Diffusion of curcumin in PLGA-based carriers for drug delivery: a molecular dynamics study.

CONTEXT: The rapid growth and diversification of drug delivery systems have been significantly supported by advancements in micro- and nano-technologies, alongside the adoption of biodegradable polymeric materials like poly(lactic-co-glycolic acid) (PLGA) as microcarriers. These developments aim to reduce toxicity and enhance target specificity in drug delivery. The use of in silico methods, particularly molecular dynamics (MD) simulations, has emerged as a pivotal tool for predicting the dynamics of species within these systems. This approach aids in investigating drug delivery mechanisms, thereby reducing the costs associated with design and prototyping. In this study, we focus on elucidating the diffusion mechanisms in curcumin-loaded PLGA particles, which are critical for optimizing drug release and efficacy in therapeutic applications. METHODS: We utilized MD to explore the diffusion behavior of curcumin in PLGA drug delivery systems. The simulations, executed with GROMACS, modeled curcumin molecules in a representative volume element of PLGA chains and water, referencing molecular structures from the Protein Data Bank and employing the CHARMM force field. We generated PLGA chains of varying lengths using the Polymer Modeler tool and arranged them in a bulk-like environment with Packmol. The simulation protocol included steps for energy minimization, T and p equilibration, and calculation of the isotropic diffusion coefficient from the mean square displacement. The Taguchi method was applied to assess the effects of hydration level, PLGA chain length, and density on diffusion. RESULTS: Our results provide insight into the influence of PLGA chain length, hydration level, and polymer density on the diffusion coefficient of curcumin, offering a mechanistic understanding for the design of efficient drug delivery systems. The sensitivity analysis obtained through the Taguchi method identified hydration level and PLGA density as the most significant input parameters affecting curcumin diffusion, while the effect of PLGA chain length was negligible within the simulated range. We provided a regression equation capable to accurately fit MD results. The regression equation suggests that increases in hydration level and PLGA density result in a decrease in the diffusion coefficient.

Clinical Trials for Oral, Inhaled and Intravenous Drug Delivery System for Lung Cancer and Emerging Nanomedicine-Based Approaches.

Lung cancer is one of the most common malignant tumors worldwide and is characterized by high morbidity and mortality rates and a poor prognosis. It is the leading cause of cancer-related death in the United States and worldwide. Most patients with lung cancer are treated with chemotherapy, radiotherapy, or surgery; however, effective treatment options remain limited. In this review, we aim to provide an overview of clinical trials, ranging from Phase I to III, conducted on drug delivery systems for lung cancer treatment. The trials included oral, inhaled, and intravenous administration of therapeutics. Furthermore, the study also talks about the evolving paradigm of targeted therapy and immunotherapy providing promising directions for personalized treatment. In addition, we summarize the best results and limitations of these drug delivery systems and discuss the potential capacity of nanomedicine.

Object-Cooperated Ternary Tree Partitioning Decision Method for Versatile Video Coding.

In this paper, we propose an object-cooperated decision method for efficient ternary tree (TT) partitioning that reduces the encoding complexity of versatile video coding (VVC). In most previous studies, the VVC complexity was reduced using decision schemes based on the encoding context, which do not apply object detecion models. We assume that high-level objects are important for deciding whether complex TT partitioning is required because they can provide hints on the characteristics of a video. Herein, we apply an object detection model that discovers and extracts the high-level object features-the number and ratio of objects from frames in a video sequence. Using the extracted features, we propose machine learning (ML)-based classifiers for each TT-split direction to efficiently reduce the encoding complexity of VVC and decide whether the TT-split process can be skipped in the vertical or horizontal direction. The TT-split decision of classifiers is formulated as a binary classification problem. Experimental results show that the proposed method more effectively decreases the encoding complexity of VVC than a state-of-the-art model based on ML.

Improved survival rate and minimal side effects of doxorubicin for lung metastasis using engineered discoidal polymeric particles.

Despite advances in cancer therapy, the discovery of effective cancer treatments remains challenging. In this study, a simple method was developed to increase the efficiency of doxorubicin (DOX) delivery in a lung metastasis model. This method comprises a simple configuration to increase the delivery efficiency via precise engineering of the size, shape, loading content, and biodegradability of the drug delivery system. This system had a 3 µm discoidal shape and exerted approximately 90% burst release of the drug within the first 24 h. There was no cytotoxicity of the drug carrier up to a concentration of 1 mg ml-1, and DOX from the carrier was delivered into the cancer cells, exhibiting an anticancer effect comparable to that of the free drug. The ex vivo results revealed a strong correlation between the location of cancer cells in the lung and the location of DOX delivered by this drug delivery system. These drug carriers were confirmed to intensively deliver DOX to cancer cells in the lung, with minimal off-target effects. These findings indicate that this delivery system can be a new approach to improving the survival rate and reducing the side effects caused by anticancer drugs without the use of targeting ligands and polyethylene glycol.

Indocyanine Green-Loaded PLGA Nanoparticles Conjugated with Hyaluronic Acid Improve Target Specificity in Cervical Cancer Tumors.

