cancer care.

Development of humanized mouse with patient-derived xenografts for cancer immunotherapy studies: A comprehensive review.

Immunotherapy has revolutionized cancer treatment, however, not all tumor types and patients are completely responsive to this approach. Establishing predictive pre-clinical models would allow for more accurate and practical immunotherapeutic drug development. Mouse models are extensively used as in vivo system for biomedical research. However, due to the significant differences between rodents and human, it is impossible to translate most of the findings from mouse models to human. Pharmacological development and advancing personalized medicine using patient-derived xenografts relies on producing mouse models in which murine cells and genes are substituted with their human equivalent. Humanized mice (HM) provide a suitable platform to evaluate xenograft growth in the context of a human immune system. In this review, we discussed recent advances in the generation and application of HM models. We also reviewed new insights into the basic mechanisms, pre-clinical evaluation of onco-immunotherapies, current limitations in the application of these models as well as available improvement strategies. Finally, we pointed out some issues for future studies.

The roles of tumor-associated macrophages in tumor angiogenesis and metastasis.

Tumor associated macrophages (TAMs) are the most frequent immune cells within tumor microenvironment (TME). There is growing evidence that TAMs are involved in tumor progression via multiple mechanisms. TAMs create an immunosuppressive TME by producing growth factors, chemokines, and cytokines which modulate recruitment of immune cells and inhibit anti-tumor responses. They also serve as angiogenesis promoting cells by production of pro-angiogenic factors and matrix metalloproteinases (MMPs) and vascular constructing which guarantee supplying oxygen and nutrients to solid tumor cells. Furthermore, TAMs play important functions in tumor metastasis through contributing to invasion, extravasation, survival, intravasation, and colonization of tumor cells. In this review, we summarized macrophage classification, TAMs polarization, and mechanisms underlying TAM-promoting angiogenesis and metastasis.

The limiting factors of oncolytic virus immunotherapy and the approaches to overcome them.

Oncolytic virus (OV) immunotherapy is characterized by viruses which specifically target cancer cells and cause their cytolysis. They provide a unique and promising new tool for the eradication of cancer as they interact with and affect the tumor microenvironment (TME), vasculature, and immune system. Advancements of genetic engineering have allowed for these viruses to be armed in such a way to have enhanced targeting, strong immunomodulation properties, and an ability to modify the TME. However, there are still major limitations in their use, mostly due to difficulties in delivering the viral particles to the tumors and in ensuring that the immunomodulatory properties are able to stimulate the host immune response to mount a complete response. Using novel delivery systems and using OVs as a complementary therapy in a combinatorial treatment have shown some significant successes. In this review, we discuss the major issues and difficulties in using OVs as anti-tumor agents and some of the strategies put in place so far to overcome these limitations. KEY POINTS: • Oncolytic viruses (OVs) infect cancer cells and cause their cytolysis. • The major limitations in using OVs as anti-tumor therapy were discussed. • The potential strategies to overcome these limitations were summarized.

Recent advances in targeting cancer stem cells using oncolytic viruses.

Oncolytic virotherapy is a promising antitumor strategy which utilizes the lytic nature of viral replication to kill cancer cells. Oncolytic viruses (OVs) can induce cancer cell death and trigger immune responses to metastatic cancer in vivo. Reverse genetic systems have aided the insertion of anticancer genes into various OVs to augment their oncolytic capacity. Furthermore, OVs target and destroy the population of tumor-initiating cancer stem cells. These cancer stem cells are associated with metastasis and development of resistance to conventional anticancer approaches. Targeting cancer stem cells is essential since killing only differentiated tumor cells may lead to enrichment of cancer stem cells and thus indicate a poor prognosis. In this review, we summarize the oncolytic activity of various classes of OVs towards different types of cancer stem cells and also discuss the synergistic activity achieved by the combination of OVs with traditional therapies on chemo- and radiotherapy-resistant cancer stem cells.

Recent advances in the use of microcarriers for cell cultures and their ex vivo and in vivo applications.

Microcarriers are 100- to 300-micron support matrices that permit the growth of adherent cells in bioreactor systems. They have a larger surface area to volume ratio in comparison to single cell monolayers, enabling cost-effective cell production and expansion. Microcarriers are composed of a solid matrix that must be separated from expanded cells during downstream processing stages. The detachment method is chosen on the basis of several factors like cell type, microcarrier surface chemistry, cell confluency and degree of aggregation. The development of microcarriers with a range of physiochemical properties permit controlled cell and protein associations that hold utility for novel therapeutics. In this review, we provide an overview of the recent advances in microcarrier cell culture technology. We also discuss its significance as an ex vivo research tool and the therapeutic potential of newly designed microcarrier systems in vivo.

Recent advances in carbohydrate-based cancer vaccines.

