Agents For Cancer Therapy Research Articles

Fabrication of NIR/CT imaging guided xGd-WO3@PEG photothermal agents for cancer therapy

Near-infrared responsive photothermal therapy is an emerging and non-invasive cancer treatment. However, the inability of real-time imaging tracking and monitoring for the photothermal agents (PTAs) severely limits the accuracy of treatment. In this study, a series of visual xGd-WO3@PEG PTAs were synthesized by a one-pot solvothermal method. The effect of different Gd doping amounts on the structure, morphology, and photothermal performance has been investigated in detail. Under the near-infrared laser irradiation, the samples exhibited satisfied photothermal properties of hyperthermia in a short time. The photothermal conversion efficiency and stability of the xGd-WO3@PEG (x = 7 %) were further investigated. Subsequently, the near-infrared thermal and CT imaging performance was studied. The in vitro cell viability on LO2 normal and 4T1 cancer cells have also been conducted. The results showed the xGd-WO3@PEG nanomaterials have excellent potential in imaging-guided photothermal cancer therapy.

Bioengineered Smart Nanocarriers for Breast Cancer Treatment: Adorned Carbon-Based Nanocomposites with Silver and Palladium Complexes for Efficient Drug Delivery.

Biocompatible and bioactive carbon-based nanocomposites are ingeniously designed and fabricated with the aim of enhancing drug delivery applicability in breast cancer treatment. Reduced graphene oxide (rGO) and multiwalled carbon nanotubes (MWCNTs) are utilized as nanocarriers for increasing penetrability into cells and the loading capacity. What sets our study apart is the strategic incorporation of the two different complexes of silver (AgL2) and palladium (PdL2) with the carboxamide-based ligand C9H7N3OS (L), which have been synthesized and decorated on nanocarriers alongside doxorubicin (DOX) for stabilizing DOX by π-π interactions and hydrogen bonding. Although DOX is a well-known cancer therapy agent, the efficacy of DOX is hindered owing to drug resistance, poor internalization, and limited site specificity. Aside from stabilizing DOX on nanocarriers, our carbon-based nanocarriers are tailored to act as a precision-guided missile, strategically by adorning with target-sensitive complexes. Based on the literature, carboxamide ligands can connect to overexpressed receptors on cancerous cells and inhibit them from proliferation signaling. Also, the complexes have an antibacterial activity that can control the infection caused by decreasing white blood cells and necrosis of cancerous cells. A high-concentration cytotoxicity assay revealed that decorating PdL2 on a DOX-containing nanocarrier not only increased cytotoxicity to breast cancerous cell lines (MDA-MB-231 and MCF-7) but also revealed higher cell viability on a normal cell line (MCF-10A). The drug release screening results showed that the presence of PdL2 led to 72 h correlate release behavior in acidic and physiological pH profiles, while the AgL2-containing nanocomposite showed an analogue behavior for just 6 h and the release of DOX continued and after about 100 h hit the top.

Size Switchable Self-Assembled Iron Oxide Aggregations Loaded with Doxorubicin for Deep Penetration and Enhanced Chemotherapy of Cancer.

Iron oxide nanoparticles (Fe3O4 NPs) have been reported to be a promising agent for cancer therapy due to their outstanding ability in catalyzing the Fenton reaction and causing peroxidation. Generally, particles with size of hundreds of nanometers exhibit enhanced accumulation in tumor due to the enhanced permeation and retention effect. However, the large size hinders penetration within the dense collagen matrix. Here, we propose a multistage system to realize pH-responsive size switch for efficient drug delivery. In this system, ultrasmall Fe3O4 (∼4 nm) NPs are simultaneously modified with hydrophilic mPEG and hydrophobic N,N-dibutylethylenediamine (DBE) to form pH-responsive self-assembled iron oxide aggregations (SIOA). In the acidic tumor microenvironment, the protonation of DBE makes it transit from the hydrophobic to hydrophilic state, causing the disassembly of the SIOA and the release of loaded doxorubicin. The multistage Fe3O4 NPs demonstrate enhanced accumulation and efficient diffusion within the tumor, holding a promise for drug delivery and cancer therapy.

