The diversity of autologous cells being used and investigated for cancer therapy continues to increase. Mast cells (MCs) are tissue cells that contain a unique set of anti-cancer mediators and are found in and around tumors. We sought to exploit the anti-tumor mediators in MC granules to selectively target them to tumor cells using tumor specific immunoglobin E (IgE) and controllably trigger release of anti-tumor mediators upon tumor cell engagement. We used a human HER2/neu-specific IgE to arm human MCs through the high affinity IgE receptor (FcεRI). The ability of MCs to bind to and induce apoptosis of HER2/neu-positive cancer cells in vitro and in vivo was assessed. The interactions between MCs and cancer cells were investigated in real time using confocal microscopy. The mechanism of action using cytotoxic MCs was examined using gene array profiling. Genetically manipulating autologous MC to assess the effects of MC-specific mediators have on apoptosis of tumor cells was developed using siRNA. We found that HER2/neu tumor-specific IgE-sensitized MCs bound, penetrated, and killed HER2/neu-positive tumor masses in vitro. Tunneling nanotubes formed between MCs and tumor cells are described that parallel tumor cell apoptosis. In solid tumor, human breast cancer (BC) xenograft mouse models, infusion of HER2/neu IgE-sensitized human MCs co-localized to BC cells, decreased tumor burden, and prolonged overall survival without indications of toxicity. Gene microarray of tumor cells suggests a dependence on TNF and TGFβ signaling pathways leading to apoptosis. Knocking down MC-released tryptase did not affect apoptosis of cancer cells. These studies suggest MCs can be polarized from Type I hypersensitivity-mediating cells to cytotoxic cells that selectively target tumor cells and specifically triggered to release anti-tumor mediators. A strategy to investigate which MC mediators are responsible for the observed tumor killing is described so that rational decisions can be made in the future when selecting which mediators to target for deletion or those that could further polarize them to cytotoxic MC by adding other known anti-tumor agents. Using autologous human MC may provide further options for cancer therapeutics that offers a unique anti-cancer mechanism of action using tumor targeted IgE’s.
This study suggested successful encapsulation of polyhexamethylene biguanide chloride (PHMB) into nano cationic liposome as a biocompatible antibacterial agent with less cytotoxicity and higher activities. Phosphatidylcholine, cholesterol and stearylamine were used to prepare nano cationic liposome using thin film hydration method along with sonication or homogeniser. Sonication was more effective in PHMB loaded nano cationic liposome preparation with smaller size (34 nm). FTIR, H NMR and XRD analyses were used to confirm the encapsulation of PHMB into nano cationic liposome. PHMB inclusion in nano cationic liposome was beneficial for increased antibacterial activity against Staphylococcus aureus and Escherichia coli. PHMB-loaded cationic liposome enables to deliver high concentrations of the antibacterial agent into the infectious cell. The cytotoxicity of PHMB entrapped in positively charged liposome was prominently reduced showing no significant visible detrimental effect on normal primary human skin fibroblast cell lines morphology confirming the effective role of cationic liposome encapsulation. Comparing with PHMB alone, encapsulation of PHMB in nano cationic liposome resulted in significant increase in cell viability from 2.4 to 63%.
The emergence of cancer immunotherapies utilizing adoptive cell transfer (ACT) continues to be one of the most promising strategies for cancer treatment. Mast cells (MCs) which occur throughout vascularized tissues, are most commonly associated with Type I hypersensitivity, bind immunoglobin E (IgE) with high affinity, produce anti-cancer mediators such as tumor necrosis factor alpha (TNF-α) and granulocyte macrophage colony-stimulating factor (GM-CSF), and generally populate the tumor microenvironments. Yet, the role of MCs in cancer pathologies remains controversial with evidence for both anti-tumor and pro-tumor effects. Here, we review the studies examining the role of MCs in multiple forms of cancer, provide an alternative, MC-based hypothesis underlying the mechanism of therapeutic tumor IgE efficacy in clinical trials, and propose a novel strategy for using tumor-targeted, IgE-sensitized MCs as a platform for developing new cellular cancer immunotherapies. This autologous MC cancer immunotherapy could have several advantages over current cell-based cancer immunotherapies and provide new mechanistic strategies for cancer therapeutics alone or in combination with current approaches.
Mast cells (MCs) are found in practically all tissues where they participate in innate and adaptive immune responses. They are also found in and around tumors, yet their interactions with cancer cells and the resulting impact on cancer cell growth and metastasis are not well understood. In this study, we examined a novel mechanism of IgE-FcεRI-mediated, intercellular communication between human adipose-derived mast cells (ADMC) and cancer cells. The formation of heterotypic tunneling nanotubes (TnT) and membrane structures between MCs and tumor cells in vitro was examined using microscopy and a diverse array of molecule-specific indicator dyes. We show that several MC-specific structures are dependent on the specific interactions between human tumor IgE-sensitized MCs and antigens on the tumor cell surface. The formation of TnT, membrane blebs and other MC-specific structures paralleled FcεRI-degranulation occurring within 30 min and persisting for up to 24 h. The TnT-specific adhesion of FcεRI-activated MCs to tumor cells was characterized by the transport of the MC granule content into the tumor cells, including tryptase and TNF-α. This interaction led to apoptosis of the tumor cells, which differs from previous studies examining tissue cells within the cancer microenvironment. The formation of heterotypic TnT results in stimulation of an invasive tumor cell phenotype and increased tumor cell invasion and chemoresistance of the cancer cells. These studies describe a heretofore-unrecognized mechanism underlying IgE-mediated interactions and FcεRI-activated MC-mediated killing of tumor cells through the formation of TnT.
In this study, nanoliposome-loaded poly(hexamethylene biguanide) is introduced as a novel biocompatible antibacterial product with higher activity than microliposomes. Soy lecithin as a clean product was used to prepare various nanoliposomes through sonication, high-pressure homogenizer, and normal homogenizer and also microliposomes through two methods of lipid film hydration and incubation methods. The nanoliposomes were formed under sonication with the size of 50 nm. The prepared liposomes were then loaded with poly(hexamethylene biguanide chloride) and the inclusion percentage was measured. The release profile of liposomes in buffer showed a release of 92% for poly(hexamethylene biguanide) during 24 h. The loaded liposomes were characterized with particle size analyzer, nuclear magnetic resonance, X-ray diffraction, Fourier transform infrared spectroscopy, and scanning electron microscopy. The antibacterial properties of different micro and nanoliposomes were investigated against a Gram-negative (Escherichia coli) and a Gram-positive (Staphylococcus aureus) bacteria. The poly(hexamethylene biguanide)–loaded nanoliposomes indicated higher antibacterial activities than microliposomes. Nanoliposomes have the potential to entrap lower poly(hexamethylene biguanide) dosages while retaining optimum therapeutic efficacy in the target site having lower cytotoxicity with lower side effects. The cytotoxicity of poly(hexamethylene biguanide) entrapped in liposomes was studied in human dermal fibroblasts and compared with free poly(hexamethylene biguanide) and blank liposomes. The maximum cytotoxicity was observed for free poly(hexamethylene biguanide) that is substantially decreased through loading within liposomes structure. Overall, the encapsulation of poly(hexamethylene biguanide) in liposomes improved the biocompatibility and safety of the product introducing a useful biocompatible antibacterial polymer for treatments of infectious diseases.
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