Selective Destruction Of Cancer Cells Research Articles

Targeted delivery of the metastasis-specific tumour homing TMTP1 peptide to non-small-cell lung cancer (NSCLC) using inhalable hybrid nano-assemblies.

Lung cancer is one of the most fatal malignancies, with the highest death rate (∼19%), and the NSCLC type accounts for ∼85% of lung cancers. In the search for new treatments, antimicrobial peptides have received much attention due to their propensity for selective destruction of cancer cells. In the current study, we evaluated the efficacy of the metastasis-specific tumour-homing-TMTP1 peptide against lung cancer using inhalable hybrid nano-assemblies of the PEG-PLGA copolymer as a carrier for pulmonary delivery which was assessed for aerodynamic and physicochemical properties, along with the peptide-release profile, physical stability, cellular uptake and biocompatibility, generation of reactive oxygen species, cell migration, autophagic flux, and apoptotic cell death in A549 lung cancer cells. Optimization of inhaled dose, lung retention, and efficacy studies was conducted to evaluate the formulation in an NNK (nicotine-derived nitrosamine ketone) induced tumour-bearing lung cancer murine model. After inhalation, the formulation with nano-scale physiognomies showed good lung deposition, retention, and metabolic stability. The inhalable nano-assemblies have shown enhanced generation of reactive oxygen species with increased autophagy flux and apoptotic cell death. Pre-clinical animal trials show substantial tumour regression by inhalable TMTP1-based nano-formulation with limited side effects. Our results on metastasis targeting and tumour-homing peptide TMTP1 demonstrate its effective tumour targeting and tumour-killing efficacy and provide a reference for the development of new therapeutics for NSCLC.

Multifaceted perspectives of detecting and targeting solid tumors.

Solid tumors are the most prevalent form of cancer. Considerable technological and medical advancements had been achieved for the diagnosis of the disease. However, detection of the disease in an early stage is of utmost importance, still far from reality. On the contrary, the treatment and therapeutic area to combat solid tumors are still in its infancy. Conventional treatments like chemotherapy and radiation therapy pose challenges due to their indiscriminate impact on healthy and cancerous cells. Contextually, efficient drug targeting is a pivotal approach in solid tumor treatment. This involves the precise delivery of drugs to cancer cells while minimizing harm to healthy cells. Targeted drugs exhibit superior efficacy in eradicating cancer cells while impeding tumor growth and mitigate side effects by optimizing absorption which further diminishes the risk of resistance. Furthermore, tailoring targeted therapies to a patient's tumor-specific molecular profile augments treatment efficacy and reduces the likelihood of relapse. This chapter discuss about the distinctive characteristics of solid tumors, the possibility of early detection of the disease and potential therapeutic angle beyond the conventional approaches. Additionally, the chapter delves into a hitherto unknown attribute of magnetic field effect to target cancer cells which exploit the relatively less susceptibility of normal cells compared to cancer cells to magnetic fields, suggesting a future potential of magnetic nanoparticles for selective cancer cell destruction. Lastly, bioinformatics tools and other unconventional methodologies such as AI-assisted codon bias analysis have a crucial role in comprehending tumor biology, aiding in the identification of futuristic targeted therapies.

Innovative approaches for cancer treatment: graphene quantum dots for photodynamic and photothermal therapies.

