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Remya Valsalakumari,1– 3 Abhilash D Pandya,3,* Lina Prasmickaite,3,* Audun Kvalvaag,1,2 Anne Grethe Myrann,1,2 Andreas KO Åslund,4 Marianne Steinsvik Kjos,4 Cristina Fontecha-Cuenca,5,6 Hajira B Haroon,5 Ana RS Ribeiro,7 Jutta Horejs-Hoeck,7,8 S Moein Moghimi,5,9,10 Ýrr Mørch,4 Tore Skotland,1,2 Kirsten Sandvig,1,2,11 Gunhild Mari Mælandsmo,3,12 Tore Geir Iversen1,2 1Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, 0379, Norway; 2Centre for Cancer Cell Reprogramming, University of Oslo, Oslo, 0379, Norway; 3Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, 0379, Norway; 4Department of Biotechnology and Nanomedicine, SINTEF AS, Trondheim, 7034, Norway; 5School of Pharmacy, Newcastle University, Newcastle upon Tyne, NE1 7RU, UK; 6Department of Biomedical Science, University of Padova, Padova, Italy; 7Department of Biosciences and Medical Biology, Paris Lodron University Salzburg, Salzburg, 5020, Austria; 8Cancer Cluster Salzburg, Salzburg, 5020, Austria; 9Faculty of Health and Medical Sciences, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK; 10Colorado Center for Nanomedicine and Nanosafety, University of Colorado Anschutz Medical Center, Aurora, CO, USA; 11Department of Biosciences, University of Oslo, Oslo, 0316, Norway; 12Department of Medical Biology, University of Tromsø, Tromsø, 9019, Norway*These authors contributed equally to this workCorrespondence: Tore Geir Iversen, Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, 0379, Norway, Tel +47 22781826, Email t.g.iversen@ous-research.noBackground: Biodegradable poly(alkyl cyanoacrylate) (PACA) nanoparticles (NPs) are receiving increasing attention in anti-cancer nanomedicine development not only for targeted cancer chemotherapy, but also for modulation of the tumor microenvironment. We previously reported promising results with cabazitaxel (CBZ) loaded poly(2-ethylbutyl cyanoacrylate) NPs (PEBCA-CBZ NPs) in a patient derived xenograft (PDX) model of triple-negative breast cancer, and this was associated with a decrease in M2 macrophages. The present study aims at comparing two endotoxin-free PACA NP variants (PEBCA and poly(2-ethylhexyl cyanoacrylate); PEHCA), loaded with CBZ and test whether conjugation with folate would improve their effect.Methods: Cytotoxicity assays and cellular uptake of NPs by flow cytometry were performed in different breast cancer cells. Biodistribution and efficacy studies were performed in PDX models of breast cancer. Tumor associated immune cells were analyzed by multiparametric flow cytometry.Results: In vitro studies showed similar NP-induced cytotoxicity patterns despite difference in early NP internalization. On intravenous injection, the liver cleared the majority of NPs. Efficacy studies in the HBCx39 PDX model demonstrated an enhanced effect of drug-loaded PEBCA variants compared with free drug and PEHCA NPs. Furthermore, the folate conjugated PEBCA variant did not show any enhanced effects compared with the unconjugated counterpart which might be due to unfavorable orientation of folate on the NPs. Finally, analyses of the immune cell populations in tumors revealed that treatment with drug loaded PEBCA variants affected the myeloid cells, especially macrophages, contributing to an inflammatory, immune activated tumor microenvironment.Conclusion: We report for the first time, comparative efficacy of PEBCA and PEHCA NP variants in triple negative breast cancer models and show that CBZ-loaded PEBCA NPs exhibit a combined effect on tumor cells and on the tumor associated myeloid compartment, which may boost the anti-tumor response. Keywords: poly(alkyl cyanoacrylate), cabazitaxel, breast cancer, patient-derived xenograft, tumor microenvironment

A peptide-based hydrogel sequence was computationally predicted from the Ala-rich cross-linked domains of elastin. Three candidate peptides were subsequently synthesised and characterised as potential drug delivery vehicles. The elastin-derived peptides are Fmoc-FFAAAAKAA-NH 2 , Fmoc-FFAAAKAA-NH 2 , and Fmoc-FFAAAKAAA-NH 2 . All three peptide sequences were able to self-assemble into nanofibers. However, only the first two could form hydrogels, which are preferred as delivery systems compared to solutions. Both of these peptides also exhibited favourable nanofiber lengths of at least 1.86 and 4.57 µm, respectively, which are beneficial for the successful delivery and stability of drugs. The shorter fibre lengths of the third peptide (maximum 0.649 µm) could have inhibited their self-assembly into the three-dimensional networks crucial to hydrogel formation.

