A triple-blind, placebo-controlled, randomized clinical trial to evaluate the effect of curcumin-containing nanomicelles on cellular immune responses subtypes and clinical outcome in COVID-19 patients.

In COVID-19 patients, cytokine storm due to excessive immune responses can cause severe complications. In this study, we investigated the effect of curcumin nanomicelles on clinical outcome and cellular immune responses subtypes changes in COVID-19 patients. A randomized, triple-blinded, placebo-controlled study was done. Forty COVID-19 patients were included into two groups of nano-curcumin and placebo. The nano-curcumin group received 40 mg of nano-curcumin capsule, four times per day for 2 weeks. Clinical signs and gene expression of TBX21, GATA3, RORC and FOXP3 genes and IFN-γ, IL-4, IL-17 and TGF-ß cytokines serum levels were measured at time points of 0, 7 and 14 days. Serum levels of IFN-γ (p = .52) and IL-17 (p = .11) decreased, while IL-4 (p = .12) and TGF-ß (p = .14) increased in the nano-curcumin group compared with placebo on day 14. Moreover, gene expressions of TBX21 (p = .02) and FOXP3 (p = .005) genes were significantly decreased and increased between nano-curcumin and placebo groups on day 7, respectively. It can be concluded that administration of nano-curcumin in inflammatory phase of COVID-19 can accelerate recovering of the acute inflammatory phase by modulating inflammatory immune responses. Therefore, it is suggested that this supplement in inflammatory diseases, including COVID-19, can be effective in controlling the inflammatory responses.

The clinical effect of Nano micelles containing curcumin as a therapeutic supplement in patients with COVID-19 and the immune responses balance changes following treatment: A structured summary of a study protocol for a randomised controlled trial.

OBJECTIVES: To investigates the effectiveness of curcumin-containing Nanomicelles as a therapeutic supplement in the treatment of patients with COVID-19 and its effect on immune responses balance changes following treatment. TRIAL DESIGN: This study is conducted as a prospective, placebo-controlled with parallel group, single-center randomized clinical trial on COVID-19 patients. PARTICIPANTS: Patients are selected from the COVID-19 ward of Shahid Mohammadi Hospital in Bandar Abbas, Iran. INCLUSION CRITERIA: 1. Real time PCR-approved positive COVID-19 test. 2. Both gender 3. Age between 18 and 75 years 4. Signing a written consent 5. Lack of participation in other clinical trials Exclusion criteria: 1. Pregnancy or lactation 2. Allergy to turmeric or curcumin 3. Smoking 4. Patient connected to the ventilator 5. SaO2 less than 90% or PaO2 less than 8 kPa 6. Having comorbidities (such as severe renal failure, Glomerular filtration rate less than 30 ml/min, liver failure, Congestive heart failure, or Chronic obstructive pulmonary disease) 7. History of gallstones 8. History of gastritis or active gastrointestinal ulcer INTERVENTION AND COMPARATOR: In addition to the routine standard treatments for COVID-19, in the intervention group, 40mg nanomicelles containing curcumin (SinaCurcumin Capsule, Exir Nano Sina Company, Iran), four times per day (after breakfast, lunch, dinner and before bedtime) and in the placebo group as the control group, capsules with the same appearance and characteristics (Placebo capsules, Exir Nano Sina Company, Iran) are prescribed for two weeks. MAIN OUTCOMES: The effectiveness of Nano micelles containing curcumin treatment will be evaluated as daily clinical examinations of patients in both groups and, on days 0, 7 and 14, complete clinical symptoms and laboratory findings including peripheral blood and serum parameters such as inflammatory markers will be measured and recorded. Moreover, in order to evaluate the balance of immune responses changes following treatments, serum level of IFN-γ, IL-17, Il-4 and TGF-ß serum cytokines will be measured in both groups at time points of 0, 7 and 14 days post treatment. Gene expression of t-bet, GATA-3, FoxP3 and ROR- γT will also be measured at mentioned time points to assess the shift of T helper1, T helper2, T regulatory and T helper 17 immune responses following treatment. RANDOMISATION: Randomized trials will be performed on 40 COVID-19 patients which will be randomized using encoded sealed boxes with computer generated random digits with 1:1 allocation ratio. In order to randomization, placebo and SinaCurcumin Capsules will be numbered first by computer generated random digits. SinaCurcumin and placebo will then be stored and numbered in sealed packages based on generated random numbers. Finally, according to the order in which patients enter the study, packages are given to patients based on their number. BLINDING (MASKING): The present study will be blind for all patients, physicians and nurses, laboratory technicians and statisticians. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): A total of 40 patients will be included in the study, 20 of them will be randomly assigned to the intervention group and 20 to the placebo group. TRIAL STATUS: This is Version 1.0 of protocol dated 21 May 2020. The recruitment was started June 24, 2020 and is expected to be completed by October 31, 2020. TRIAL REGISTRATION: This present clinical trial has been registered in the Iranian Registry of Clinical Trials (IRCT) with the registration code of "IRCT20200611047735N1", https://www.irct.ir/trial/48843 . Dated: 19 June 2020. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