Conditionally Activatable Pyroptosis‐Inducing Agents for Cancer Therapy

Pyroptosis is a recently defined form of immunogenic cell death that shows great promise in cancer immunotherapy. However, almost all small‐molecule pyroptosis‐inducing agents (PyAs) reported to date indiscriminately induce pyroptosis in multiple cell types, leading to off‐target pyroptotic death of normal and immune cells. One promising approach to addressing this biosafety issue is the design of conditionally activatable PyAs that specifically respond to disease biomarkers. Herein, a general solution for facilely tailoring and synthesizing activatable PyAs based on a newly developed class of photoactive PyAs, termed PyPSs, is reported. The unique structurally encoded properties of PyPSs, including endo reticulum targeting, hypoxia tolerance, and sensing properties, excitingly meet a demanding set of performance requirements for constructing conditionally activatable PyAs for cancer immunotherapy. Based on PyPS‐1 scaffold, hypoxia‐activatable PyPS‐NF as a proof‐of‐concept example is prepared, demonstrating specific hypoxia‐activated pyroptotic cell death and favorable immunotherapeutic efficacy of solid tumors. Herein, a general design strategy for tailoring activatable PyAs to precisely control GSDME‐mediated cell pyroptosis is established, with great potential to advance cancer immunotherapy.

Abstract B003: Inhibition of cell growth and migration by polyisoprenylated cysteinyl amide inhibitors of a mutant KRAS Black American lung cancer cell line involves MAPK pathway activation and disruption of the cytoskeleton

Abstract KRAS mutations are the most common oncogenic mutations in lung adenocarcinoma in Black Americans. Polyisoprenylated Cysteinyl Amide Inhibitors (PCAIs) constitute a group of potential cancer therapy agents that we designed to specifically disrupt and suppress hyperactive G-protein signaling, as caused by mutated RAS proteins. Here we investigate the effects of PCAIs on the viability, G-protein levels, downstream mediators, cytoskeletal structure, focal adhesion protein and apoptosis-related proteins on the KRAS-mutated, Black American-derived lung adenocarcinoma cell line, NCI-H23. Western blotting was used to determine the effect of the PCAIs on the phosphorylation levels of MAPK pathway enzymes. After 48-hour exposure to 5 μM of the PCAIs, 57 ± 3.6 to 150 ± 4.1 % increases of BRAF, MEK1/2, ERK1/2, and p90RSK phosphorylation along with a 60 ± 6.5 to 78 ± 4.0 % decrease of pRAF1 phosphorylation were observed, indicating significant changes in RAS signaling. Furthermore, 5 μM of NSL-YHJ-2-27 depleted the singly polyisoprenylated monomeric G-proteins RAC 1/2/3 and CDC42 by 77 ± 5.5 and 76 ± 2.0 %, respectively. The depletion of these key cytoskeletal proteins, and collapse of F-actin and vinculin punctates, may account for the observed inhibition of cell migration after 72-hour exposure to NSL-YHJ-2-27 and NSL-YHJ-2-46, respectively. The invasion area of 3D NCI-H23 spheroids after treatment with 10 μM of NSL-YHJ-2-27 and NSL-YHJ-2-46 decreased by 87 ± 0.1% and 92 ± 0.3 %, respectively. Treatment with 0.5 μM NSL-YHJ-2-27 and NSL-YHJ-2-46 caused cell rounding and reduction of mean cell areas by 30 ± 5.0 and 42 ± 0.6 %, respectively. Mean cell area occupied by vinculin punctates decreased by 51 ± 2.6 % and 31 ± 2.8 % after exposure to 0.5 μM NSL-YHJ-2-27 and NSL-YHJ-2-46, respectively. NSL-YHJ-2-27 (5 μM) depleted full-length inactive caspase 3 and 7 levels by 72 ± 5.8 and 91 ± 7.0 %, respectively. These findings show the direct effects of the PCAIs on the KRAS signaling pathway thereby supporting their continuous development as potential targeted therapies for cancers with RAS mutations. Citation Format: Kweku Ofosu-Asante. Inhibition of cell growth and migration by polyisoprenylated cysteinyl amide inhibitors of a mutant KRAS Black American lung cancer cell line involves MAPK pathway activation and disruption of the cytoskeleton [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr B003.