Graphene quantum dots (GQDs) hold great promise for photodynamic and photothermal cancer therapies. Their unique properties, such as exceptional photoluminescence, photothermal conversion efficiency, and surface functionalization capabilities, make them attractive candidates for targeted cancer treatment. GQDs have a high photothermal conversion efficiency, meaning they can efficiently convert light energy into heat, leading to localized hyperthermia in tumors. By targeting the tumor site with laser irradiation, GQD-based nanosystems can induce selective cancer cell destruction while sparing healthy tissues. In photodynamic therapy, light-sensitive compounds known as photosensitizers are activated by light of specific wavelengths, generating reactive oxygen species that induce cancer cell death. GQD-based nanosystems can act as excellent photosensitizers due to their ability to absorb light across a broad spectrum; their nanoscale size allows for deeper tissue penetration, enhancing the therapeutic effect. The combination of photothermal and photodynamic therapies using GQDs holds immense potential in cancer treatment. By integrating GQDs into this combination therapy approach, researchers aim to achieve enhanced therapeutic efficacy through synergistic effects. However, biodistribution and biodegradation of GQDs within the body present a significant hurdle to overcome, as ensuring their effective delivery to the tumor site and stability during treatment is crucial for therapeutic efficacy. In addition, achieving precise targeting specificity of GQDs to cancer cells is a challenging task that requires further exploration. Moreover, improving the photothermal conversion efficiency of GQDs, controlling reactive oxygen species generation for photodynamic therapy, and evaluating their long-term biocompatibility are all areas that demand attention. Scalability and cost-effectiveness of GQD synthesis methods, as well as obtaining regulatory approval for clinical applications, are also hurdles that need to be addressed. Further exploration of GQDs in photothermal and photodynamic cancer therapies holds promise for advancements in targeted drug delivery, personalized medicine approaches, and the development of innovative combination therapies. The purpose of this review is to critically examine the current trends and advancements in the application of GQDs in photothermal and photodynamic cancer therapies, highlighting their potential benefits, advantages, and future perspectives as well as addressing the crucial challenges that need to be overcome for their practical application in targeted cancer therapy.

Advancements in the Application of the Fenton Reaction in the Cancer Microenvironment.

Cancer is a complex and multifaceted disease that continues to be a global health challenge. It exerts a tremendous burden on individuals, families, healthcare systems, and society as a whole. To mitigate the impact of cancer, concerted efforts and collaboration on a global scale are essential. This includes strengthening preventive measures, promoting early detection, and advancing effective treatment strategies. In the field of cancer treatment, researchers and clinicians are constantly seeking new approaches and technologies to improve therapeutic outcomes and minimize adverse effects. One promising avenue of investigation is the utilization of the Fenton reaction, a chemical process that involves the generation of highly reactive hydroxyl radicals (·OH) through the interaction of hydrogen peroxide (H2O2) with ferrous ions (Fe2+). The generated ·OH radicals possess strong oxidative properties, which can lead to the selective destruction of cancer cells. In recent years, researchers have successfully introduced the Fenton reaction into the cancer microenvironment through the application of nanotechnology, such as polymer nanoparticles and light-responsive nanoparticles. This article reviews the progress of the application of the Fenton reaction, catalyzed by polymer nanoparticles and light-responsive nanoparticles, in the cancer microenvironment, as well as the potential applications and future development directions of the Fenton reaction in the field of tumor treatment.

Dysregulated Iron Homeostasis as Common Disease Etiology and Promising Therapeutic Target

Iron is irreplaceably required for animal and human cells as it provides the activity center for a wide variety of essential enzymes needed for energy production, nucleic acid synthesis, carbon metabolism and cellular defense. However, iron is toxic when present in excess and its uptake and storage must, therefore, be tightly regulated to avoid damage. A growing body of evidence indicates that iron dysregulation leading to excess quantities of free reactive iron is responsible for a wide range of otherwise discrete diseases. Iron excess can promote proliferative diseases such as infections and cancer by supplying iron to pathogens or cancer cells. Toxicity from reactive iron plays roles in the pathogenesis of various metabolic, neurological and inflammatory diseases. Interestingly, a common underlying aspect of these conditions is availability of excess reactive iron. This underpinning aspect provides a potential new therapeutic avenue. Existing hematologically used iron chelators to take up excess iron have shown serious limitations for use but new purpose-designed chelators in development show promise for suppressing microbial pathogen and cancer cell growth, and also for relieving iron-induced toxicity in neurological and other diseases. Hepcidin and hepcidin agonists are also showing promise for relieving iron dysregulation. Harnessing iron-driven reactive oxygen species (ROS) generation with ferroptosis has shown promise for selective destruction of cancer cells. We review biological iron requirements, iron regulation and the nature of iron dysregulation in various diseases. Current results pertaining to potential new therapies are also reviewed.

