Phytochemical-Based Nanomedicine for Advanced Cancer Theranostics: Perspectives on Clinical Trials to Clinical Use.

In the current chapter, a new strategic compilation of phytochemicals with potent antitumor properties has been addressed, most importantly focusing on cell cycle arrest and apoptotic signaling mechanism. A promising approach in tumor prevention is to eliminate cancer cells preferably via cell cycle arrest and programmed cell death with lesser harm to neighboring normal cells. Cancer cells have a survival advantage to escape apoptosis and relentlessly divide to proliferate, gearing up the cell cycle process. Recently, the use of phytochemical-derived conjugated chemotherapeutic agents has increased dramatically owing to its biocompatibility, low cytotoxicity, low resistance, and dynamic physiochemical properties discriminating normal cells in the treatment of various cancer types. For decades, biomedical investigations have targeted cell cycle and apoptotic cell death mechanism as an effective cancer-killing tool for systemically assessing the potential biological interactions of functional phytocompounds compared to its synthetic counterparts during their complete life cycles from entry, biodistribution, cellular/molecular interactions to excretion. Newly emerging nanotechnology application in anticancer drug formulations has revolutionized cancer therapy. Tissue-specific phyto-nanomedicine plays a vital role in advanced cancer diagnostics using liposome, micelle, and nanoparticles as a precise and effective delivery vehicle. This chapter specifically focuses on the therapeutic phytomolecules approved by the Food and Drug Administration (FDA, USA) along with phyto-chemopreventives currently on clinical trials (Phase-I/II/III/IV). Besides, detailed coverage is given to the FDA-approved nanotechnology-based formulations only in the areas of cancer theranostics via cell cycle arrest and apoptotic pathways including present challenges and future perspectives.

Ameliorating effect of CpG-ODN (oligodeoxynucleotide) against radiation-induced lung injury in mice.

While radiation-induced lung injury (RILI) is known to be progressed by Th2 skewed, pro-inflammatory immune response, there have been few therapeutic attempts through Th1 immune modulation. We investigated whether the immunostimulant CpG-oligodeoxynucleotide (CpG-ODN) would be effective against RILI by way of measuring reactive oxygen species (ROS) and nitric oxides (NO), histopathology, micro-three-dimensional computer tomography (CT), and cytokine profiling. We found that KSK CpG-ODN (K-CpG) significantly reduced histopathological fibrosis when compared to the positive control (PC) group (p < 0.01). The levels of ROS production in serum and splenocyte of PC group were significantly higher than that of K-CpG group (p < 0.01). The production of nitric oxide (NO) in CpG-ODNs group was higher than that of PC group. Last, cytokine profiling illustrated that the protein concentrations of Th1-type cytokines such as IL-12 and TNF-α as well as Th2-type cytokine IL-5 in K-CpG group inclined to be significantly (p < 0.001 or p < 0.01) higher than those of in PC group. Collectively, our study clearly indicates that K-CpG is effective against RILI in mice by modulating the innate immune response. To our knowledge, this is the first note on anti-RILI effect of human type, K-CpG, clinically implying the potential of immunotherapy for RILI control.

Immunotoxicity of titanium dioxide nanoparticles via simultaneous induction of apoptosis and multiple toll-like receptors signaling through ROS-dependent SAPK/JNK and p38 MAPK activation.

BACKGROUND: Titanium dioxide nanoparticles (TiO2 NPs) represent a scientific breakthrough in the areas of biological and medicinal applications. Interaction of TiO2 NPs with components of innate immune system remains elusive. AIM: This study explored in vitro immunotoxicity of murine macrophage RAW 264.7 to TiO2 NPs (20 nm, negative charge) and its underlying molecular mechanism by way of immunoredox profiling. MATERIALS AND METHODS: In this study, chemically synthesized BSA-functionalized TiO2 NPs (20 nm, negative charge) were characterized and immunotoxicity was investigated on RAW 264.7 cells. RESULTS: We found that reactive oxygen species levels significantly increased with increasing nitric oxide production, whereas depleting endogenous antioxidant super oxide dismutase as well as nuclear factor erythroid 2-related factor 2 (Nrf2) protein levels. Furthermore, NPs exposure increased the expression of apoptotic factors such as BAX, BIM, and PUMA with disruption of mitochondrial membrane potential (Δψm) that lead to decrease in immunocytes. Molecular immune profiling revealed the activation of multiple toll-like receptors (TLRs) 4/9/12/13 simultaneously with the phosphorylation of p-p38MAPK and p-SAPK/c-Jun N-terminal kinase (JNK) compared to untreated control. CONCLUSION: Collectively, this study shows that the molecular nature of TiO2 SA20(-) NP-induced immunotoxicity in RAW 264.7 macrophage is simultaneous induction of immunocyte apoptosis and multiple TLRs signaling through oxidative stress-dependent SAPK/JNK and p38 mitogen-associated protein kinase activation. This is the first study to address newer molecular mechanism of TiO2 SA20(-) NP-induced immunotoxicity.

Implication of immunokine profiling for cancer staging.

Tumor may arise from the dysregulation of immune system, which plays pivotal roles in counteracting tumor colonization, late-stage tumors, and metastases. In the midst of the establishment of cancer in vivo, immune cells are activated to release a multitude of immunokines, such as cytokines, and chemokines. Thus, since cytokine levels in tumor bearing host would be differential among local (intratumoral lesion, peritumoral normal tissue), and systemic sample site (serum), these differences might be significantly correlated to prognosis and treatment outcome for cancer patients. Previously, despite small number of patients, we demonstrated the feasibility of this proposition via only cytokine profiling. Based on this, herein we propose that immunokine profiling would be used as a surrogate, predictive tool for cancer staging, and progression.