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Significance We constructed simple cells (SimCells) whose native chromosomes were removed and replaced by synthetic genetic circuits. The chromosome-free SimCells can process designed DNA and express target genes for an extended period of time. The strategy of SimCell generation is applicable to most bacteria, creating a universal platform for reprogramming bacteria. We demonstrated that SimCells can be designed as safe agents for bacterial therapy through synthesis and delivery of a potent anticancer drug against a variety of cancer cell lines. This showed that the nonreplicating and programmable property of SimCells is advantageous for applications in sensitive environments. The results of this work will both improve our understanding of natural living systems and simultaneously lay the foundations for future advances in synthetic biology., A type of chromosome-free cell called SimCells (simple cells) has been generated from Escherichia coli, Pseudomonas putida, and Ralstonia eutropha. The removal of the native chromosomes of these bacteria was achieved by double-stranded breaks made by heterologous I-CeuI endonuclease and the degradation activity of endogenous nucleases. We have shown that the cellular machinery remained functional in these chromosome-free SimCells and was able to process various genetic circuits. This includes the glycolysis pathway (composed of 10 genes) and inducible genetic circuits. It was found that the glycolysis pathway significantly extended longevity of SimCells due to its ability to regenerate ATP and NADH/NADPH. The SimCells were able to continuously express synthetic genetic circuits for 10 d after chromosome removal. As a proof of principle, we demonstrated that SimCells can be used as a safe agent (as they cannot replicate) for bacterial therapy. SimCells were used to synthesize catechol (a potent anticancer drug) from salicylic acid to inhibit lung, brain, and soft-tissue cancer cells. SimCells represent a simplified synthetic biology chassis that can be programmed to manufacture and deliver products safely without interference from the host genome.

Recent clinical cohort studies have highlighted that there is a three-fold greater SARS-Cov-2 infection risk in cancer patients, and overall mortality in individuals with tumours is increased by 41% with respect to general COVID-19 patients. Thus, access to therapeutics and intensive care is compromised for people with both diseases (comorbidity) and there is risk of delayed access to diagnosis. This comorbidity has resulted in extensive burden on the treatment of patients and health care system across the globe; moreover, mortality of hospitalized patients with comorbidity is reported to be 30% higher than for individuals affected by either disease. In this data-driven review, we aim specifically to address drug discoveries and clinical data of cancer management during the COVID-19 pandemic. The review will extensively address the treatment of COVID-19/cancer comorbidity; treatment protocols and new drug discoveries, including the description of drugs currently available in clinical settings; demographic features; and COVID-19 outcomes in cancer patients worldwide.

‘Bioinks’ are important tools for the fabrication of artificial living-tissue constructs that are able to mimic all properties of native tissues via 3D bioprinting technologies. Bioinks are most commonly made by incorporating live cells of interest within a natural or synthetic biocompatible polymeric matrix. In oncology research, the ability to recreate atumor microenvironment(TME) using by 3D bioprinting constitutes a promising approach for drug development, screening, andin vitrocancer modeling. Here, we review the different types of bioink used for 3D bioprinting, with a focus on its application in cancer management. In addition, we consider the fabrication of bioink using customized materials/cells and their properties in the field of cancer drug discovery.

Rhabdomyosarcoma (RMS) is a rare type of soft tissue sarcoma most commonly found in pediatric patients. Despite progress, new and improved drug regimens are needed to increase survival rates. Citral, a natural product plant oil can induce cell death in cancer cells. Another compound, metformin, isolated originally from French lilac and used by diabetics, has been shown to reduce the incidence of cancer in these patients. Application of citral to RMS cells showed increase in cell death, and RD and RH30 cells showed half maximal inhibitory concentration (IC50) values as low as 36.28 μM and 62.37 μM, respectively. It was also shown that the citral initiated cell apoptosis through an increase in reactive oxygen species (ROS) and free calcium. In comparison, metformin only showed moderate cell death in RMS cell lines at a very high concentration (1,000 μM). Combinatorial experiments, however, indicated that citral and metformin worked antagonistically when used together. In particular, the ability of metformin to quench the ROS induced by citral could lead to the suppression of activity. These results clearly indicate that while clinical use of citral is a promising anti-tumor therapy, caution should be exercised in patients using metformin for diabetes.

Plant volatile organic compounds (volatiles) are secondary plant metabolites that play crucial roles in the reproduction, defence, and interactions with other vegetation. They have been shown to exhibit a broad range of biological properties and have been investigated for antimicrobial and anticancer activities. In addition, they are thought be more environmentally friendly than many other synthetic chemicals 1. Despite these facts, their applications in the medical, food, and agricultural fields are considerably restricted due to their volatilities, instabilities, and aqueous insolubilities. Nanoparticle encapsulation of plant volatile organic compounds is regarded as one of the best strategies that could lead to the enhancement of the bioavailability and biological activity of the volatile compounds by overcoming their physical limitations and promoting their controlled release and cellular absorption. In this review, we will discuss the biosynthesis and analysis of plant volatile organic compounds, their biological activities, and limitations. Furthermore, different types of nanoparticle platforms used to encapsulate the volatiles and the biological efficacies of nanoencapsulated volatile organic compounds will be covered.