Smart Magnetic Drug Delivery Systems for the Treatment of Cancer

Cancer remains the most devastating disease, being one of the main factors of death and morbidity worldwide since ancient times. Although early diagnosis and treatment represent the correct approach in the fight against cancer, traditional therapies, such as chemotherapy, radiotherapy, targeted therapy, and immunotherapy, have some limitations (lack of specificity, cytotoxicity, and multidrug resistance). These limitations represent a continuous challenge for determining optimal therapies for the diagnosis and treatment of cancer. Cancer diagnosis and treatment have seen significant achievements with the advent of nanotechnology and a wide range of nanoparticles. Due to their special advantages, such as low toxicity, high stability, good permeability, biocompatibility, improved retention effect, and precise targeting, nanoparticles with sizes ranging from 1 nm to 100 nm have been successfully used in cancer diagnosis and treatment by solving the limitations of conventional cancer treatment, but also overcoming multidrug resistance. Additionally, choosing the best cancer diagnosis, treatment, and management is extremely important. The use of nanotechnology and magnetic nanoparticles (MNPs) represents an effective alternative in the simultaneous diagnosis and treatment of cancer using nano-theranostic particles that facilitate early-stage detection and selective destruction of cancer cells. The specific properties, such as the control of the dimensions and the specific surface through the judicious choice of synthesis methods, and the possibility of targeting the target organ by applying an internal magnetic field, make these nanoparticles effective alternatives for the diagnosis and treatment of cancer. This review discusses the use of MNPs in cancer diagnosis and treatment and provides future perspectives in the field.

Phytoestrogens decorated nanocapsules for therapeutic methionine γ-lyase targeted delivery

The main task of targeted therapy is the selective destruction of cancer cells without affecting normal ones. For these purposes, small molecules and antibodies are used that target specific receptors and proteins or block signaling pathways in tumor cells. The natural phytoestrogens daidzein (Dz) and genistein (Gn) possess binding capacity to estrogen receptors (ER). Methionine γ-lyase (MGL) is promising in two strategies of antitumor therapy: for the elimination of l-methionine, which is necessary for the proliferation of tumor cells, and for the production of cytotoxic dialkyl thiosulfinates in situ. For delivery of MGL-loaded nanocapsules (nanoreactors) to the surface of cancer cells a technique for Dz or Gn incorporation into the shell of polyionic vesicles (PICsomes) was developed. The nanoreactors were characterized by dynamic light scattering and transmission electron microscopy. The enzyme retained its catalytic efficiency inside the decorated PICsomes. The binding of Dz/Gn-nanoreactors to the surface of ER + MCF7 breast adenocarcinoma cells was demonstrated. For the first time an influence of enzyme-loaded PICsomes and their individual components on embryos development was evaluated. The high rate of blastocysts formation (>80%) was observed for all tested components and nanoreactors themselves. A strong inhibitory effect on the early embryonic development of MGL-loaded PICsomes in the presence of S-alkyl-l-cysteine sulfoxide substrates was showed. This proves that the substrates can freely penetrate through the polymer shell of the polyionic vesicle and are cleaved by MGL to form cytotoxic thiosulfinates. The data obtained for phytoestrogens decorated PICsomes may be applied in enzyme therapy of malignant tumors.

