Nanotechnology-mediated photodynamic therapy: Focus on overcoming tumor hypoxia.

The oxygen level in the tumor is a critical marker that determines response to different treatments. Cancerous cells can adapt to hypoxia and low pH conditions within the tumor microenvironment (TME) to regulate tumor metabolism, proliferation, and promote tumor metastasis as well as angiogenesis, consequently leading to treatment failure and recurrence. In recent years, widespread attempts have been made to overcome tumor hypoxia through different methods, such as hyperbaric oxygen therapy (HBOT), hyperthermia, O2 carriers, artificial hemoglobin, oxygen generator hydrogels, and peroxide materials. While oxygen is found to be an essential agent to improve the treatment response of photodynamic therapy (PDT) and other cancer treatment modalities, the development of hypoxia within the tumor is highly associated with PDT failure. Recently, the use of nanoparticles has been a hot topic for researchers and exploited to overcome hypoxia through Oxygen-generating hydrogels, O2 nanocarriers, and O2 -generating nanoparticles. This review aimed to discuss the role of nanotechnology in tumor oxygenation and highlight the challenges, prospective, and recent advances in this area to improve PDT outcomes. This article is categorized under: Nanotechnology Approaches to Biology > Cells at the Nanoscale Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.

Understanding the Photodynamic Therapy Induced Bystander and Abscopal Effects: A Review.

Photodynamic therapy (PDT) is a clinically approved minimally/non-invasive treatment modality that has been used to treat various conditions, including cancer. The bystander and abscopal effects are two well-documented significant reactions involved in imparting long-term systemic effects in the field of radiobiology. The PDT-induced generation of reactive oxygen and nitrogen species and immune responses is majorly involved in eliciting the bystander and abscopal effects. However, the results in this regard are unsatisfactory and unpredictable due to several poorly elucidated underlying mechanisms and other factors such as the type of cancer being treated, the irradiation dose applied, the treatment regimen employed, and many others. Therefore, in this review, we attempted to summarize the current knowledge regarding the non-targeted effects of PDT. The review is based on research published in the Web of Science, PubMed, Wiley Online Library, and Google Scholar databases up to June 2023. We have highlighted the current challenges and prospects in relation to obtaining clinically relevant robust, reproducible, and long-lasting antitumor effects, which may offer a clinically viable treatment against tumor recurrence and metastasis. The effectiveness of both targeted and untargeted PDT responses and their outcomes in clinics could be improved with more research in this area.

Photodynamic therapy induced cell cycle arrest and cancer cell synchronization: review.

Cell cycle arrest (CCA) is seen as a prime candidate for effective cancer therapy. This mechanism can help researchers to create new treatments to target cancer cells at particular stages of the cell cycle (CC). The CCA is a characteristic of various therapeutic modalities, including radiation (RT) and chemotherapy (CT), which synchronizes the cells and facilitates the standardization of radio-chemotherapy protocols. Although it was discovered that photodynamic treatment (PDT) had a biological effect on CCA in cancer cells, the mechanism remains unclear. Furthermore, besides conventional forms of cell death such as apoptosis, autophagy, and necrosis, various unconventional types of cell death including pyroptosis, mitotic catastrophe, paraptosis, ferroptosis, necroptosis, and parthanatos after PDT have been reported. Thus, a variety of elements, such as oxygen, the tumor's microenvironment, the characteristics of light, and photosensitizer (PS), influence the effectiveness of the PDT treatment, which have not yet been studied clearly. This review focuses on CCA induced by PDT for a variety of PSs agents on various cell lines. The CCA by PDT can be viewed as a remarkable effect and instructive for the management of the PDT protocol. Regarding the relationship between the quantity of reactive oxygen species (ROS) and its biological consequences, we have proposed two mathematical models in PDT. Finally, we have gathered recent in vitro and in vivo studies about CCA post-PDT at various stages and made suggestions about how it can standardize, potentiate, and customize the PDT methodology.

Biomedical applications of PLGA nanoparticles in nanomedicine: advances in drug delivery systems and cancer therapy.