Cancer is a complex multifactorial disease for which many promising therapeutic strategies such as immunotherapy are emerging. Malignant cells frequently express aberrant cell surface carbohydrates, which differentiate them from normal "healthy" cells. This characteristic presents a window for the development of synthetic carbohydrate antigen-based cancer vaccines which can be recognized by the immune system and can bring about T cell-dependent immune responses. Antibodies generated against the carbohydrate antigens partake in the inactivation of carbohydrate-decorated cancer cells, by slowing down tumor cell growth and inducing cancer cell apoptosis. Novel synthetic strategies for carbohydrate antigens have led to several synthetic cancer vaccine candidates. In the present review, we describe the latest progress in carbohydrate-based cancer vaccines and their clinical evaluation in various cancers.

Clostridium difficile carriage in hospitalized cancer patients: a prospective investigation in eastern China.

BACKGROUND: Clostridium difficile carriage has been considered as a potential source for the deadly infection, but its role in cancer patients is still unclear. We aimed to identify the clinical and immunological factors that are related to C. difficile carriage in Chinese cancer patients. METHODS: A total of 400 stool samples were collected from cancer patients who received chemotherapy in three hospitals of eastern China. Bacterial genomic DNA was extracted and two toxin genes (tcdA and tcdB) were detected. PCR ribotyping was performed using capillary gel electrophoresis. Concentrations of prostaglandin E2 (PGE2), transforming growth factor beta (TGF-ß) and interleukin-10 (IL-10) were measured using enzyme-linked immunosorbent assay (ELISA) kits. RESULTS: Eighty-two (20.5%) samples were confirmed to be C. difficile-positive and positive for tpi, tcdA, and tcdB genes. The C. difficile-positive rates in patients with diarrhea and no diarrhea were 35% and 19.7%, respectively (p = 0.09). Patients who were younger than 50 years old and were hospitalized for at least 10 days had a C. difficile-positive rate as high as 35%. In contrast, patients who were older than 50 years old and were hospitalized for less than 10 days had a C. difficile-positive rate of only 12.7% (p = 0.0009). No association was found between C. difficile carriage and chemotherapy regimen, antibiotic drug use, or immunosuppressive mediators, such as prostaglandin E2 (PGE2), transforming growth factor beta (TGF-ß), or interleukin-10 (IL-10). Twelve ribotypes of C. difficile were identified, but none of them belonged to ribotype 027. CONCLUSIONS: We conclude that younger patients and those with longer hospitalization stays may be more prone to C. difficile carriage. Studies of larger populations are warranted to clarify the exact role of C. difficile carriage in hospitalized cancer patients in China.

Targeted drug delivery of engineered mesenchymal stem/stromal-cell-derived exosomes in cardiovascular disease: recent trends and future perspectives.

In recent years, stem cells and their secretomes, notably exosomes, have received considerable attention in biomedical applications. Exosomes are cellular secretomes used for intercellular communication. They perform the function of intercellular messengers by facilitating the transport of proteins, lipids, nucleic acids, and therapeutic substances. Their biocompatibility, minimal immunogenicity, targetability, stability, and engineerable characteristics have additionally led to their application as drug delivery vehicles. The therapeutic efficacy of exosomes can be improved through surface modification employing functional molecules, including aptamers, antibodies, and peptides. Given their potential as targeted delivery vehicles to enhance the efficiency of treatment while minimizing adverse effects, exosomes exhibit considerable promise. Stem cells are considered advantageous sources of exosomes due to their distinctive characteristics, including regenerative and self-renewal capabilities, which make them well-suited for transplantation into injured tissues, hence promoting tissue regeneration. However, there are notable obstacles that need to be addressed, including immune rejection and ethical problems. Exosomes produced from stem cells have been thoroughly studied as a cell-free strategy that avoids many of the difficulties involved with cell-based therapy for tissue regeneration and cancer treatment. This review provides an in-depth summary and analysis of the existing knowledge regarding exosomes, including their engineering and cardiovascular disease (CVD) treatment applications.

Tumor-targeted delivery of copper-manganese biomineralized oncolytic adenovirus for colorectal cancer immunotherapy.