Mitochondria-targeted pentacyclic triterpenoid carbon dots for selective cancer cell destruction via inducing autophagy, apoptosis, as well as ferroptosis

Natural products have been an important database for anti-cancer drug development. However, low water solubility and poor biocompatibility limit the efficacy of natural products. Carbon dots (CDs), as an emerging 0D material, have unique properties in bioimaging, water solubility and biocompatibility. Here, we prepared three pentacyclic triterpenoids (PTs) included glycyrrhetinic acid (GA), ursolic acid (UA) and oleanolic acid (OA), which have anticancer activity but poor water solubility, as raw materials into CDs to improve disadvantages. Our data indicated that the active surface groups of all three CDs were largely preserved and were able to excite green fluorescence. Their carboxyl edges not only exhibited excellent water solubility, but also specifically targeted tumor cell mitochondria due to high sensitivity to ROS-induced damage and high internal oxidative stress. In cancer cells, the PT-CDs induced cell death through three pathways (apoptosis, ferroptosis, and autophagy), which is essentially the same way their raw materials induce death, but the effect was much stronger than raw materials. Notably, functionalized PT-CDs also exhibited extremely low toxicity. In summary, PT-CDs not only have improved water solubility and biocompatibility, but also retain the structure of their raw materials well and exert better efficacy, which provides new ideas for the development of anti-cancer natural product drugs.

Nanotechnology: A Promising Approach for Cancer Diagnosis, Therapeutics and Theragnosis.

Cancer remains the most devastating disease and the major cause of mortality worldwide. Although early diagnosis and treatment are the key approach in fighting against cancer, the available conventional diagnostic and therapeutic methods are not efficient. Besides, ineffective cancer cell selectivity and toxicity of traditional chemotherapy remain the most significant challenge. These limitations entail the need for the development of both safe and effective cancer diagnosis and treatment options. Due to its robust application, nanotechnology could be a promising method for in-vivo imaging and detection of cancer cells and cancer biomarkers. Nanotechnology could provide a quick, safe, cost-effective, and efficient method for cancer management. It also provides simultaneous diagnosis and treatment of cancer using nano-theragnostic particles that facilitate early detection and selective destruction of cancer cells. Updated and recent discussions are important for selecting the best cancer diagnosis, treatment, and management options, and new insights on designing effective protocols are utmost important. This review discusses the application of nanotechnology in cancer diagnosis, therapeutics, and theragnosis and provides future perspectives in the field.

Role of EMT in the DNA damage response, double-strand break repair pathway choice and its implications in cancer treatment.

Numerous epithelial–mesenchymal transition (EMT) characteristics have now been demonstrated to participate in tumor development. Indeed, EMT is involved in invasion, acquisition of stem cell properties, and therapy‐associated resistance of cancer cells. Together, these mechanisms offer advantages in adapting to changes in the tumor microenvironment. However, recent findings have shown that EMT‐associated transcription factors (EMT‐TFs) may also be involved in DNA repair. A better understanding of the coordination between the DNA repair pathways and the role played by some EMT‐TFs in the DNA damage response (DDR) should pave the way for new treatments targeting tumor‐specific molecular vulnerabilities, which result in selective destruction of cancer cells. Here we review recent advances, providing novel insights into the role of EMT in the DDR and repair pathways, with a particular focus on the influence of EMT on cellular sensitivity to damage, as well as the implications of these relationships for improving the efficacy of cancer treatments.

Role of Vitamin C in Selected Malignant Neoplasms in Women.

Since the first reports describing the anti-cancer properties of vitamin C published several decades ago, its actual effectiveness in fighting cancer has been under investigation and widely discussed. Some scientific reports indicate that vitamin C in high concentrations can contribute to effective and selective destruction of cancer cells. Furthermore, preclinical and clinical studies have shown that relatively high doses of vitamin C administered intravenously in ‘pharmacological concentrations’ may not only be well-tolerated, but significantly improve patients’ quality of life. This seems to be particularly important, especially for terminal cancer patients. However, the relatively high frequency of vitamin C use by cancer patients means that the potential clinical benefits may not be obvious. For this reason, in this review article, we focus on the articles published mainly in the last two decades, describing possible beneficial effects of vitamin C in preventing and treating selected malignant neoplasms in women, including breast, cervical, endometrial, and ovarian cancer. According to the reviewed studies, vitamin C use may contribute to an improvement of the overall quality of life of patients, among others, by reducing chemotherapy-related side effects. Nevertheless, new clinical trials are needed to collect stronger evidence of the role of this nutrient in supportive cancer treatment.