INTRODUCTION: During the last decades, the ever-increasing proportion of patients with cancer has been led to serious concerns worldwide. Therefore, the development and use of novel pharmaceuticals, like nanoparticles (NPs)-based drug delivery systems (DDSs), can be potentially effective in cancer therapy. AREA COVERED: Poly lactic-co-glycolic acid (PLGA) NPs, as a kind of bioavailable, biocompatible, and biodegradable polymers, have approved by the Food and Drug Administration (FDA) for some biomedical and pharmaceutical applications. PLGA is comprised of lactic acid (LA) and glycolic acid (GA) and their ratio could be controlled during various syntheses and preparation approaches. LA/GA ratio determines the stability and degradation time of PLGA; lower content of GA results in fast degradation. There are several approaches for preparing PLGA NPs that can affect their various aspects, such as size, solubility, stability, drug loading, pharmacokinetics, and pharmacodynamics, and so on. EXPERT OPINION: These NPs have indicated the controlled and sustained drug release in the cancer site and can use in passive and active (via surface modification) DDSs. This review aims to provide an overview of PLGA NPs, their preparation approach and physicochemical aspects, drug release mechanism and the cellular fate, DDSs for efficient cancer therapy, and status in the pharmaceutical industry and nanomedicine.

Critical parameters to translate gold nanoparticles as radiosensitizing agents into the clinic.

Radiotherapy is an inevitable choice for cancer treatment that is applied as combinatorial therapy along with surgery and chemotherapy. Nevertheless, radiotherapy at high doses kills normal and tumor cells at the same time. In addition, some tumor cells are resistant to radiotherapy. Recently, many researchers have focused on high-Z nanomaterials as radiosensitizers for radiotherapy. Among them, gold nanoparticles (GNPs) have shown remarkable potential due to their promising physical, chemical, and biological properties. Although few clinical trial studies have been performed on drug delivery and photosensitization with lasers, GNPs have not yet received Food and Drug Administration approval for use in radiotherapy. The sensitization effects of GNPs are dependent on their concentration in cells and x-ray energy deposition during radiotherapy. Notably, some limitations related to the properties of the GNPs, including their size, shape, surface charge, and ligands, and the radiation source energy should be resolved. At the first, this review focuses on some of the challenges of using GNPs as radiosensitizers and some biases among in vitro/in vivo, Monte Carlo, and clinical studies. Then, we discuss the challenges in the clinical translation of GNPs as radiosensitizers for radiotherapy and proposes feasible solutions. And finally, we suggest that certain areas be considered in future research. This article is categorized under: Therapeutic Approaches and Drug Discovery > NA.

Immunoregulation by resveratrol; implications for normal tissue protection and tumour suppression.

Immune reactions are involved in both tumour and normal tissue in response to therapy. Elevated secretion of certain chemokines, exosomes and cytokines triggers inflammation, pain, fibrosis and ulceration among other normal tissue side effects. On the other hand, secretion of tumour-promoting molecules suppresses activity of anticancer immune cells and facilitates the proliferation of malignant cells. Novel anticancer drugs such as immune checkpoint inhibitors (ICIs) boost anticancer immunity via inducing the proliferation of anticancer cells such as natural killer (NK) cells and CD8+ T lymphocytes. Certain chemotherapy drugs and radiotherapy may induce anticancer immunity in the tumour, however, both have severe side effects for normal tissues through stimulation of several immune responses. Thus, administration of natural products with low side effects may be a promising approach to modulate the immune system in both tumour and normal organs. Resveratrol is a well-known phenol with diverse effects on normal tissues and tumours. To date, a large number of experiments have confirmed the potential of resveratrol as an anticancer adjuvant. This review focuses on ensuing stimulation or suppression of immune responses in both tumour and normal tissue after radiotherapy or anticancer drugs. Later on, the immunoregulatory effects of resveratrol in both tumour and normal tissue following exposure to anticancer agents will be discussed.

Induction of Cancer Cell Death by Apigenin: A Review on Different Cell Death Pathways.