Abstract C063: Frequency and spectrum of KRAS mutations in lung adenocarcinoma from Black/African American and White/European patients

Abstract Lung cancer is the most common cause of cancer death in the United States and a major source of cancer health disparity. Lung cancer incidence and mortality rates are higher in Black/African American (B/AA) men than in men from other racial/ethnic groups. Lung adenocarcinoma, arising in the alveoli or air sacs of the lung, is the most common subtype of lung cancer in all ethnic/racial groups. Genetic driver mutations can differ among racial/ethnic groups, in the identity of the mutated genes, their mutation frequencies, and the spectrum of mutations for each given gene. In addition, the same mutation could have different effects depending on an individual patient’s genetic background, resulting in differential responses to therapies. Therefore, it is important to identify the frequency and spectrum of driver mutations in different population groups. Protooncogenes from the RAS family, KRAS, NRAS, and HRAS, play a crucial role in cell growth regulation, cell proliferation, and survival. KRAS is frequently mutated in numerous cancer types, including lung adenocarcinoma, and has been reported to be the driver gene in ~30% of lung adenocarcinomas from White/European (W/E) patients. Due to the much lower number of lung cancer samples analyzed from B/AA patients, it has been unclear if the KRAS mutational frequency and spectrum in B/AA lung adenocarcinoma patients differs from that in W/E patients. Here we collected available existing data sets with mutational information on KRAS muations in lung adenocarcinoma from B/AA and W/E patients. We obtained data for 1555 B/AA and 13840 White lung adenocarcinoma patients. While B/AA lung adenocarcinoma patients had a lower prevalence of KRAS mutations (27% vs. 35%) than W/E patients, (χ2 p-value= 5.877e-10), KRAS was still the most frequently mutated cancer driver gene in both groups. The most common KRAS mutations in both B/AA and W/E patients were alterations of glycine 12 to cysteine (G12C), valine (G12V), aspartic acid (G12D), and alanine (G12A), as well as glutamine 61 to histidine (Q61H) and glycine 13 to cysteine (G13C). Given that a substantial proportion of lung adenocarcinoma patients carry a mutated KRAS gene, investigating new potential KRAS-targeting therapies remains especially urgent. To this end, we are investigating polyisoprenylated cysteinyl amide inhibitors (PCAIs), a group of potential cancer therapy agents designed to specifically disrupt and suppress hyperactive G-protein signaling, as caused by mutated RAS proteins. We are testing PCAI efficiacy on B/AA and W/E lung adenocarcinoma cell lines carrying various KRAS mutations. Citation Format: Daniel J. Mullen, Pablo E. Puente, Christopher Leon, Diana I. Romero, Kweku Ofosu-Asante, Yong Huang, Nazarius S. Lamango, Ite A. Offringa. Frequency and spectrum of KRAS mutations in lung adenocarcinoma from Black/African American and White/European patients [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr C063.

Nanomaterials as Theranostic Agents for Cancer Therapy

Nanomaterials as Theranostic Agents for Cancer Therapy

Toward Type I/II ROS Generation Photoimmunotherapy by Molecular Engineering of Semiconducting Perylene Diimide.

As prospective phototheranostic agents for cancer imaging and therapy, semiconducting organic molecule-based nanomedicines are developed. However, near-infrared (NIR) emission, and tunable type I (O2 • -) and type II (1O2) photoinduced reactive oxygen species (ROS) generation to boost cancer photoimmunotherapy remains a big challenge. Herein, a series of D-π-A structures, NIR absorbing perylene diimides (PDIs) with heavy atom bromide modification at the bay position of PDIs are prepared for investigating the optimal photoinduced type I/II ROS generation. The heavy atom effect has demonstrated a reduction of molecular ∆EST and promotion of the intersystem crossing processes of PDIs, enhancing the photodynamic therapy (PDT) efficacy. The modification of three bromides and one pyrrolidine at the bay position of PDI (TBDT) has demonstrated the best type I/II PDT performance by batch experiments and theoretical calculations. TBDT based nanoplatforms (TBDT NPs) enable type I/II PDT in the hypoxic tumor microenvironment as a strong immunogenic cell death (ICD) inducer. Moreover, TBDT NPs showing NIR emission allow in vivo bioimaging guided phototherapy of tumor. This work uses novel PDIs with adjustable type I/II ROS production to promote antitumor immune response and accomplish effective tumor eradication, consequently offering molecular guidelines for building high-efficiency ICD inducers.