Strengths and Challenges of Secretory Ribonucleases as AntiTumor Agents.

Approaches to develop effective drugs to kill cancer cells are mainly focused either on the improvement of the currently used chemotherapeutics or on the development of targeted therapies aimed at the selective destruction of cancer cells by steering specific molecules and/or enhancing the immune response. The former strategy is limited by its genotoxicity and severe side effects, while the second one is not always effective due to tumor cell heterogeneity and variability of targets in cancer cells. Between these two strategies, several approaches target different types of RNA in tumor cells. RNA degradation alters gene expression at different levels inducing cell death. However, unlike DNA targeting, it is a pleotropic but a non-genotoxic process. Among the ways to destroy RNA, we find the use of ribonucleases with antitumor properties. In the last few years, there has been a significant progress in the understanding of the mechanism by which these enzymes kill cancer cells and in the development of more effective variants. All the approaches seek to maintain the requirements of the ribonucleases to be specifically cytotoxic for tumor cells. These requirements start with the competence of the enzymes to interact with the cell membrane, a process that is critical for their internalization and selectivity for tumor cells and continue with the downstream effects mainly relying on changes in the RNA molecular profile, which are not only due to the ribonucleolytic activity of these enzymes. Although the great improvements achieved in the antitumor activity by designing new ribonuclease variants, some drawbacks still need to be addressed. In the present review, we will focus on the known mechanisms used by ribonucleases to kill cancer cells and on recent strategies to solve the shortcomings that they show as antitumor agents, mainly their pharmacokinetics.

Wireless Portable Evaluation Platform for Photodynamic Therapy: In vitro Assays on Human Gastric Adenocarcinoma Cells

Photodynamic Therapy (PDT) is a technique used in the selective destruction of cancer cells and requires the previous knowledge of light dosimetry and photosensitizer drug (PS) concentration to apply on cells. Therefore, a laboratory platform is required for further evaluation, e.g. to make evaluation and assays on previously collected cells by biopsy to determine the best combination of light dose and PS concentration. In this context, this paper presents a low-cost, low-sized and flexible Wireless Portable Evaluation Platform for PDT assays on cells. The W-PEP was tested and evaluated using assays with Human Gastric Adenocarcinoma (AGS) cells. The AGS cells were exposed to the 5-aminolevulinic acid (ALA), which is a precursor of the photosensitive agent Protoporphyrin IX (PpIX) with absorption at 635nm. The W-PEP is composed by 16 small-sized LEDs matrix with peak transmittance at 634nm mounted in a PCB and controlled by ESP32-DevKitC®, a power bank to supply the lighting and the controlling systems and 3D printed components specially designed to allow portability and PDT assays. A graphical user interface (GUI) application for mobile devices was developed allowing the bi-directional communication between the smartphone and W-PEP via Bluetooth. The measurements with AGS cells proved this W-PEP was effective in its purpose and promoted cell death in samples treated with ALA and a final light dose of 5J/cm2 after 49 minutes of light exposure. This W-PEP has 140mm of both length and width, 75mm of height and costs about $82.10. To finish, this system checks the optimal conditions that will be applied in the treatment after, thereby decreasing the costs and time of the application.

Activatable Photodynamic Therapy with Therapeutic Effect Prediction Based on a Self-correction Upconversion Nanoprobe.