Induction of cell death and inhibition of cell proliferation in cancer have been set as some of the main goals in anti-tumor therapy. Cancer cell resistance leads to less efficient cancer therapy, and consequently, to higher doses of anticancer drugs, which may eventually increase the risk of serious side effects in normal tissues. Apigenin, a nature-derived and herbal agent, which has shown anticancer properties in several types of cancer, can induce cell death directly and/or amplify the induction of cell death through other anti-tumor modalities. Although the main mechanism of apigenin in order to induce cell death is apoptosis, other cell death pathways, such as autophagic cell death, senescence, anoikis, necroptosis, and ferroptosis, have been reported to be induced by apigenin. It seems that apigenin enhances apoptosis by inducing anticancer immunity and tumor suppressor genes, like p53 and PTEN, and also by inhibiting STAT3 and NF-κB signaling pathways. Furthermore, it may induce autophagic cell death and ferroptosis by inducing endogenous ROS generation. Stimulation of ROS production and tumor suppressor genes, as well as downregulation of drug-resistance mediators, may induce other mechanisms of cell death, such as senescence, anoikis, and necroptosis. It seems that the induction of each type of cell death is highly dependent on the type of cancer. These modulatory actions of apigenin have been shown to enhance anticancer effects by other agents, such as ionizing radiation and chemotherapy drugs. This review explains how cancer cell death may be induced by apigenin at the cellular and molecular levels.

Resveratrol as an Enhancer of Apoptosis in Cancer: A Mechanistic Review.

The resistance to therapy of cancer cells is a challenge for achieving an appropriate therapeutic outcome. Cancer (stem) cells possess several mechanisms for increasing their survival following exposure to toxic agents such as chemotherapy drugs, radiation, as well as immunotherapy. Evidences show that apoptosis plays a key role in the response of cancer (stem) cells and their multi-drug resistance. Modulation of both intrinsic and extrinsic pathways of apoptosis can increase the efficiency of tumor response and amplify the therapeutic effects of radiotherapy, chemotherapy, targeted therapy, and also immunotherapy. To date, several agents, as adjuvant, have been proposed to overcome the resistance of cancer cells to apoptosis. Natural products are interesting because of the low toxicity on normal tissues. Resveratrol is a natural herbal agent that has shown interesting anti-cancer properties. It has been shown to kill cancer cells selectively while protecting normal cells. Resveratrol can augment reduction/oxidation (redox) reactions, thus increases the production of ceramide and the expression of apoptosis receptors, such as Fas Ligand (FasL). Resveratrol also triggers some pathways which induce the mitochondrial pathway of apoptosis. On the other hand, resveratrol has an inhibitory effect on antiapoptotic mediators, such as Nuclear Factor κ B (NF-κB), Cyclooxygenase-2 (COX-2), Phosphatidylinositol 3- Kinase (PI3K), and mTOR. In this review, we explain the modulatory effects of resveratrol on apoptosis, which can augment the therapeutic efficiency of anti-cancer drugs or radiotherapy.

Iron oxide/gold nanoparticles-decorated reduced graphene oxide nanohybrid as the thermo-radiotherapy agent.

The main focus of the current study is the fabrication of a multifunctional nanohybrid based on graphene oxide (GO)/iron oxide/gold nanoparticles (NPs) as the combinatorial cancer treatment agent. Gold and iron oxide NPs formed on the GONPs via the in situ synthesis approach. The characterisations showed that gold and iron oxide NPs formed onto the GO. Cell toxicity assessment revealed that the fabricated nanohybrid exhibited negligible toxicity against MCF-7 cells in low doses (<50 ppm). Temperature measurement showed a time and dose-dependent heat elevation under the interaction of the nanohybrid with the radio frequency (RF) wave. The highest temperature was recorded using 200 ppm concentration nanohybrid during 40 min exposure. The combinatorial treatments demonstrated that the maximum cell death (average of 53%) was induced with the combination of the nanohybrid with RF waves and radiotherapy (RT). The mechanistic study using the flow cytometry technique illustrated that early apoptosis was the main underlying cell death. Moreover, the dose enhancement factor of 1.63 and 2.63 were obtained from RT and RF, respectively. To sum up, the authors' findings indicated that the prepared nanohybrid could be considered as multifunctional and combinatorial cancer therapy agents.

