DNA TARGETED ANTHRAQUINONE DERIVATIVES: AN IMPORTANT ANTICANCER AGENTS

Deoxyribonucleic acid, DNA is the source of various genetic information and is currently one of the most important and studied biological receptor. Lately, a wide range of chemotherapeutic agents are known wherein they affect cell division or DNA synthesis, leading to inhibition of cell growth and cell death. Out of various agents anthraquinone, having a planar tricyclic structure is the backbone of many known antitumor drugs like doxorubicin and mitoxantrone capable of targeting at the molecular/DNA level. This review embraces discussion on DNA-binding molecules with special attention to anthraquinone based compounds having application in anticancer activity by DNA damage mechanism. The review also compiles the work reported on anthraquinone based molecule in molecular imaging.Keywords: Anthraquinone, DNA, Cancer, Molecular imagin

PRELIMINARY EVALUATION OF AN ANTHRAQUINONE CONJUGATED DOTA DERIVATIVE AS SPECT AGENT

Objective: An anthraquinone derivative, DO3A-Act-AQ having DO3A (1, 4, 7, 10-tetraazacyclododecane-1, 4, 7-trisacetic acid) scaffold is radio labeled with 99mTc radioisotope and evaluated as a SPECT imaging agent for tumor.Methods: Preliminary in-vivo evaluation of 99mTc-DO3A-Act-AQ radioconjugate including blood kinetics, biodistribution and gamma scintigraphic imaging is performed on BMG-1 tumor xenografted mice after successful optimization of the radiolabeling condition.Results: The radiotracer, 99mTc-DO3A-Act-AQ was produced in high radiochemical yield of>96% and specific activity of 3.62 MBq/nmol at pH 7.5 and 150 µg stannous chloride. Radioconjugate displayed excellent in-vitro and in-vivo stability with only ~2% transchelation of radiometal at 24 h p. i and rapid blood clearance from the system with t1/2(F) = 38.04±0.35 min and t1/2(S) = 5 h 30 min±0.67. Significant tumor-to-muscle ratio of>7 at 2 h p. i. in biodistribution and SPECT imaging studies in BMG-1 tumor xenografted mice suggested the tumor specificity of the radioconjugate.Conclusion: Stable radiocomplex formation of 99mTc-DO3A-Act-AQ and its significant tumor specificity demonstrated its future application as a promising SPECT radioligand for tumor imaging

Formulation and Evaluation of Solid Dispersion of Celecoxib

The aim of this study was to develop celecoxib (CLX) -polyvinylpyrrolidone (PVP) solid dispersion nanoparticles with and without surfactant using the supercritical antisolvent (SAS) process. The effect of different surfactants such as gelucire 44/14, poloxamer 188, poloxamer 407, Ryoto sugar ester L1695, and D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) on nanoparticle formation and dissolution as well as oral absorption of CLX -PVP K30 solid dispersion nanoparticles was investigated. Spherical CLX solid dispersion nanoparticles <300 nm in size were successfully developed using the SAS process. Analysis by differential scanning calorimetry and powder X-ray diffraction showed that CLX existed in the amorphous form within the solid dispersion nanoparticles fabricated using the SAS process. The CLX -PVPTPGS solid dispersion nanoparticles significantly enhanced in vitro dissolution and oral absorption of CLX relative to that of the unprocessed form. The area under the concentration-time curve (AUC0 24 h) and peak plasma concentration (Cmax) increased 4.6 and 5.7 times, respectively, with the CLX -PVP-TPGS formulation. In addition, in vitro dissolution efficiency was well correlated with in vivo pharmacokinetic parameters. The present study demonstrated that formulation of CLX -PVP-TPGS solid dispersion nanoparticles using the SAS process is a highly effective strategy for enhancing the bioavailability of poorly water-soluble CLX

Mapping of Translocator Protein (18 kDa) in Peripheral Sterile Inflammatory Disease and Cancer through PET Imaging

Positron emission tomography (PET) imaging of the translocator 18 kDa protein (TSPO) with radioligands has become an effective means of research in peripheral inflammatory conditions that occur in many diseases and cancers. The peripheral sterile inflammatory diseases (PSIDs) are associated with a diverse group of disorders that comprises numerous enduring insults including the cardiovascular, respiratory, gastrointestinal, or musculoskeletal system. TSPO has recently been introduced as a potential biomarker for peripheral sterile inflammatory diseases (PSIDs). The major critical issue related to PSIDs is its timely characterization and localization of inflammatory foci for proper therapy of patients. As an alternative to metabolic imaging, protein imaging expressed on immune cells after activation is of great importance. The five transmembrane domain translocator protein-18 kDa (TSPO) is upregulated on the mitochondrial cell surface of macrophages during inflammation, serving as a potential ligand for PET tracers. Additionally, the overexpressed TSPO protein has been positively correlated with various tumor malignancies. In view of the association of escalated TSPO expression in both disease conditions, it is an immensely important biomarker for PET imaging in oncology and PSIDs. In this review, we summarize the most outstanding advances on TSPO-targeted PSIDs and cancer in the development of TSPO ligands as a potential diagnostic tool, specifically discussing the last five years.KEYWORDS:translocator protein inflammation PET cancer polymorphis