Though emerging as a promising therapeutic approach for cancers, the crucial challenge for photodynamic therapy (PDT) is activatable phototoxicity for selective cancer cell destruction with low "off-target" damage and simultaneous therapeutic effect prediction. Here, we design an upconversion nanoprobe for intracellular cathepsin B (CaB)-responsive PDT with in situ self-corrected therapeutic effect prediction. The upconversion nanoprobe is composed of multishelled upconversion nanoparticles (UCNPs) NaYF4:Gd@NaYF4:Er,Yb@NaYF4:Nd,Yb, which covalently modified with an antenna molecule 800CW for UCNPs luminance enhancement under NIR irradiation, photosensitizer Rose Bengal (RB) for PDT, Cy3 for therapeutic effect prediction, and CaB substrate peptide labeled with a QSY7 quencher. The energy of UCNPs emission at 540 nm is transferred to Cy3/RB and eventually quenched by QSY7 via two continuous luminance resonance energy transfer processes from interior UCNPs to its surface-extended QSY7. The intracellular CaB specifically cleaves peptide to release QSY7, which correspondingly activates RB with reactive oxygen species (ROS) generation for PDT and recovers Cy3 luminance for CaB imaging. UCNPs emission at 540 nm remains unchanged during the peptide cleavage process, which is served as an internal standard for Cy3 luminance correction, and the fluorescence intensity ratio of Cy3 over UCNPs (FI583/FI540) is measured for self-corrected therapeutic effect prediction. The proposed self-corrected upconversion nanoprobe implies significant potential in precise tumor therapy.

PEGylated-folic acid–modified black phosphorus quantum dots as near-infrared agents for dual-modality imaging-guided selective cancer cell destruction

Abstract Biological systems have high transparence to 700–1100-nm near-infrared (NIR) light. Black phosphorus quantum dots (BPQDs) have high optical absorbance in this spectrum. This optical property of BPQDs integrates both diagnostic and therapeutic functions together in an all-in-one processing system in cancer theranostic approaches. In the present study, BPQDs were synthesized and functionalized by targeting moieties (PEG-NH2-FA) and were further loaded with anticancer drugs (doxorubicin) for photodynamic–photothermal–chemotherapy. The precise killing of cancer cells was achieved by linking BPQDs with folate moiety (folic acid), internalizing BPQDs inside cancer cells with folate receptors and NIR triggering, without affecting the receptor-free cells. These in vitro experiments confirm that the agent exhibited an efficient photokilling effect and a light-triggered and heat-induced drug delivery at the precise tumor sites. Furthermore, the nanoplatform has good biocompatibility and effectively obliterates tumors in nude mice, showing no noticeable damages to noncancer tissues. Importantly, this nanoplatform can inhibit tumor growth through visualized synergistic treatment and photoacoustic and photothermal imaging. The present design of versatile nanoplatforms can allow for the adjustment of nanoplatforms for good treatment efficacy and multiplexed imaging, providing an innovation for targeted tumor treatment.

Attaining threshold antibody cytotoxicity for selective tumor cell destruction: an opinion article.

We propose a novel immunotherapeutic paradigm that justifies application of several antibodies to various membrane-associated antigens to achieve a critical threshold density of immune complexes on the surface of cancer cells sufficient for triggering downstream cytolytic pathways. Indeed, some cancer-associated antigens (such as cancer/testis antigens) were found to be expressed on many cancer (but not normal) cells, with their baseline membrane expression levels being originally quite low for some of them, or even further down-regulated due to immune-driven cell selection. To achieve the mandatory threshold density of membrane-associated immune complexes on malignant cells, the concept stipulates combined application of antibodies specific for a cancer-associated antigen along with antibodies against an antigen expressed not only on tumor, but also on normal cells. In the proposed scenario it is of vital importance that the latter antibodies should be applied in suboptimal dosage to exclude the destruction of normal cells devoid of a cancer-associated antigen. Malignant cells often co-express antigens not present concurrently on normal cells at high levels. In such cases, suboptimal dosages of antibodies specific for those antigens could also be applied to achieve cumulative effect leading to selective destruction of tumour cells. Hence, the described immunotherapeutic technology could be used metaphorically speaking as a kind of ‘immunological knife’, which is capable of highly selective destruction of cancer cells without destroying normal cells.