Application of statistical methodology for the optimization of l-glutaminase enzyme production from Streptomyces pseudogriseolus ZHG20 under solid-state fermentation

BackgroundActinomycetes are excellent microbial sources for various chemical structures like enzymes, most of which are used in pharmaceutical and industrial products. Actinomycetes are preferred sources of enzymes due to their high ability to produce extracellular enzymes. l-glutaminase has proven its essential role as a pharmaceutical agent in cancer therapy and an economic agent in the food industry. The current study aimed to screen the potent l-glutaminase producer and optimize the production media for maximum enzyme yield using one factor at a time (OFAT) approach and statistical approaches under solid-state fermentation (SSF). ResultsOut of 20 actinomycetes strains isolated from rhizosphere soil, 5 isolates produced extracellular l-glutaminase. One isolate was chosen as the most potent strain, and identified as Streptomyces pseudogriseolus ZHG20 based on 16S rRNA. The production and optimization process were carried out under SSF, after optimization using OFAT method, the enzyme production increased up to 884.61 U/gds. Further, statistical strategy, response surface methodology (RSM), and central composite design (CCD) were employed for the level optimization of significant media component (p < 0.05), i.e., wheat bran, sesame oil cake, and corn steep liquor which are leading to increase 3.21-fold l-glutaminase production as compared to unoptimized media. ConclusionsThe presented investigation reveals the optimization of various physicochemical parameters using OFAT and RSM-CCD. Statistical approaches proved to be an effective method for increasing the yield of extracellular l-glutaminase from S. pseudogriseolus ZHG20 where l-glutaminase activity increased up to 1297.87 U/gds which is 3.21-fold higher than the unoptimized medium using a mixture of two solid substrates (wheat bran and sesame oil cake) incubated at pH 7.0 for 6 days at 33 °C.

ER-α36 is involved in calycosin inhibition of IL-6 production in macrophages.

The tumour microenvironment (TME) is crucial for tumour development and progression. Tumour-associated macrophages (TAMs) in the TME can promote tumour progression and metastasis by releasing cytokines, such as IL-6. Calycosin, a phytoestrogen that is one of the active compounds in Radix Astragali, has been shown to inhibit tumour growth and metastasis. However, the underlying mechanism by which calycosin inhibits tumour growth remains unclear. Thus, this study aimed to investigate the effect of calycosin on IL-6 production in peripheral blood mononuclear cell (PBMC)- and THP-1-derived macrophages and explore its potential mechanisms using co-immunoprecipitation, western blotting, immunofluorescence, chromatin immunoprecipitation and luciferase assays. We found that calycosin treatment substantially upregulated the expression of ER-α36, a variant of the ER, and reduced IL-6 production in macrophages. Mechanistically, ER-α36 physically interacted with NF-κBp65 and retained p65 in the cytoplasm to attenuate NF-κB function as an IL-6 transcriptional inducer. In conclusion, our result indicated that calycosin inhibited IL-6 production by enhancing ER-α36 expression and its interaction with p65, which attenuated NF-κB function as an IL-6 inducer. Therefore, calycosin can be developed as an effective agent for cancer therapy by targeting TAMs.

Hemin-Coated Nanoparticles as Drug Delivery Vehicles for Chemotherapeutic Agents in Cancer Therapy

Hemin-Coated Nanoparticles as Drug Delivery Vehicles for Chemotherapeutic Agents in Cancer Therapy

Enhanced apoptotic activity of Pluronic F127 polymer-encapsulated chlorogenic acid nanoparticles through the PI3K/Akt/mTOR signaling pathway in liver cancer cells and in vivo toxicity studies in zebrafish

Abstract In this study, chlorogenic acid nanoparticles encapsulated in Pluronic F127 polymer were synthesized and characterized to determine if they could treat human liver cancer. The nanoparticles were synthesized using standard procedures and characterized using physical and biological techniques such as X-ray diffraction, Fourier transform infrared spectroscopy, UV-Vis, dynamic light scattering, Photoluminescence, scanning electron microscopy, and transmission electron microscopy. The anticancer effects were assessed using MTT analysis, acridine orange/ethidium bromide, reactive oxygen species (ROS), COMET assay, annexin-V/FITC, cell cycle analysis, and expression of marker genes against HepG2 cell lines. The results showed significant cytotoxicity, apoptosis induction, and increased ROS production in treated cells compared to control cells. The nanoparticles also activated the apoptotic cascade and regulated the PI3K/AKT/mTOR pathways. The nanocomposites exhibited unique characteristics such as anticancer efficacy in vitro. Further research was conducted using zebrafish to model hematological parameters, liver enzymes, and histopathology to study effectiveness. Green-synthesized Pluronic F127–chlorogenic acid nanoparticles can be considered potential cancer therapy agents.