The complement system is a multicomponent and multifunctional arm of the innate immune system. Complement contributes to non-specific host defence and maintains homeostasis through multifaceted processes and pathways, including crosstalk with the adaptive immune system, the contact (coagulation) and the kinin systems, and alarmin high-mobility group box 1. Complement is also present intracellularly, orchestrating a wide range of housekeeping and physiological processes in both immune and nonimmune cells, thus showing its more sophisticated roles beyond innate immunity, but its roles are still controversial. Particulate drug carriers and nanopharmaceuticals typically present architectures and surface patterns that trigger complement system in different ways, resulting in both beneficial and adverse responses depending on the extent of complement activation and regulation as well as pathophysiological circumstances. Here we consider the role of complement system and complement regulations in host defence and evaluate the mechanisms by which nanoparticles trigger and modulate complement responses. Effective strategies for the prevention of nanoparticle-mediated complement activation are introduced and discussed., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [P.N.T. declares financial interests in CosmoPHOS Ltd (Greece). Z.S.F. & S.M.M. declare financial interests in S. M. Discovery Inc. and S. M. Discovery Ltd. H.B.H., E.D. & D.S. declare that they have no competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.]., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

The complement system, professional phagocytes and other cells such as Natural killer cells and mast cells are among the important components of the innate arm of the immune system. These constituents provide an orchestrated array of defences and responses against tissue injury and foreign particles, including nanopharmaceuticals. While interception of nanopharmaceuticals by the immune system is beneficial for immunomodulation and treatment of phagocytic cell disorders, it is imperative to understand the multifaceted mechanisms by which nanopharmaceuticals interacts with the immune system and evaluate the subsequent balance of beneficial versus adverse reactions. An example of the latter is adverse infusion reactions to regulatory-approved nanopharmaceuticals seen in human subjects. Here, we discuss collective opinions and findings from our laboratories in mapping nanoparticle-mediated complement and leucocyte/macrophage responses., Competing Interests: Declaration of Competing Interest S.M.M. & P.N.T. are named inventors on PCT, EPO and US patent filings on dendrimers. P.N.T. declares financial interests in CosmoPHOS Ltd. (Greece). S.M.M. is named inventor on EPO, divisional and US granted patents on NanoLigand Carriers. Z.S.F. & S.M.M declares financial interests in S. M. Discovery Inc. and S. M. Discovery Ltd. H.B.H., A.Y., A.C.H., E.P. & D.S. declare that they have no competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

The contribution of the complement system to non-specific host defence and maintenance of homeostasis is well appreciated. Many particulate systems trigger complement activation but the underlying mechanisms are still poorly understood. Activation of the complement cascade could lead to particle opsonisation by the cleavage products of the third complement protein and might promote inflammatory reactions. Antibody binding in a controlled manner and/or sensing of particles by the complement pattern-recognition molecules such as C1q and mannose-binding lectin can trigger complement activation. Particle curvature and spacing arrangement/periodicity of surface functional groups/ligands are two important parameters that modulate complement responses through multivalent engagement with and conformational regulation of surface-bound antibodies and complement pattern-recognition molecules. Thus, a better fundamental understanding of nanometer- and angstrom-scale parameters that modulate particle interaction with antibodies and complement proteins could portend new possibilities for engineering of particulate drug carriers and biomedical platforms with tuneable complement responses and is discussed here., Competing Interests: Declaration of Competing Interest S.M.M. & P.N.T. are named inventors on PCT, EPO and US patent filings on dendrimers. P.N.T. declares financial interests in CosmoPHOS Ltd. (Greece). H.B.H., A.Y. & D.S. declare that they have no competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

The propensity of the hepatic macrophages (Kupffer cells) to rapidly intercept particulate materials from the blood has been frustrating in redirecting intravenously injected nanomedicines to pathological sites in sufficient quantities to exert appropriate pharmacological effect. The development of long circulating nanoparticles has offered unprecedented opportunities for controlled drug release within vasculature and for drug delivery to sites other than Kupffer cells. These developments were based on mechanistic understanding of complex and integrated body's defences against intruders as well as translation of protective strategies developed by the body's own cells and virulent pathogens against immune attack. Thanks to interdisciplinary and integrated approaches, numerous organic and inorganic nanoparticles with long circulating properties have become available. By long circulation we mean particles that remain in the blood for periods of hours rather than minutes, but blood longevity must be tuned in accordance with therapeutic needs. Here, we provide a brief history of these efforts and highlight important lessons learned in camouflaging nanoparticles with strategies that avoid rapid interception by Kupffer cells., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