Lipopeptisomes: Anticancer peptide-assembled particles for fusolytic oncotherapy

Anticancer peptides (ACPs) are cationic amphiphiles that preferentially kill cancer cells through folding-dependent membrane disruption. Although ACPs represent attractive therapeutic candidates, particularly against drug-resistant cancers, their successful translation into clinical practice has gone unrealized due to their poor bioavailability, serum instability and, most importantly, severe hemolytic toxicity. Here, we exploit the membrane-specific interactions of ACPs to prepare a new class of peptide-lipid particle, we term a lipopeptisome (LP). This design sequesters loaded ACPs within a lipid lamellar corona to avoid contact with red blood cells and healthy tissues, while affording potent lytic destruction of cancer cells following LP-membrane fusion. Biophysical studies show ACPs rapidly fold at, and integrate into, liposomal membranes to form stable LPs with high loading efficiencies (>80%). Rational design of the particles to possess lipid combinations mimicking that of the aberrant cancer cell outer leaflet allows LPs to rapidly fuse with tumor cell membranes and afford localized assembly of loaded ACPs within the bilayer. This leads to preferential fusolytic killing of cancer cells with minimal collateral toxicity towards non-cancerous cells and erythrocytes, thereby imparting clinically relevant therapeutic indices to otherwise toxic ACPs. Thus, integration of ACPs into self-assembled LPs represents a new delivery strategy to improve the therapeutic utility of oncolytic agents, and suggests this technology may be added to targeted combinatorial approaches in precision medicine. Statement of SignificanceDespite their significant clinical potential, the therapeutic utility of many ACPs has been limited by their collateral hemolysis during administration. Leveraging the membrane-specific interactions of ACPs, here we prepare self-assembled peptide-lipid nanoparticles, or ‘lipopeptisomes’ (LPs), capable of preferentially fusing with and lysing cancer cell membranes. Key to this fusolytic action is the construction of LPs from lipids simulating the cancer cell outer leaflet. This design recruits the oncolytic peptide payload into the carrier lamella and allows for selective destruction of cancer cells without disrupting healthy cells. Consequently, LPs impart clinically relevant therapeutic indexes to previously toxic ACPs, and thus open new opportunities to improve the clinical translation of oncolytics challenged by narrow therapeutic windows.

Profiling Bis(monoacylglycero)phosphate Lipids in Cancer Cell Lysosomes as Therapeutic Targets

BackgroundTumor resistance to apoptosis underlies the clinical failure of conventional chemotherapeutics and commonly employed molecularly targeted drugs. Cancer cells frequently activate survival pathways to evade destruction by apoptosis‐inducing therapies and persist following treatment to seed tumor recurrence and metastatic outgrowth. Lysosomal cell death is an alternative death pathway that triggers non‐apoptotic mechanisms. The lysosome, a major degradative component of eukaryotic cells, is altered by oncogenic transformation. Key to the function and stability of lysosome‐associated enzymes are bis(monoacylglycero)‐phosphate lipids (BMP). BMPs are negatively charged and highly enriched in the internal lysosome membrane. Untargeted analytical methods for the measurement of BMPs and in silico libraries to support the discovery of new BMP species are currently lacking.MethodWe present here an expanded BMP library to include over 1800 BMP species in both positive and negative ESI modes. We have chromatographic separation of BMP from isobaric species, and have used this method to profile cancerous and non‐cancerous immortalized cell lines. Lipidomic analysis was performed using Waters Acquity UPLC CSH C18 (100 mm length × 2.1 mm id; 1.7 μm) column coupled to a Thermo Scientific Q‐Exactive HF mass spectrometer. Data processing was done using MS‐DIAL software and in‐silico structure predictions were done using MS‐FINDER.ResultsIn breast cancer cells (Met‐1), we found that all BMP species measured were significantly less abundant relative to non‐transformed mammary epithelial cells (nMUMG), (n = 10). As BMPs are key to lysosome stability, we hypothesize the dramatic loss of BMPs observed in transformed cells renders cancer‐associated lysosomes unstable. Therefore, targeting BMPs might represent an effective therapeutic strategy for selective cancer cell destruction.Support or Funding InformationThis work was funded by NIH U24 DK097154.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Improved Fenton Therapy Using Cancer Cell Hydrogen Peroxide