Cancer cell resistance to chemotherapeutics (chemoresistance) poses a significant clinical challenge that oncology research seeks to understand and overcome. Multiple anticancer drugs and targeting agents can be incorporated in nanomedicines, in addition to different treatment modalities, forming a single nanoplatform that can be used to address tumor chemoresistance. Nanomedicine-driven molecular assemblies using nucleic acids, small interfering (si)RNAs, miRNAs, and aptamers in combination with stimuli-responsive therapy improve the pharmacokinetic (PK) profile of the drugs and enhance their accumulation in tumors and, thus, therapeutic outcomes. In this review, we highlight nanomedicine-driven molecular targeting and therapy combination used to improve the 3Rs (right place, right time, and right dose) for chemoresistant tumor therapies.

To date, various chemically synthesized and biosynthesized nanoparticles, or hybrid nanosystems and/or nanoplatforms, have been developed under the umbrella of nanomedicine. These can be introduced into the body orally, nasally, intratumorally or intravenously. Successfully translating hybrid nanoplatforms from preclinical proof-of-concept to therapeutic value in the clinic is challenging. Having made significant advances with drug delivery technologies, we must learn from other areas of oncology drug development, where patient stratification and target-driven design have improved patient outcomes. This review aims to identify gaps in our understanding of the current strengths of nanomedicine platforms in drug delivery and cancer theranostics. We report on the current approaches of nanomedicine at preclinical and clinical stages.

Glioblastoma is a heterogeneous disease with multiple genotypic origins. Despite treatment protocols such as surgery, radiotherapy and chemotherapy, the prognosis for patients remains poor. This study investigates the cytotoxic and radiation dose-enhancing and radiosensitizing ability of five rare earth oxide nanoparticles, in two different immortalized mammalian cell lines; U-87 MG and Mo59K. Significant cytotoxicity was observed in U-87 MG cells when exposed to Nd

Rachel A Morrison,1,* Malgorzata J Rybak-Smith,1,* James M Thompson,2 Bénédicte Thiebaut,3 Mark A Hill,2 Helen E Townley1,4 1Department of Engineering Science, 2Gray Laboratories, CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, 3Johnson Matthey, Technology Centre, Reading, Berkshire, 4Nuffield Department of Obstetrics and Gynaecology, John Radcliffe Hospital, University of Oxford, Oxford, UK *These authors have contributed equally to this work Abstract: The aim of this study was to develop a manufacturing protocol for large-scale production of doped titania radiosensitizing nanoparticles (NPs) to establish their activity under hypoxia and to produce a multimodal radiosensitizing embolic particle for cancer treatment. We have previously shown that radiosensitizing NPs can be synthesized from titania doped with rare earth elements, especially gadolinium. To translate this technology to the clinic, a crucial step is to find a suitable, scalable, high-throughput method. Herein, we have described the use of flame spray pyrolysis (FSP) to generate NPs from titanium and gadolinium precursors to produce titania NPs doped with 5at% gadolinium. The NPs were fully characterized, and their capacity to act as radiosensitizers was confirmed by clonogenic assays. The integrity of the NPs in vitro was also ascertained due to the potentially adverse effects of free gadolinium in the body. The activity of the NPs was then studied under hypoxia since this is often a barrier to effective radiotherapy. In vitro radiosensitization experiments were performed with both the hypoxia mimetics deferoxamine and cobalt chloride and also under true hypoxia (oxygen concentration of 0.2%). It was shown that the radiosensitizing NPs were able to cause a significant increase in cell death even after irradiation under hypoxic conditions such as those found in tumors. Subsequently, the synthesized NPs were used to modify polystyrene embolization microparticles. The NPs were sintered to the surface of the microparticles by heating at 230°C for 15minutes. This resulted in a good coverage of the surface and to generate embolization particles that were shown to be radiosensitizing. Such multimodal particles could therefore result in occlusion of the tumor blood vessels in conjunction with localized reactive oxygen species generation, even under hypoxic conditions such as those found in the center of tumors. Keywords: cancer, ROS, reactive oxygen species, titania, multimodal