The major challenge associated with the treatment of neurological disorders is the inefficiency of drugs to enter the Central Nervous System (CNS). Polymer-drug conjugates are now being tailored to overcome this hindrance associated with conventional drugs. The study aimed at developing polymer hybrid nasal nanocomposite for enhanced delivery of Centella to the CNS. Thiolated chitosan was complexed with Centella to form a composite using EDAC hydrochloride. The composite was characterized by FTIR, XRD, NMR, and MS. Further, this composite was converted into a nanoformulation by the ionic-gelation method, characterized, and subjected to ex vivo permeation studies. Additionally, MTT assay was performed using Human Uumbilical cord Vein Endothelial Cells (HUVECs) mimicking Blood-Brain Barrier (BBB) to establish the safety of nanocomposite. The targeting efficacy was predicted by molecular docking studies against receptors associated with BBB. The FTIR, XRD, NMR, and MS studies confirmed the chemical conjugation of thiolated chitosan with Centella. Nanocomposite characterization through SEM, AFM, and DLS confirmed the size and stability of the developed nanocomposite having a zeta potential of - 14.5 mV and PDI of 0.260. The nanocomposite showed no signs of nasal ciliotoxicity and good permeation of 89.44 ± 1.75% (mean ± SD, n = 3) at 8 h across the nasal mucosa. MTT assay showed that the nanocomposite had lesser toxicity compared to the free drug (IC 50 of Centella-269.1 μg/mL and IC 50 of CTC nanocomposite-485.375 μg/mL). The affinity of polymer to the BBB receptors as proved by docking studies suggests the ability of polymer-based nanocomposite to concentrate in the brain post nasal administration., (© 2021. American Association of Pharmaceutical Scientists.)

Development of diabetic cataract is mainly associated with the accumulation of sorbitol via the polyol pathway through the action of Aldose reductase (AR). Hence, AR inhibitors are considered as potential agents in the management of diabetic cataract. This study explored the AR inhibition potential of Hemidesmus indicus var. pubescens root extract by in silico and ex vivo methods. Molecular docking studies (Auto Dock tool) between β-sitosterol, hemidesminine, hemidesmin-1, hemidesmin-2, and AR showed that β-sitosterol (- 10.2 kcal/mol) and hemidesmin-2 (- 8.07 kcal/mol) had the strongest affinity to AR enzyme. Ex vivo studies were performed by incubating isolated goat lenses in artificial aqueous humor using galactose (55 mM) as cataract inducing agent at room temperature (pH 7.8) for 72 h. After treatment with Vitamin E acetate - 100 µg/mL (standard) and test extract (500 and 1000 µg/mL) separately, the estimation of biochemical markers showed inhibition of lens AR activity and decreased sorbitol levels. Additionally, extract also normalized the levels of antioxidant markers like SOD, CAT, GSH. Our results showed evidence that H. indicus var. pubescens root was able to prevent cataract by prevention of opacification and formation of polyols that underlines its potential as a possible therapeutic agent against diabetic complications.

Objectives: Cardiovascular diseases (CVDs) are highly prevalent in various countries, and heart failure accounts for the majority of deaths. The present study focuses on determining the protective effect of ethanol extract of leaves of Tamarindus indica (TIEE) by in vitro and in vivo methods., Methods: In vitro cardiotonic activity was determined using Langendorff's heart perfusion assembly. In vivo studies were performed using Doxorubicin (1.5 mg/kg, i.p for seven days) induced cardiotoxicity in rats. These animals were simultaneously treated with the TIEE at a low dose (200 mg/kg, p.o), high dose (400 mg/kg, p.o) and standard drug Digoxin (100 μg/kg, p.o) for seven days. At the end of the study, various parameters like electrocardiogram (ECG) recording, serum levels of serum glutamic pyruvic transaminase (SGPT), lactate dehydrogenase (LDH), creatinine phosphokinase (CPK), and presence of cardiac troponin (cTnI) were determined . Isolated hearts were subjected to histopathological studies., Results: The TIEE at a concentration of 60 μg/mL showed a significant cardiotonic effect in vitro that was evident by increased force of contraction, heart rate, and cardiac output. In vivo studies revealed that the TIEE decreased the prolongation of QT and RR interval of ECG, lowered the serum enzyme levels like LDH, CPK indicating cardiac protection, and the same was established by the absence of cTnI in blood. Histopathological examinations of heart tissue sections showed improved architecture in the treatment groups when compared with diseased groups., Conclusions: The study revealed the cardioprotective activity of T. indica leaf extract by both in vitro and in vivo methods., (© 2021 Walter de Gruyter GmbH, Berlin/Boston.)