Fenton cancer therapy as a new methodology for the treatment of tumour cells is largely restricted owing to the low stability, high aggregation, and poor selectivity of reported nanoparticles. In this study, an improved approach for the selective destruction of cancer cells is reported. Metal–organic framework (MOF) nanoparticles were synthesized and reduced via a hydrothermal method, and then PEGylated through the surface-initiated atom transfer radical polymerization (SI-ATRP) reaction to produce a PEGylated reduced MOF (P@rMOF). The ratio of PEG to nanoparticles was used to optimize the size and aggregation of the nanoparticles, with 2P@rMOF (2 : 1 mass ratio) having the smallest hydrodynamic diameter. The nanoparticles were further conjugated with folic acid for cell targeting. In vitro cell uptake experiments demonstrated that the internalization of 2P@rMOF-FA nanoparticles into cancer cells (HeLa) was almost 3-fold that of normal cells (NIH-3T3). In the presence of 2P@rMOF-FA, the HeLa cell viability decreased dramatically to 22 %, whereas the NIH-3T3 cell viability remained higher than 80 % after 24 h incubation. The selectivity index for 2P@rMOF-FA is 4.48, which is significantly higher than those reported in the literature for similar strategies. This work thus demonstrates the most stable and selective nanoparticle system for the treatment of cancer cells using the cell’s own H2O2.

2.5 MeV CW 4-vane RFQ accelerator design for BNCT applications

Boron Neutron Capture Therapy (BNCT) promises a bright future in cancer therapy for its highly selective destruction of cancer cells, using the 10B +n→7Li +4 He reaction. It offers a more satisfactory therapeutic effect than traditional methods for the treatment of malignant brain tumors, head and neck cancer, melanoma, liver cancer and so on. A CW 4-vane RFQ, operating at 162.5 MHz, provides acceleration of a 20 mA proton beam to 2.5 MeV, bombarding a liquid lithium target for neutron production with a soft neutron energy spectrum. The fast neutron yield is about 1.73×1013n∕s. We preliminarily develop and optimize a beam shaping assembly design for the 7Li(p, n)7Be reaction with a 2.5 MeV proton beam. The epithermal neutron flux simulated at the beam port will reach up to 1.575×109 n/s/cm2. The beam dynamics design, simulation and benchmark for 2.5 MeV BNCT RFQ have been performed with both ParmteqM (V3.05) and Toutatis, with a transmission efficiency higher than 99.6% at 20 mA. To ease the thermal management in the CW RFQ operation, we adopt a modest inter-vane voltage design (U=65 kV), though this does increase the accelerator length (reaching 5.2 m). Using the well-developed 3D electromagnetic codes, CST MWS and ANSYS HFSS, we are able to deal with the complexity of the BNCT RFQ, taking the contribution of each component in the RF volume into consideration. This allows us to optimize the longitudinal field distribution in a full-length model. Also, the parametric modeling technique is of great benefit to extensive modifications and simulations. In addition, the resonant frequency tuning of this RFQ is studied, giving the tuning sensitivities of vane channel and wall channel as −16.3 kHz/°C and 12.4 kHz/°C, respectively. Finally, both the multipacting level of this RFQ and multipacting suppressing in the coaxial coupler are investigated.