Royan Institute

Advanced therapy medicinal products (ATMPs) represent a groundbreaking category of medications that utilize biological-based products to treat or replace damaged organs. It offers potential solutions for complex diseases through gene therapy, somatic cell therapy, tissue engineering, and combined therapies. Although ATMPs have offered significant improvement for a variety of severe illnesses, their progressive development is faced with numerous challenges. Some of these challenges are current complexities in their manufacturing, such as scaling up, scaling out, product efficacy, packaging, storage, stability, and logistic concerns. Other challenges include manufacturing, efficacy, and scaling up of ATMPs, as well as establishing Good Manufacturing Practice (GMP)-compliant processes that align with product specifications derived from non-clinical studies conducted under Good Laboratory Practice (GLP). Additionally, safety concerns such as tumorigenesis are potential. Regulatory and ethical concerns, along with the need for standardization and clear clinical guidelines, are also critical obstacles. To address these challenges, novel technologies such as organoids, artificial intelligence, dynamic culture systems, and biobanking are being explored, providing new opportunities to enhance the consistency, scalability, and precision of ATMP production. Development in artificial intelligence (AI) technology helped scientists to address monitoring concerns, automation, and data management. Introducing advanced guidelines in biobanking helps researchers to overcome the storage and stability concerns. Organoid technology holds a significant promise in overcoming the challenges associated with preclinical and modeling of ATMPs by providing more accurate models for diseases, drug screening, and personalized medicine. This article reviews the current challenges in ATMP manufacturing and application, highlights the advancements in technology that are paving the way for improved therapeutic strategies, and offers future perspectives on overcoming these barriers.

Diabetes, via chronic metabolic and inflammatory dysregulation, may impair immune function and contribute to cognitive decline, particularly in executive functions. In this study, we examined changes in the cytokines IL-10 and TNF, as well as their balance, alongside executive function, physical performance, and diabetes-related indices following a combined, dual-task, home-based exercise training program. A total of 85 inactive women aged 50-75 years with type 2 diabetes were randomly assigned to either an exercise training group or a control group. During the pre- and post-test phases, assessments were conducted in both groups to measure executive function, physical performance, levels of IL-10 and TNF, their ratio, and diabetes-related indices. The dual-tasked home-based exercise program improved physical performance and body composition (P < 0.05). Executive function significantly improved in the exercise group (Effect size (ES) = 0.44, P < 0.05), accompanied by reductions in IL-10 (ES = 1.11, P < 0.05) and TNF levels (ES = 0.76, P < 0.05). However, no significant changes were observed in the balance of these two cytokines or diabetes-related indices (P > 0.05), except for HDL levels (ES = 0.87, P < 0.05). Based on the results of the present study, engaging in multi-task home-based exercise training can enhance executive function and reduce inflammatory cytokines in women with type 2 diabetes. However, this training did not significantly affect the balance between IL-10 and TNF, which may be due to the moderate intensity of the exercises. Further long-term studies that take into account additional factors-such as nutrition, medication use, and cognitive status-are warranted to gain a clearer understanding of the cytokine-modulating effects of dual-task exercise training in individuals with type 2 diabetes.

Hepatocellular carcinoma (HCC) still has a high mortality rate and an increasing prevalence trend. Therefore, improving treatment methods is essential for the management of this cancer. Turmerones, which are the main volatile natural components of Curcuma longa Linn, have shown a number of beneficial biological activities both in vitro and in vivo. However, because of their hydrophobicity, their delivery methods need substantial improvement. Niosomes, which are made of non-ionic surfactants, have shown promising results in drug delivery systems (DDSs). Due to their appropriate encapsulation rate, stability, bioavailability, and predictable release patterns, they could be useful tools in DDSs. In this study, we demonstrated the benefit of treatment with turmerone-loaded niosomes on cancerous phenotypes of two HCC cell line in vitro and in vivo.

Turmerone-loaded niosomes were synthesized through thin-film hydration method and characterized with dynamic light scattering (DLS), scanning electron microscopy (SEM), and Fourier transform infrared (FTIR). The impact of turmerone-loaded niosomes on Huh-7 and Hep3B cells were assessed in vitro in term of gene expression, protein production, apoptosis, cell cycle, and some functional assessments such as colony formation potential and migration. Furthermore, tumorigenesis potential of the turmerone-loaded niosomes treated hepatoma cells was assessed in an in vivo model using nude mice.

Our in vitro experiments showed that turmerone-loaded niosomes induced apoptosis (26.04 % for Huh-7 and 29.7 % for Hep3B) and cell cycle arrest in Huh-7 and Hep3B cells. Additionally, turmerone-loaded niosomes treatment down-regulated EMT-inducing genes and significantly decreased the EMT phenotype, as well as decreased colony formation capacity in both cell lines (surviving fraction of 0.27 for Huh-7 and 0.032 for Hep3B). In vivo study showed that upon transplantation, hepatoma cells which have been pre-treated with turmerone-loaded niosomes have less growth rate and produced smaller tumors with significantly few proliferating cells in nude mice.

This study showed that turmerone delivery through niosome have higher anti-cancer potentials in comparison to free-turmerone treatment on HCC cell line. Therefore, this approach could have a promising therapeutic potential in combination with other approved clinical settings for HCC treatment.