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Vaikunthavasan Thiruchenthooran,1 Marta Świtalska,2 Gabriela Maciejewska,3,4 Anna Palko-Łabuz,5 Lorena Bonilla-Vidal,6,7 Joanna Wietrzyk,2 Eliana B Souto,8 Elena Sánchez-López,6,7,* Anna Gliszczyńska1,* 1Department of Food Chemistry and Biocatalysis, Wrocław University of Environmental and Life Sciences, Wrocław, Poland; 2Department of Experimental Oncology, Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wrocław, Poland; 3Central Laboratory of the Instrumental Analysis, Wrocław University of Technology, Wrocław, Poland; 4Omics Research Center, Wrocław Medical University, Wrocław, Poland; 5Department of Biophysics and Neuroscience, Wrocław Medical University, Wrocław, Poland; 6Department of Pharmacy, Pharmaceutical Technology and Physical Chemistry, University of Barcelona, Barcelona, 08028, Spain; 7Institute of Nanoscience and Nanotechnology (IN2UB), University of Barcelona, Barcelona, 08028, Spain; 8UCD School of Chemical and Bioprocess Engineering, University College Dublin, Dublin, D04 V1W8, Ireland*These authors contributed equally to this workCorrespondence: Anna Gliszczyńska; Elena Sánchez-López, Email anna.gliszczynska@upwr.edu.pl; esanchezlopez@ub.eduPurpose: It is well known that the nonsteroidal anti-inflammatory drug (NSAID) indomethacin (IND) exhibits significant anticancer potential reported not only by in vitro and in vivo studies, but also in clinical trials. Despite promising results, IND is not widely used as an adjunctive agent in cancer therapy due to the occurrence of several gastrointestinal side effects, primarily after oral administration. Therefore, this study aimed to develop a nanosystem with reduced toxicity and risk of side effects for the delivery of IND for cancer treatment.Methods: IND was encapsulated in nanostructured lipid carriers (NLC) in the form of a phospholipid conjugate, where a covalent bond exists between the drug and phosphatidylcholine skeleton. For this purpose, seven new hybrid molecules were synthesized, and subsequently evaluated as anticancer agents in an in vitro model against selected cancer cell lines.Results: Biological studies demonstrated that the synthesized conjugates possessed excellent antiproliferative effects, exhibiting a 2.7-fold to even 100-fold higher activity against selected cancer cells, while remaining non-toxic to healthy cells. Based on biological studies and molecular calculations, heterosubstituted phosphatidylcholine containing IND and oleic acid (IND-OA-PC) in the sn-1 and sn-2 positions, respectively, was identified as the most potent molecule. Subsequently, IND-OA-PC was encapsulated in nanostructured lipid carriers (IND-OA-PC-NLC). The results revealed that IND-OA-PC-NLC has a spherical shape with an average diameter of 155 nm and a negatively charged surface (– 17.4 ± 0.49 mV). In this study, it was proven that the encapsulated conjugate of indomethacin with PC exhibits high activity against triple-negative (TNBC, Her2-, PR-, and ER-) breast cancer cells MDA-MB-468. While free IND was active at a concentration of 270.5 μM, in the form of the phospholipid conjugate (IND-OA-PC), it inhibited the growth of cancer cells at 67.5 μM and after conjugate encapsulation (IND-OA-PC-NLC) it was effective at only 10.3 μM.Conclusion: Our study revealed that the conjugation of NSAID with phosphatidylcholine and its combination with nanotechnology techniques create opportunities to repurpose well-known drugs from this group for new therapeutic applications.Keywords: indomethacin, phospholipid conjugates, long-chain fatty acids, nanostructured lipid carrier, nanoparticles, anticancer properties

Vaikunthavasan Thiruchenthooran,1 Marta Espina,2,3 Marta Świtalska,4 Lorena Bonilla-Vidal,2,3 Joanna Wietrzyk,4 Maria Luisa Garcia,2,3 Eliana B Souto,5 Elena Sánchez-López,2,3,6,* Anna Gliszczyńska1,* 1Department of Food Chemistry and Biocatalysis, Wrocław University of Environmental and Life Sciences, Wrocław, Poland; 2Department of Pharmacy, Pharmaceutical Technology and Physical Chemistry, University of Barcelona, Barcelona, Spain; 3Institute of Nanoscience and Nanotechnology (IN2UB), University of Barcelona, Barcelona, Spain; 4Department of Experimental Oncology, Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wrocław, Poland; 5Laboratory of Pharmaceutical Technology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal; 6Unit of Synthesis and Biomedical Applications of Peptides, IQAC-CSIC, Barcelona, Spain*These authors contributed equally to this workCorrespondence: Anna Gliszczyńska; Elena Sánchez-López, Email anna.gliszczynska@upwr.edu.pl; esanchezlopez@ub.eduPurpose: The anticancer potential of indomethacin and other nonsteroidal anti-inflammatory drugs (NSAIDs) in vitro, in vivo, and in clinical trials is well known and widely reported in the literature, along with their side effects, which are mainly observed in the gastrointestinal tract. Here, we present a strategy for the application of the old drug indomethacin as an anticancer agent by encapsulating it in nanostructured lipid carriers (NLC). We describe the production method of IND-NLC, their physicochemical parameters, and the results of their antiproliferative activity against selected cancer cell lines, which were found to be higher compared to the activity of free indomethacin.Methods: IND-NLC were fabricated using the hot high-pressure homogenization method. The nanocarriers were physicochemically characterized, and their biopharmaceutical behaviour and therapeutic efficacy were evaluated in vitro.Results: Lipid nanoparticles IND-NLC exhibited a particle size of 168.1 nm, a negative surface charge (– 30.1 mV), low polydispersity index (PDI of 0.139), and high encapsulation efficiency (over 99%). IND-NLC were stable for over 60 days and retained integrity during storage at 4 °C and 25 °C. The potential therapeutic benefits of IND-NLC were screened using in vitro cancer models, where nanocarriers with encapsulated drug effectively inhibited the growth of breast cancer cell line MDA-MB-468 at dosage 15.7 μM.Conclusion: We successfully developed IND-NLC for delivery of indomethacin to cancer cells and confirmed their antitumoral efficacy in in vitro studies. The results suggest that indomethacin encapsulated in lipid nanoparticles possesses high anticancer potential. Moreover, the presented strategy is highly promising and may offer a new alternative for future therapeutic drug innovations. Keywords: lipid nanoparticles, indomethacin, antitumoral activity, tumor-targeting