The trip of a drug inside the body: From a lipid-based nanocarrier to a target cell.

To date, enormous investigations have been conducted to enhance medicines' target-oriented delivery to improve their therapeutic index. In this regard, lipid-based carrier system might have been regarded as prime delivery systems that are very close to the naturally cell-derived vesicles used for biomolecular communication among cells from occasionally remote tissues. Upon examination of the literature, we found a chasm between groups of investigations in drug pharmaceutics and thought that maybe holistic research could provide better information with respect to drug delivery inside the body, especially when they are going to be injected directly into the bloodstream for systemic distribution. While a collection of older research in most cases dealt with the determination of drug partition coefficient between the aqueous and cell membrane compartments, the link has been overlooked in newer investigations that were mostly focused on drug formulation optimization and their association with particle biodistribution. This gap in the literature motivated us to present the current opinion paper, in which drug physicochemical properties like drug lipophilicity/hydrophilicity is considered as an important element in designing drug-carrying liposomes or micelles. How a hypothetical high throughput cell-embedded chromatographic technique might help to investigate a nanocarrier tissue distribution and to design 'multi-epitope grafted lipid-based drug carrier systems' are discussed. Whenever we would need support for our opinions, we have provided analogy from hydrophobic biomolecules like cholesterol, steroid hormones, and sex hormones and encouraged readers to consider our principle hypothesis: If these molecules could reach their targets far away from the site of production, then a large list of hydrophobic drugs could be delivered to their targets using the same principles.

Liposomal CpG-ODN: An in vitro and in vivo study on macrophage subtypes responses, biodistribution and subsequent therapeutic efficacy in mice models of cancers.

CpG oligodeoxynucleotides (CpG-ODN), a common immune stimulator and vaccine adjuvant, was reported to switch Tumor Associated Macrophages (TAMs) from M2 to M1 phenotype inducing anti-tumor responses. Liposomes are of the successfully applied carriers for CpG-ODN. The aim of present study was design and preparation of a liposomal formulation containing phosphodiester CpG-ODN, evaluation of its effect on macrophages responses, and subsequent antitumor responses in mice. Liposomal formulations containing phosphodiester CpG-ODN or non-CpG-ODN were prepared and characterized. MTT reduction assay in four different cell lines, uptake, arginase and iNOS activity evaluation in macrophage cell lines, biodistribution study and therapeutic anti-tumor effects of formulations in mice bearing C26 colon carcinoma or B16F0 melanoma were carried out. The size of liposomes containing CpG-ODN was ~200 nm with the encapsulation efficiency of 33%. The iNOS activity assay showed high nitric oxide (NO) level in M2 phenotype of macrophage cell lines treated by liposomes containing CpG-ODN. In mice which received liposomes containing CpG-ODN as a monotherapy, maximum tumor growth delay with remarkable survival improvement was observed compared to control groups. Biodistribution study showed the accumulation of liposomal formulation in tumor micro-environment. In conclusion, considerable anti-tumor responses observed by liposomes containing CpG-ODN was due to enhanced delivery of CpG-ODN to immune cells and subsequent initiation of anti-tumoral immune responses.