Preclinical Evaluation of DO3A-Act-AQ: A Polyazamacrocyclic Monomeric Anthraquinone Derivative as a Theranostic Agent

An anthraquinone conjugated macrocyclic chelating agent, 2,2′,2″-(10-(2-(9,10-dioxo-9,10-dihydroanthracen-1-ylamino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)­triacetic acid or DO3A-Act-AQ, was synthesized by reacting trisubstituted cyclen (DO3A) with 2-chloro-<i>N</i>-(9,10-dioxo-9,10-dihydro-anthracen-1-yl)-acetamide and radiolabeled with ⁶⁸GaCl₃ in 84% efficiency and a specific activity of 4.62 MBq/nmol. The IC₅₀ value for BMG-1 cells was 0.1 mM, while the same concentration of DO3A-Act-AQ rendered no significant toxicity in HEK cells. The exposure of BMG-1 cells with 0.1 mM DO3A-Act-AQ displayed a time-dependent increase in apoptosis (40.7% at 4 h and 53% at 24 h), and the effect was 2.8- and 3.6-fold % higher as seen in HEK cells. An increase in S-phase cell population suggested S-phase arrest concomitant with induction of apoptosis in BMG-1 cells reaching to 4.5 times after 24 h with respect to control cells. DNA binding studies on CT-DNA (calf thymus) revealed a quenching pattern in the presence of DO3A-Act-AQ (10–70 μM), and the Stern–Volmer quenching constant was 2.4157 × 10⁶ L mol^–1, indicative of strong binding with ds-DNA. A decrease in the positive and negative bands of CT-DNA was seen at 278 nm and 240 nm, respectively, on addition of 0.05 mM of DO3A-Act-AQ in CD studies. ⁶⁸Ga-DO3A-Act-AQ was stable <i>in vitro</i> in both PBS and human serum for at least 2 h. The <i>in vivo</i> blood kinetics study performed on normal rabbits indicated fast clearance with <i>t</i>_1/2(F) = 40 ± 0.3 min and <i>t</i>_1/2(S) = 3 h 30 min ± 0.1 min. <i>Ex vivo</i> biodistribution analysis displayed a favorable tumor-to-muscle ratio of 8.4 after 2 h in athymic nude mice xenografted with BMG-1 cells, suggesting the specificity of ⁶⁸Ga-DO3A-Act-AQ toward tumors

Maintenance of Broad Neutralising Antibodies and Memory B Cells 12 Months Post-Infection Is Predicted by SARS-CoV-2 Specific CD4+ T Cell Responses

Understanding the long-term maintenance of SARS-CoV-2 immunity is critical for prediction of protection against reinfection. In a cohort of 24 participants, the association of disease severity and early immunological measurements on the maintenance of humoral immune responses 12 months post-infection were examined. All severely affected participants maintained a stable subset of SARS-CoV-2 receptor-binding domain (RBD) specific memory B cells (MBCs) and good neutralising antibody breadth against the majority of the variants of concern, including the Delta variant. Modelling these immune responses on vaccine efficacy data indicated a level equivalent to a vaccine efficacy of approximately 45-76% against symptomatic reinfection (variant dependent). Overall, these findings indicate durable humoral responses in most participants, provide an estimate of the level of protection and identifies the magnitude and phenotype of baseline antigen-specific CD4+ T cell response as a predictor of maintenance of both antibody neutralisation breadth and RBD-specific MBC levels at 12 months post-infection.Funding: The Kirby Institute is funded by the Australian Government Department of Health and Ageing. The views expressed in this publication do not necessarily represent the position of the Australian Government. Research reported in this publication was supported by Snow Medical Foundation as an investigator-initiated study. The content is solely the responsibility of the authors. RAB, MM, CR and ARL are fellows funded by National Health and Medical Research Council (NHMRC). MWAC is in part funded by the Research Infrastructure Programme of UNSW.Declaration of Interests: The authors declare no competing interests.Ethics Approval Statement: The protocol was approved by the Human Research Ethics Committees of the Northern Sydney Local Health District and the University of New South Wales, NSW Australia (ETH00520) and was conducted according to the Declaration of Helsinki and International Conference on Harmonization Good Clinical Practice (ICH/GCP) guidelines and local regulatory requirements. Written informed consent was obtained from all participants before study procedures

Maintenance of broad neutralizing antibodies and memory B cells 1 year post-infection is predicted by SARS-CoV-2-specific CD4+ T cell responses

Understanding the long-term maintenance of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunity is critical for predicting protection against reinfection. In an age- and gender-matched cohort of 24 participants, the association of disease severity and early immune responses on the maintenance of humoral immunity 12 months post-infection is examined. All severely affected participants maintain a stable subset of SARS-CoV-2 receptor-binding domain (RBD)-specific memory B cells (MBCs) and good neutralizing antibody breadth against the majority of the variants of concern, including the Delta variant. Modeling these immune responses against vaccine efficacy data indicate a 45%–76% protection against symptomatic infection (variant dependent). Overall, these findings indicate durable humoral responses in most participants after infection, reasonable protection against reinfection, and implicate baseline antigen-specific CD4+ T cell responses as a predictor of maintenance of antibody neutralization breadth and RBD-specific MBC levels at 12 months post-infection