Lorena Bonilla-Vidal,1,2 Marta Świtalska,3 Marta Espina,1,2 Joanna Wietrzyk,3 Maria Luisa García,1,2 Eliana B Souto,4,5 Anna Gliszczyńska,6,* Elena Sánchez López1,2,7,* 1Department of Pharmacy, Pharmaceutical Technology and Physical Chemistry, University of Barcelona, Barcelona, Spain; 2Institute of Nanoscience and Nanotechnology (IN2UB), University of Barcelona, Barcelona, Spain; 3Department of Experimental Oncology, Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wrocław, Poland; 4Laboratory of Pharmaceutical Technology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal; 5Associate Laboratory i4HB—Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, Porto, Portugal; 6Department of Food Chemistry and Biocatalysis, Wrocław University of Environmental and Life Sciences, Wrocław, Poland; 7Unit of Synthesis and Biomedical Applications of Peptides, IQAC-CSIC, Barcelona, Spain*These authors contributed equally to this workCorrespondence: Elena Sánchez López; Anna Gliszczyńska, Email esanchezlopez@ub.edu; anna.gliszczynska@upwr.edu.plPurpose: Cancer is one of the major causes of death worldwide affecting more than 19 million people. Traditional cancer therapies have many adverse effects and often result in unsatisfactory outcomes. Natural flavones, such as apigenin (APG), have demonstrated excellent antitumoral properties. However, they have a low aqueous solubility. To overcome this drawback, APG can be encapsulated in nanostructured lipid carriers (NLC). Therefore, we developed dual NLC encapsulating APG (APG-NLC) with a lipid matrix containing rosehip oil, which is known for its anti-inflammatory and antioxidant properties.Methods: Optimisation, physicochemical characterisation, biopharmaceutical behaviour, and therapeutic efficacy of this novel nanostructured system were assessed.Results: APG-NLC were optimized obtaining an average particle size below 200 nm, a surface charge of − 20 mV, and an encapsulation efficiency over 99%. The APG-NLC released APG in a sustained manner, and the results showed that the formulation was stable for more than 10 months. In vitro studies showed that APG-NLC possess significant antiangiogenic activity in ovo and selective antiproliferative activity in several cancer cell lines without exhibiting toxicity in healthy cells.Conclusion: APG-NLC containing rosehip oil were optimised. They exhibit suitable physicochemical parameters, storage stability for more than 10 months, and prolonged APG release. Moreover, APG-NLC were internalised inside tumour cells, showing the capacity to cause cytotoxicity in cancer cells without damaging healthy cells.Keywords: antitumoral, lipid nanoparticles, apigenin, rosehip oil

In this study, we report a series of newly synthesised sulphonamides of aziridine-2-carboxylic acid (Az-COOH) ester and amide analogues as potent protein disulphide isomerase (PDI, EC 5.3.4.1) inhibitors. The inhibitory activity on PDI was determined against recombinant human PDIA1 and PDIA3 proteins using an insulin reduction assay. These compounds in low micromolar to low nanomolar concentrations showed the effective in vitro inhibitory properties of PDIA1 with weaker effects on PDIA3. Complexes of 15N- and 15N,13C- uniformly labelled recombinant human PDIA1a with two PDIA1 inhibitors were produced and investigated by a protein nuclear magnetic resonance (NMR) spectroscopy. It was found that both C53 and C56 of the PDIA1 enzyme were involved in covalent binding. Finally, in a range of pharmacological studies, we demonstrated that investigated compounds displayed anti-cancer and anti-thrombotic activity. These findings demonstrate that sulphonamides of Az-COOH derivatives are promising candidates for the development of novel anti-cancer and anti-thrombotic agents. [ABSTRACT FROM AUTHOR]

One-step synthesis of novel biologically active 4- or 6-(4-methylidene-4 H-3,1-benzothiazin-2yl)benzene-1,3-diols is described. The target compounds were prepared by the reaction of aryl-modified sulfinylbis[(2,4-dihydroxyphenyl)methanethione]s with 1-(2-aminophenyl)ethanones. Newly synthesized compounds were characterized by IR, H NMR, and mass spectral data. Their antiproliferative potency against human cancer cell lines was determined. Some descriptors were calculated to find the relationship between the structure and activity. It is revealed that the presence of hydrophobic substituents in the benzenediol ring intensifies the biological potency. [ABSTRACT FROM AUTHOR]