Systematic Investigation of Cellular Response to Hydroxyl Group Orientation Differences on Gold Glyconanoparticles.

Nanoparticle (NP) surfaces act as the interface as they interact with living systems and play a critical role in defining their cellular response. The nature of these interactions should be well understood to design safer and more effective NPs to be used in a wide range of biomedical applications. At the moment, it is not clear how a subtle change in surface chemistry will affect an NP's behavior in a biological system. Thus, understanding the role of such a small change is critical and may allow one to fine-tune a biological response. In this study, the cellular response to -OH orientation differences generated on gold glyconanoparticles, which are recently considered promising therapeutic agents as they mimic a glycocalyx, is investigated. As model molecules, glucose and mannose (C2 epimer) as monosaccharides and lactose and maltose (galactose and glucose as free units, C4 epimer) as disaccharides were chosen to monitor the cellular response in A549, BEAS-2b, and MDA-MB-231 cells through cellular uptake, cytotoxicity, and cell cycle progression. The three cell lines gave various and remarkable cellular responses to the same subtle -OH differences on gold glyconanoparticles, and it is determined that not only -OH orientation differences but also the number of saccharides on gold glyconanoparticles affect the cellular response. It was shown that mannose (C2 epimer to glucose) was significant with the promise of being a therapeutic agent for lung cancer therapy, whereas the toxicological profile of MDA-MB-231 cells was affected by AuNPs-glucose the most. This study demonstrates that clearly small chemical alterations on a NP surface can result in a significant cellular response. It can be concluded that the -OH orientation at the second and fourth carbon of a carbohydrate ring has a critical role in designing and engineering novel gold glyconanoparticles (consisting of monolayer mono- or disaccharides) for a specific cancer therapy.

Design of Silica@Au Hybrid Nanostars for Enhanced SERS and Photothermal Effect.

Core-shell nanostructures of silicon oxide@noble metal have drawn a lot of interest due to their distinctive characteristics and minimal toxicity with remarkable biocompatibility. Due to the unique property of localized surface plasmon resonance (LSPR), plasmonic nanoparticles are being used as surface-enhanced Raman scattering (SERS) based detection of pollutants and photothermal (PT) agents in cancer therapy. Herein, we demonstrate the synthesis of multifunctional silica core - Au nanostars shell (SiO2 @Au NSs) nanostructures using surfactant free aqueous phase method. The SERS performance of the as-synthesized anisotropic core-shell NSs was examined using Rhodamine B (RhB) dye as a Raman probe and resulted in strong enhancement factor of 1.37×106 . Furthermore, SiO2 @Au NSs were also employed for PT killing of breast cancer cells and they exhibited a concentration-dependent increase in the photothermal effect. The SiO2 @Au NSs show remarkable photothermal conversion efficiency of up to 72 % which is unprecedented. As an outcome, our synthesized NIR active SiO2 @Au NSs are of pivotal importance to have their dual applications in SERS enhancement and PT effect.

Exploiting the Powerful Anti-tumor Effects of Salmonella Typhimurium: Systematic Review

