Microfluidic-Assisted ZIF-Silk-Polydopamine Nanoparticles as Promising Drug Carriers for Breast Cancer Therapy.

Metal-organic frameworks (MOFs) are heralded as potential nanoplatforms for biomedical applications. Zeolitic imidazolate framework-8 (ZIF-8), as one of the most well known MOFs, has been widely applied as a drug delivery carrier for cancer therapy. However, the application of ZIF-8 nanoparticles as a therapeutic agent has been hindered by the challenge of how to control the release behaviour of anti-cancer zinc ions to cancer cells. In this paper, we designed microfluidic-assisted core-shell ZIF-8 nanoparticles modified with silk fibroin (SF) and polydopamine (PDA) for sustained release of zinc ions and curcumin (CUR) and tested these in vitro in various human breast cancer cells. We report that microfluidic rapid mixing is an efficient method to precisely control the proportion of ZIF-8, SF, PDA, and CUR in the nanoparticles by simply adjusting total flow rates (from 1 to 50 mL/min) and flow rate ratios. Owing to sufficient and rapid mixing during microfluidic-assisted nanoprecipitation, our designer CUR@ZIF-SF-PDA nanoparticles had a desired particle size of 170 nm with a narrow size distribution (PDI: 0.08), which is much smaller than nanoparticles produced using traditional magnetic stirrer mixing method (over 1000 nm). Moreover, a properly coated SF layer successfully enhanced the capability of ZIF-8 as a reservoir of zinc ions. Meanwhile, the self-etching reaction between ZIF-8 and PDA naturally induced a pH-responsive release of zinc ions and CUR to a therapeutic level in the MDA-MB-231, SK-BR-3, and MCF-7 breast cancer cell lines, resulting in a high cellular uptake efficiency, cytotoxicity, and cell cycle arrest. More importantly, the high biocompatibility of designed CUR@ZIF-SF-PDA nanoparticles remained low in cytotoxicity on AD-293 non-cancer cells. We demonstrate the potential of prepared CUR@ZIF-SF-PDA nanoparticles as promising carriers for the controlled release of CUR and zinc ions in breast cancer therapy.

Oncolytic Virotherapy Treatment of Breast Cancer: Barriers and Recent Advances.

Oncolytic virotherapy (OV) is an emerging class of immunotherapeutic drugs. Their mechanism of action is two-fold: direct cell lysis and unmasking of the cancer through immunogenic cell death, which allows the immune system to recognize and eradicate tumours. Breast cancer is the most common cancer in women and is challenging to treat with immunotherapy modalities because it is classically an immunogenically "cold" tumour type. This provides an attractive niche for OV, given viruses have been shown to turn "cold" tumours "hot," thereby opening a plethora of treatment opportunities. There has been a number of pre-clinical attempts to explore the use of OV in breast cancer; however, these have not led to any meaningful clinical trials. This review considers both the potential and the barriers to OV in breast cancer, namely, the limitations of monotherapy and the scope for combination therapy, improving viral delivery and challenges specific to the breast cancer population (e.g., tumour subtype, menopausal status, age).

A peptide derived from TIMP-3 inhibits multiple angiogenic growth factor receptors and tumour growth and inflammatory arthritis in mice.

The binding of vascular endothelial growth factor (VEGF) to VEGF receptor-2 (VEGFR-2) on the surface of vascular endothelial cells stimulates many steps in the angiogenic pathway. Inhibition of this interaction is proving of value in moderating the neovascularization accompanying age-related macular degeneration and in the treatment of cancer. Tissue inhibitor of metalloproteinases-3 (TIMP-3) has been shown to be a natural VEGFR-2 specific antagonist-an activity that is independent of its ability to inhibit metalloproteinases. In this investigation we localize this activity to the C-terminal domain of the TIMP-3 molecule and characterize a short peptide, corresponding to part of this domain, that not only inhibits all three VEGF-family receptors, but also fibroblast growth factor and platelet-derived growth factor receptors. This multiple-receptor inhibition may explain why the peptide was also seen to be a powerful inhibitor of tumour growth and also a partial inhibitor of arthritic joint inflammation in vivo.

Khat (Catha edulis) alters the phenotype and anti-microbial activity of peripheral blood mononuclear cells.

AIMS OF STUDY: The habit of khat chewing has been associated with increased risk of systemic and oral disease. Although research has been conducted on the affects of khat on oral epithelial cells, little is known about its influence on immune cells. This study examined the biological effects of khat on the phenotype and function of peripheral blood mononuclear cells (PBMCs). MATERIAL AND METHODS: Khat-stimulated PBMCs were examined for signs of cytotoxicity, apoptosis and changes in cell surface receptor and cytokine expression. Khat-induced regulation of transcription factors and stress-related factors were examined, as was PBMC phagocytic activity against oral bacteria. RESULTS: Khat was cytotoxic to PBMC in a dose- and time-dependent manner and cell death was mediated by apoptosis. Khat-treated PBMC showed increased expression of co-stimulatory molecules (CD80, CD86 and MHC II) and pattern recognition receptors (TLR-2, TLR-4 and TREM-1) but secretion of inflammatory cytokines (TNFα, IL-6, CCL5, CXCL8) was inhibited. In contrast, khat induced an increase in the anti-inflammatory cytokine IL-10 as well as IL-2, IFN-γ, FasL and HSP70. These khat-induced alterations were accompanied by increased expression of transcription factors p38 MAPK and HIF-1α, whilst expression of NFκB p65 was inhibited. Although the ability of PBMC to phagocytose dextran and oral bacteria was inhibited, production of reactive oxygen species was increased. CONCLUSION: These data suggest that khat may severely influence the effectiveness of immune surveillance and anti-microbial capacity of PBMCs.

Tumour infiltrating host cells and their significance for hyperthermia.

Much information can be gained by investigating the consequences of hyperthermia on individual cell populations in vitro, however the precise effects of such a therapeutic modality in vivo depend on the tumour microenvironment and the cellular composition therein. Although the direct cytotoxic effects of hyperthermia on tumour tissue can lead to an immediate reduction in tumour volume, long-term benefits to local and distal tumour recurrence will very much depend on the induction of immunity and the capacity of effector cells to traffic to tumours and elicit their cytotoxic functions. The immunological sequelae to hyperthermia are even more important in those instances when large tumour volumes preclude the delivery of appropriate thermal damage. The development of protective anti-tumour immunity requires a plethora of interactions and responses, the vast majority of which can be influenced by temperatures that are consistent with fever-like temperatures (39 degrees -40 degrees C), as well as hyperthermia treatment (<41 degrees C). This article reviews current knowledge relating to the effects of hyperthermia treatment on aspects of the induction and manifestation of immunological responses that are most pertinent to the development and maintenance of protective anti-tumour immunity.