Nanoparticles may be used in vaccinology as an antigen delivery and/or an immunostimulant to enhance immunity. Porous silica has been identified as an effective adjuvant for more than a decade, and we have therefore investigated the take up rate by an immortalized macrophage-like cell line of a number of mesoporous silica nanoparticles (MSNPs) with differing diameter and pore size. The MSNPs were synthesized using a sol-gel reaction and post-synthesis removal of the template. The MSNPs showed a clear distribution in take up rate peaking at 217 nm, whereas a comparison with solid spherical nanoparticles showed a similar distribution peaking at 377 nm. The MSNPs were investigated before and after loading with antigen. Diphtheria toxoid was used as a proof-of-concept antigen and showed a peak macrophage internalization of 53.42% for loaded LP3 particles which had a diameter of 217.75 ± 5.44 nm and large 16.5 nm pores. Optimal MSNP sizes appeared to be in the 200–400 nm range, and larger pores showed better antigen loading. The mesoporous silica particles were shown to be generally biocompatible, and cell viability was not altered by the loading of particles with or without antigen.

Dysregulation of iron metabolism is a common characteristic of cancer cells. The rapid proliferation of the tumour cells means that there is an increased dependence upon iron compared to healthy cells. Chelation of iron can be undertaken with a number of different compounds, however, simply lowering systemic iron levels to control tumour growth is not possible since iron is essential for cellular metabolism in the rest of the body. Nanoparticulate iron chelators could overcome this difficulty by targeting to the tumour either by the passive enhanced permeation and retention effect, or by targeting ligands on the surface. Nanoparticles were prepared from melanin, which is a naturally occurring pigment that is widely distributed within the body, but that can chelate iron. The prepared nanoparticles were shown to be ~220 nm, and could adsorb 16.45 mmoles iron/g melanin. The nanoparticles showed no affect on control fibroblast cells at a concentration of 200 μM, whereas the immortalised cancer cell lines showed at least 56% reduction in cell growth. At a concentration of 1 mM melanin nanoparticles the cell growth could be reduced by 99% compared to the control. The nanoparticles also show no significant haemotoxicity, even at concentration of 500 μM. Melanin nanoparticles are therefore a viable prospect for destroying cancer cells via iron starvation.

Benjamin White,1 Anna Evison,1 Eszter Dombi,1 Helen E Townley1,2 1Nuffield Department of Obstetrics and Gynaecology, Women’s Centre, John Radcliffe Hospital, 2Department of Engineering Science, Oxford University, Oxford, UK Abstract: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children, with a 5-year survival rate of between 30 and 65%. Standard treatment involves surgery, radiation treatment, and chemotherapy. However, there is a high recurrence rate, particularly from locoregional spread. We investigated the use of the natural compound citral (3,7-dimethyl-2,6-octadienal), which can be found in a number of plants, but is particularly abundant in lemon grass (Cymbopogon citratus) oil, for activity against immortalized RMS cells. Significant cancer cell death was seen at concentrations above 150 μM citral, and mitochondrial morphological changes were seen after incubation with 10 μM citral. However, since citral is a highly volatile molecule, we prepared albumin particles by a desolvation method to encapsulate citral, as a means of stabilization. We then further incorporated the loaded nanoparticles into a biodegradable polyanhydride wafer to generate a slow release system. The wafers were shown to degrade by 50% over the course of 25 days and to release the active compound. We therefore propose the use of the citral-nanoparticle-polymer wafers for implantation into the tumor bed after surgical removal of a sarcoma as a means to control locoregional spread due to any remaining cancerous cells. Keywords: citral, nanoparticle, wafer, biodegradable, mitochondria, toroidal, cancer, rhabdomyosarcoma, Cymbopogon citratus

The prognosis of brain cancer glioblastoma (GBM) is poor, and despite intense research, there have been no significant improvements within the last decade. This stasis implicates the need for more novel therapeutic investigation. One such option is the use of nanoparticles (NPs), which can be beneficial due to their ability to penetrate the brain, overcome the blood–brain barrier and take advantage of the enhanced permeation and retention effect of GBM to improve specificity. Rare earth elements possess a number of interesting natural properties due to their unique electronic configuration, which may prove therapeutically advantageous in an NP formulation. The underexplored exciting potential for rare earth elements to augment the therapeutic potential of NPs in GBM treatment is discussed in this review.

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma that is found in children and has a poor outcome for those with metastatic disease. Two histological groups have been distinguished - embryonal (ERMS) and alveolar (ARMS) forms. The ARMS subtype has higher rates of metastasis, as well as higher levels of ELMO1, which is thought to be involved in cell migration. Therefore, the knock-down of ELMO1 by targeted siRNA could provide a mechanism to prevent the metastatic behaviour of ARMS cells. However, challenges still lie in the delivery of nucleotides to a tumour site. Herein, we have described the use of a variety of mesoporous silica nanoparticles as a delivery system for siRNA that is specific for ELMO1 and shown the effective reduction in cell invasive behaviour in these cells.