Introduction: Salmonella typhimurium (S. typhimurium) has emerged as a promising agent for cancer therapy. This systematic review aims to comprehensively analyze the existing literature regarding the utilization of S. typhimurium as a therapeutic strategy against cancer. The present systematic review aimed to evaluate the current state of knowledge regarding the anti-tumor properties of S. typhimurium, encompassing its tumor-targeting mechanisms, impact on tumor growth, modulation of the tumor microenvironment, and potential for combination therapies. Materials and methods: A systematic literature search was conducted across major scientific databases, including PubMed, Web of Science, and Scopus, using predefined search terms. Studies published between 2000 and 2023 were included if they investigated the anti-tumor effects of S. typhimurium in vivo. Studies were independently screened, selected, and evaluated for quality by two reviewers. Results: The systematic review identified 152 relevant studies that met the inclusion criteria. These studies collectively demonstrated the ability of S. typhimurium to selectively target and colonize tumors, resulting in significant tumor growth inhibition in various cancer types. Mechanistic insights revealed that S. typhimurium can induce direct cytotoxicity, modulate the tumor microenvironment, and activate anti-tumor immune responses. Additionally, studies highlighted the potential of combining S. typhimurium with conventional therapies or immune checkpoint inhibitors to enhance therapeutic efficacy. Conclusion: This systematic review underscores the promising potential of S. typhimurium as a novel and multifaceted approach to cancer therapy. The accumulated evidence suggests that S. Typhimurium possesses inherent tumor-targeting capabilities, exerts direct anti-tumor effects, and can synergize with other treatment modalities.

Ultrasmall iron-doped zinc oxide nanoparticles for ferroptosis assisted sono-chemodynamic cancer therapy

The efficacy and biosafety of sonodynamic therapy (SDT) are closely related to the properties of sonosensitizers. Inorganic sonosensitizers with high chemical stability and low dark toxicity are generally limited by slow metabolism and accumulation in vivo. Combined treatment strategies by inducing more redox imbalance are expected to improve the efficacy of sonodynamic antitumor therapy. Herein, we report the development of ultra-small iron-doped zinc oxide nanoparticles (FZO NPs) to achieve synergistic sono-chemodynamic therapy and low accumulation in vivo. The surface of FZO NPs with diameter of 5 nm was modified with 3-aminopropyltriethoxysilane and polyethylene glycol 600 to obtain FZO-ASP with good aqueous stability. FZO-ASP with iron doping could trigger Fenton reaction and induce ferroptosis in cancer cells. With the assistance of ultrasonic energy, FZO-ASP demonstrated enhanced inhibitory effects on proliferation of various cancer cells and murine breast tumor growth than undoped counterpart. In addition, FZO-ASP injected intravenously could be effectively excreted in vivo and showed no obvious cumulative toxicity to the treated mice. Hence, this type of ultra-small iron-doped zinc oxide nanoparticles could serve as a safe and efficient sonosensitizer agent for synergistic sono-chemodynamic cancer therapy.

Electrical stimulation induces anti-tumor immunomodulation via a flexible microneedle-array-integrated interdigital electrode

Immunotherapy has revolutionized cancer therapy, using chemical or biological agents to reinvigorate the immune system. However, most of these agents have poor tumor penetration and inevitable side effects that complicate therapeutic outcomes. Electrical stimulation (ES) is a promising alternative therapy against cancers that does not involve chemical or biological agents but is limited in the fabrication and operation of complex micrometer-scale ES devices. Here, we present an optically microprinted flexible interdigital electrode with a gold-plated polymer microneedle array to generate alternating electric fields for cancer treatment. A flexible microneedle-array-integrated interdigital electrode (FMIE) was fabricated by combining optical 3D microprinting and electroless plating processes. FMIE-mediated ES of cancer cells induced necrotic cell death through mitochondrial Ca2+ overload and increased intracellular reactive oxygen species (ROS) production. This led to the release of damage-associated molecular patterns that activated the immune response and potentiated immunogenic cell death (ICD). FMIE-based ES has an excellent safety profile and systemic anti-tumor effects, inhibiting the growth of primary and distant tumors as well as melanoma lung metastasis. FMIE-based ES-driven cancer immunomodulation provides a new pathway for drug-free cancer therapy.

Liposomes for Cancer Theranostics.