Oncolytic viral therapy (OVT) is a novel anti-tumor immunotherapy approach, specifically replicating within tumor cells. Currently, oncolytic viruses are mainly administered by intratumoral injection. However, achieving good results for distant metastatic tumors is challenging. In this study, a multifunctional oncolytic adenovirus, OA@CuMnCs, was developed using bimetallic ions copper and manganese. These metal cations form a biomineralized coating on the virus's surface, reducing immune clearance. It is known that viruses upregulate the expression of PD-L1. Copper ions in OA@CuMnCs can decrease the PD-L1 expression of tumor cells, thereby promoting immune cell-related factor release. This process involves antigen presentation and the combination of immature dendritic cells, transforming them into mature dendritic cells. It changes "cold" tumors into "hot" tumors, further inducing immunogenic cell death. While oncolytic virus replication requires oxygen, manganese ions in OA@CuMnCs can react with endogenous hydrogen peroxide. This reaction produces oxygen, enhancing the virus's replication ability and the tumor lysis effect. Thus, this multifunctionally coated OA@CuMnCs demonstrates potent amplification in immunotherapy efficacy, and shows great potential for further clinical OVT. STATEMENT OF SIGNIFICANCE: Oncolytic virus therapy (OVs) is a new anti-tumor immunotherapy method that can specifically replicate in tumor cells. Although the oncolytic virus can achieve a therapeutic effect on some non-metastatic tumors through direct intratumoral injection, there are still three major defects in the treatment of metastatic tumors: immune response, hypoxia effect, and administration route. Various studies have shown that the immune response in vivo can be overcome by modifying or wrapping the surface protein of the oncolytic virus. In this paper, a multifunctional coating of copper and manganese was prepared by combining the advantages of copper and manganese ions. The coating has a simple preparation method and mild conditions, and can effectively enhance tumor immunotherapy.

Engineered Luminescent Oncolytic Vaccinia Virus Activation of Photodynamic-Immune Combination Therapy for Colorectal Cancer.

Oncolytic virus therapy is currently regarded as a promising approach in cancer immunotherapy. It has greater therapeutic advantages for colorectal cancer that is prone to distant metastasis. However, the therapeutic efficacy and clinical application of viral agents alone for colorectal cancer remain suboptimal. In this study, an engineered oncolytic vaccinia virus (OVV-Luc) that expresses the firefly luciferase gene is developed and loaded Chlorin e6 (Ce6) onto the virus surface through covalent coupling, resulting in OVV-Luc@Ce6 (OV@C). The OV@C infiltrates tumor tissue and induces endogenous luminescence through substrate catalysis, resulting in the production of reactive oxygen species. This unique system eliminates the need for an external light source, making it suitable for photodynamic therapy (PDT) in deep tissues. Moreover, this synergistic effect between PDT and viral immunotherapy enhances dendritic cell maturation, macrophage polarization, and reversal of the immunosuppressive microenvironment. This synergistic effect has the potential to convert a "cold" into a "hot" tumor, it offers valuable insights for clinical translation and application.

Combining of Oncolytic Virotherapy and Other Immunotherapeutic Approaches in Cancer: A Powerful Functionalization Tactic.

Oncolytic viruses have found a good place in the treatment of cancer. Administering oncolytic viruses directly or by applying genetic changes can be effective in cancer treatment through the lysis of tumor cells and, in some cases, by inducing immune system responses. Moreover, oncolytic viruses induce antitumor immune responses via releasing tumor antigens in the tumor microenvironment (TME) and affect tumor cell growth and metabolism. Despite the success of virotherapy in cancer therapies, there are several challenges and limitations, such as immunosuppressive TME, lack of effective penetration into tumor tissue, low efficiency in hypoxia, antiviral immune responses, and off-targeting. Evidence suggests that oncolytic viruses combined with cancer immunotherapy-based methods such as immune checkpoint inhibitors and adoptive cell therapies can effectively overcome these challenges. This review summarizes the latest data on the use of oncolytic viruses for the treatment of cancer and the challenges of this method. Additionally, the effectiveness of mono, dual, and triple therapies using oncolytic viruses and other anticancer agents has been discussed based on the latest findings.

Upregulation of MED7 was associated with progression in hepatocellular carcinoma.

OBJECTIVE: MED subunits have been reported to be associated with various types of tumors, however, the potential role of MED7 in hepatocellular carcinoma (HCC) was still unclear. The aim of the study was to explore the role of MED7 in HCC. METHODS: In this study, MED7 mRNA expression levels between HCC and adjacent normal tissues were first analyzed by several public datasets. Then we utilized a tissue microarray (TMA) to investigate the clinical role of MED7 in HCC by immunohistochemistry (IHC). Meanwhile, the potential mechanisms of MED7 based on gene-gene correlation analyses were also explored. RESULTS: High mRNA level of MED7 correlated with advanced stage and worse grade of differentiation. IHC results showed that MED7 protein level was upregulated in HCC and associated with Edmondson grade and Microvascular invasion in 330 cases of HCC. GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) analysis revealed that MED7 co-expressed genes participate primarily in ribonucleoprotein complex biogenesis, protein targeting, mRNA processing and nucleoside triphosphate metabolic process et cetera. Further analysis also revealed that MED7 mRNA level has significant correlation with immune cells infiltration levels. CONCLUSION: MED7 was upregulated in HCC and correlated with progression of HCC. Meanwhile, MED7 may promote HCC through participating in multiple gene networks to influence tumorigenesis as well as immune response in HCC microenvironment.