Alginate hydrogel co-loaded with cisplatin and gold nanoparticles for computed tomography image-guided chemotherapy.

The biomedical applications of gold nanoparticles (AuNPs) have experienced rapid growth in recent years, due to their expected benefits in medical imaging and therapy. In this work, we report the development of a theranostic nanocomplex constructed from alginate hydrogel co-loaded with cisplatin and AuNPs (abbreviated as ACA) for simultaneous drug delivery and computed tomography imaging. CT26 cells derived from mouse colon adenocarcinoma were exposed to various concentrations of ACA nanocomplex (for 24 h) and the cytotoxicity was measured using MTT assay. Moreover, the cells treated with ACA nanocomplex were imaged in a computed tomography scanner and the contrast enhancement due to the presence of nanocomplex was assessed. The cytotoxicity results showed that ACA nanocomplex had a more potent chemotherapy efficacy than free cisplatin, so that ACA nanocomplex at the concentration of 5 µg/ml (per cisplatin) and 20 µg/ml of free cisplatin resulted in the same cytotoxicity (survival rate: 66%). The computed tomography imaging study revealed that ACA nanocomplex increased the brightness of computed tomography images, the computed tomography number value, and contrast-to-noise ratio (CNR). ACA nanocomplex can be presented as a computed tomography-traceable nanocarrier that allows to monitor the delivery of therapeutics by assessing their localized accumulation and in vivo biodistribution.

Effects of artifact removal on cone-beam computed tomography images.

BACKGROUND: Dental implants and metal fillings may cause artifacts in cone-beam computed tomography (CBCT) images and reduce image quality and anatomic accuracy. The purposes of this study are a subjective evaluation of anatomic landmarks and linear bone measurements after applying artifact removal (low-medium) option on CBCT images. MATERIALS AND METHODS: In this cross-sectional study, thirty CBCT images from thirty qualified patients were selected in a private radiology center. Low and medium artifact removal was applied to images. Three radiologists assessed the visibility of the mandibular canal, mental foramen, and lamina dura in images. Crestal width and bone length were also measured in three groups of images and was compared by exact McNemar test. ICC test (two-way random model, absolute agreement types) was calculated for comparison of linear bone measurements in three images groups. P ≤ 0.05 was considered statistically significant. RESULTS: Percent agreement of determining mental foramen (outline and location), mandibular canal (outline and location), and lamina dura between three groups of images were 100%, 100%, 83.3%, 96.7%, and 56.6%, respectively. The results of exact McNemar test revealed that medium artifact removal group had a statistical difference in lamina dura observation with none and low artifact removal groups (P < 0.001). Intraclass correlation coefficient showed no statistical differences in crestal width and bone length between groups (P < 0.001). CONCLUSION: Applying artifact removal does not affect the visibility of large anatomical structures and linear bone measurements, but delicate structures such as lamina dura may become less clear after artifact removal.

Synergistic Effects of Arsenic Trioxide and Radiation: Triggering the Intrinsic Pathway of Apoptosis

Background: Arsenic trioxide (ATO) has been reported as an effective anti-cancer and a US Food and Drug Administration (FDA) approved drug for treatment of some cancers. The aim of this study was to determine the underlying apoptosis molecular and cellular mechanisms of ATO in the presence or absence of ionizing radiation (IR) in vitro in the glioblastoma multiforme (GBM) cell line, U87MG. Methods: Cells were treated by different concentrations of ATO either in presence or absence of IR. Viability and apoptosis pathway of both treated and control groups were evaluated using MTT assay and the expression analysis of Bax, Bcl-2, and caspase-3 genes, respectively. All treatments were performed on 100-µm diameter spheroids. Results: Results showed a significant reduction in the survival of the cells in all treated groups. As expected, cell survival was much less in combination treatment than treatment with only ATO. Moreover, combination therapy made Bax and caspase-3 up-regulated and Bcl-2 down-regulated. Conclusion: ATO and radiation had a synergistic apoptotic effect on GBM cells by up-regulation of caspase-3 and alteration of the Bax-Bcl-2 balance; therefore, ATO may act as a potential anti-cancer agent against GBM cells through triggering the mitochondrial pathway of apoptosis.