Cancer is one of the most well-studied diseases and there have been significant advancements over the last few decades in understanding its molecular and cellular mechanisms. Although the current treatments (e.g., chemotherapy, radiotherapy, gene therapy and immunotherapy) have provided complete cancer remission for many patients, cancer still remains one of the most common causes of death in the world. The main reasons for the poor response rates for different cancers include the lack of drug specificity, drug resistance and toxic side effects (i.e., in healthy tissues). For addressing the limitations of conventional cancer treatments, nanotechnology has shown to be an important field for constructing different nanoparticles for destroying cancer cells. Due to their size (i.e., less than 1 μm), nanoparticles can deliver significant amounts of cancer drugs to tumors and are able to carry moieties (e.g., folate, peptides) for targeting specific types of cancer cells (i.e., through receptor-mediated endocytosis). Liposomes, composed of phospholipids and an interior aqueous core, can be used as specialized delivery vehicles as they can load different types of cancer therapy agents (e.g., drugs, photosensitizers, genetic material). In addition, the ability to load imaging agents (e.g., fluorophores, radioisotopes, MRI contrast media) enable these nanoparticles to be used for monitoring the progress of treatment. This review examines a wide variety of different liposomes for cancer theranostics, with the different available treatments (e.g., photothermal, photodynamic) and imaging modalities discussed for different cancers.

Characterization of type I L-asparaginase encoding gene from the thermohalophilic bacterium Bacillus subtilis CAT3.4 from Wawolesea Hot Spring, Southeast Sulawesi, Indonesia

Abstract. Muzuni, Ilham M, Ardiansyah, Suriana, Putri Y, Kartina. 2023. Characterization of type I L-asparaginase encoding gene from the thermohalophilic bacterium Bacillus subtilis CAT3.4 from Wawolesea Hot Spring, Southeast Sulawesi, Indonesia. Biodiversitas 24: 5167-5178. This study aims to determine the molecular characteristics of the gene encoding type 1 L-asparaginase from CAT3.4 thermohalophilic bacterial isolates from the hot springs of Wawolesea, North Konawe, Southeast Sulawesi. This enzyme can be used as a cancer therapy agent and prevents the formation of acrylamide in food products. It is a kind of exploratory research. The characterization was done by amplifying the ansA gene sequence encoding L-asparaginase from CAT3.4 isolate by polymerase chain reactions (PCR) technique using primers AsnBac1-F1 (5'-ACGCGATATTTCTTTTGGCCGG-3') and AsnBac1-R1 (5'-CAGTGAAGAGGTGCATGGTATG-3'). The amplified PCR product was used as a template for sequencing by the Sanger method. The amino acid coding regions (CDS) obtained were bioinformatically characterized using the NCBI website for BLASTn analysis, restriction site and hydrophobicity profiles were analyzed using the BioEdit program, phylogenetic tree was analyzed using the MEGA X program, and type 1 L-asparaginase amino acid sequence was analyzed using the Expasy translate program. The characterization results showed that the target gene has a high similarity to the ansA gene sequence of 20 Bacillus subtilis strains, i.e., 99-100%, is closely related to the ansA gene of Bacillus subtilis strain SRCM103629 and Bacillus subtilis strain GOT9, can be identified using restriction enzymes MluI and BstI to differentiate the species of organisms they produce, has CDS encoding 329 amino acids with a dominant composition of polar amino acids (54.1%) and has a hydrophobicity profile of amino acids dominated by hydrophilic regions. All these characteristics have confirmed that the characterized gene is the ansA gene encoding type 1 L-asparaginase from Bacillus subtilis. The finding of the ansA gene from Bacillus subtilis in a thermohalophilic region in Southeast Sulawesi, Indonesia is a novelty of the research.

Discovery of novel amidobenzimidazole derivatives as orally available small molecule modulators of stimulator of interferon genes for cancer immunotherapy

Stimulator of interferon genes (STING) agonists show promise as immunomodulatory agents for cancer therapy. In this study, we report the discovery of a novel orally available STING agonist, SAP-04, that exhibits potent immunomodulatory effects for cancer therapy. By optimizing the amidobenzimidazole core with various pyridine-based heterocyclic substituents, we identified a monomeric variant that displayed more efficient STING agonistic activity than the corresponding dimer. SAP-04 efficiently induced cytokine secretion related to innate immunity by directly binding of the compound to the STING protein, followed by sequential signal transduction for the STING signaling pathway and type I interferon (IFN) responses. Further pharmacological validation in vitro and in vivo demonstrated the potential utility of SAP-04 as an immunomodulatory agent for cancer therapy in vivo. The in vivo anticancer effect was observed in a 4T1 breast tumor syngeneic mouse model through oral administration of the compound. Our findings suggest a possible strategy for developing synthetically accessible monomeric variants as orally available STING agonists.