A narrative review of new research progress regarding the use of airway stents in benign airway stenosis.

INTRODUCTION: Benign airway stenosis is a severe disease that can result in death with improper treatment. Clinicians must know about airway stents to choose the best one in their daily practice. AREAS COVERED: PubMed, Embase, and other electronic databases and websites were searched to identify relevant randomized controlled trials and meta-analyses. This review summarizes different types of airway stents and analyzes their advantages and disadvantages. EXPERT OPINION: Increasing attention has been given to the indications and prognosis of benign airway stenosis treated with different airway stents. With more investigations and data, better alternatives to silicone stents could be developed in the future.

Carbohydrates based stimulus responsive nanocarriers for cancer-targeted chemotherapy: a review of current practices.

INTRODUCTION: Many nanocarriers have been developed to react physicochemically to exterior stimuli like ultrasonic, light, heat, and magnetic fields, along with various internal stimuli including pH, hypoxia, enzyme, and redox potential. Nanocarriers are capable to respond various stimuli within the cancer cells to enable on-demand drug delivery, activation of bioactive compounds, controlled drug release, and targeting ligands, as well as size, charge, and conformation conversion, enabling sensing and signaling, overcoming multidrug resistance, accurate diagnosis, and precision therapy. AREAS COVERED: Carbohydrates are ubiquitous biomolecules with a high proclivity for supramolecular network formation. Numerous carbohydrate-based nanomaterials have been used in biological solicitations and stimuli-based responses. Particular emphasis has been placed on the utilization of carbohydrate-based NPs and nanogels in various fields including imaging, drug administration, and tissue engineering. Because the assembly process is irreversible, carbohydrate-based systems are excellent ingredients for the development of stimulus-responsive nanocarriers for cancer-targeted chemotherapy. This review aims to summarise current research on carbohydrate-based nanomaterials, with an emphasis on stimuli-sensitive nanocarriers for cancer-targeted chemotherapy. EXPERT OPINION: Carbohydrates-based stimulus-responsive nanomaterials have been proved highly efficient for targeted delivery of anticancer drugs, thus leading to effective chemotherapy with minimum off-target effects.

Oncolytic Virotherapy in Peritoneal Metastasis Gastric Cancer: The Challenges and Achievements.

Gastric cancer (GC) is the fourth most common cancer and the second leading cause of cancer death globally. Although the mortality rate in some parts of the world, such as East Asia, is still high, new treatments and lifestyle changes have effectively reduced deaths from this type of cancer. One of the main challenges of this type of cancer is its late diagnosis and poor prognosis. GC patients are usually diagnosed in the advanced stages of the disease, which is often associated with peritoneal metastasis (PM) and significantly reduces survival. This type of metastasis in patients with GC poses a serious challenge due to limitations in common therapies such as surgery and tumor resection, as well as failure to respond to systemic chemotherapy. To solve this problem, researchers have used virotherapy such as reovirus-based anticancer therapy in patients with GC along with PM who are resistant to current chemotherapies because this therapeutic approach is able to overcome immune suppression by activating dendritic cells (DCs) and eventually lead to the intrinsic activity of antitumor effector T cells. This review summarizes the immunopathogenesis of peritoneal metastasis of gastric cancer (PMGC) and the details for using virotherapy as an effective anticancer treatment approach, as well as its challenges and opportunities.

Low Expression of KAT6B May Affect Prognosis in Hepatocellular Carcinoma.

AIMS: Lysine acetyltransferase 6B (KAT6B), is a histone acetyltransferase implicated to have a role in tumor suppression. However, the relationship between KAT6B and hepatocellular carcinoma (HCC) is unclear. The purpose of this study was to detect the expression of KAT6B in HCC tissues and analyze its connection with the clinicopathological features of HCC. METHODS: First, we performed immunohistochemical staining on 250 HCC tissues and 222 non-tumor liver tissues to examine the expression of KAT6B.Then the relation between KAT6B expression and clinicopathological parameters was analyzed by chi-square test, and the overall survival analysis was conducted by Kaplan-Meier survival method. In addition, based on the Oncomine expression array online and the UALCAN database, we compared KAT6B expression differences between normal liver tissues and HCC tissues more broadly. RESULTS: Compared with normal tissues, KAT6B expression was significantly lower in HCC tissues. Low KAT6B expression was found to be related to gender, AFP level, and tumor size. According to the online database, KAT6B expression was found to be decreased in HCC tissues and high in normal tissues. CONCLUSIONS: Lower expression of KAT6B is associated with poor prognosis of HCC, and KAT6B may be a potential tumor suppressor in liver cancer.