PURPOSE: Indocyanine green (ICG) is a promising agent for intraoperative visualization of tumor tissues and sentinel lymph nodes in early-stage gynecological cancer. However, it has some limitations, including a short half-life and poor solubility in aqueous solutions. This study aimed to enhance the efficacy of near-infrared (NIR) fluorescence imaging by overcoming the shortcomings of ICG using a nano-drug delivery system and improve target specificity in cervical cancer. MATERIALS AND METHODS: ICG and poly(lactic-co-glycolic acid) (PLGA) conjugated with polyethylenimine (PEI) were assembled to enhance stability. Hyaluronic acid (HA) was coated on PEI-PLGA-ICG nanoparticles to target CD44-positive cancer cells. The manufactured HA-ICG-PLGA nanoparticles (HINPs) were evaluated in vitro and in vivo on cervical cancer cells (SiHa; CD44+) and human dermal cells (ccd986sk; CD44-), respectively, using NIR imaging to compare intracellular uptake and to quantify the fluorescence intensities of cells and tumors. RESULTS: HINPs were confirmed to have a mean size of 200 nm and a zeta-potential of 33 mV using dynamic light scattering. The stability of the HINPs was confirmed at pH 5.0-8.0. Cytotoxicity assays, intracellular uptake assays, and cervical cancer xenograft models revealed that, compared to free ICG, the HINPs had significantly higher internalization by cervical cancer cells than normal cells (p<0.001) and significantly higher accumulation in tumors (p<0.001) via CD44 receptor-mediated endocytosis. CONCLUSION: This study demonstrated the successful application of HINPs as nanocarriers for delivering ICG to CD44-positive cervical cancer, with improved efficacy in NIR fluorescence imaging.

Porous discoidal polymeric particles for effective drug delivery minimizing phagocytosis.

Curcumin has great potential in cancer treatment and prevention. However, free curcumin for anticancer effect is limited due to its low water solubility and instability. Delivery of free curcumin using biodegradable and biocompatible polymers, such as poly (lactic-co-glycolic acid) (PLGA), can improve these undesirable problems. In this study, a top-down fabrication method using PLGA was employed to deliver free curcumin, engineering size, shape, and surface properties. As a result, porous discoidal polymeric particles (DPPs) were produced in ammonium bicarbonate with a hydrodynamic diameter of 5 µm and a negatively charged surface. The loading amount of free curcumin in the porous DPPs was higher than non-porous DPPs. In vitro drug release study showed that curcumin release from porous DPPs was 1.4-fold higher than non-porous ones. The confocal microscopy and flow cytometry results demonstrated that porous DPPs decrease phagocytosis by macrophages than non-porous ones. This study suggests that porous DPPs have significant advantages for effective drug delivery of curcumin, minimizing phagocytosis.

Therapeutic Efficacy of Curcumin Enhanced by Microscale Discoidal Polymeric Particles in a Murine Asthma Model.

Curcumin is considered a potential anti-asthmatic agent owing to its anti-inflammatory properties. The objective of the present study was to prepare curcumin-containing poly(lactic-co-glycolic acid)-based microscale discoidal polymeric particles (Cur-PLGA-DPPs) and evaluate their anti-asthmatic properties using a murine asthma model. Cur-PLGA-DPPs were prepared using a top-down fabrication method. The prepared Cur-PLGA-DPPs had a mean particle size of 2.5 ± 0.4 µm and a zeta potential value of -34.6 ± 4.8 mV. Ex vivo biodistribution results showed that the Cur-PLGA-DPPs mainly accumulated in the lungs and liver after intravenous injection. Treatment with Cur-PLGA-DPPs effectively suppressed the infiltration of inflammatory cells in bronchoalveolar lavage fluid, and reduced bronchial wall thickening and goblet-cell hyperplasia compared to those in the phosphate-buffered-saline-treated control group. No significant changes in hematology and blood biochemistry parameters were observed after treatment with Cur-PLGA-DPPs. At equal curcumin concentrations, treatment with Cur-PLGA-DPPs exhibited better therapeutic efficacy than treatment with free curcumin. Our results suggest that the microscale Cur-PLGA-DPPs can be potentially used as a lung-targeted asthma therapy.

Biodegradable micro-sized discoidal polymeric particles for lung-targeted delivery system.

Various types of particle-based drug delivery systems have been explored for the treatment of pulmonary diseases; however, bio-distribution and elimination of the particles should be monitored for better understanding of their therapeutic efficacy and safety. This study aimed to characterize the biological properties of micro-sized discoidal polymeric particles (DPPs) as lung-targeted drug delivery carriers. DPPs were prepared using a top-down fabrication approach and characterized by assessing size and zeta potential. They were labeled with zirconium-89 (89Zr), and bio-distribution studies and PET imaging were performed for 7 days after intravenous administration. Their hydrodynamic size was 2.8 ±â€¯6.1 µm and average zeta potential was -39.9 ±â€¯5.39 mV. At doses of 5, 12.5, and 25 mg/kg, they showed no acute toxicity in nude mice. Desferrioxamine (DFO)-functionalized 89Zr-labeled DPPs gave a decay-corrected radiochemical yield of 82.1 ±â€¯0.2%. Furthermore, 89Zr-DPPs, from chelate-free labeling methods, showed a yield of 48.5 ±â€¯0.9%. Bio-distribution studies and PET imaging showed 89Zr-DFO-DPPs to be mainly accumulated in the lungs and degraded within 3 d of injection. However, 89Zr-DFO-DPPs showed significantly low uptake in the bone. Overall, our results suggested micro-sized DPPs as promising drug delivery carriers for the targeted treatment of various pulmonary diseases.

Biomimetic surface modification of discoidal polymeric particles.

The rationale for the design of drug delivery nanoparticles is traditionally based on co-solvent self-assembly following bottom-up approaches or in combination with top-down approaches leading to tailored physiochemical properties to regulate biological responses. However, the optimal design and control of material properties to achieve specific biological responses remain the central challenge in drug delivery research. Considering this goal, we herein designed discoidal polymeric particles (DPPs) whose surfaces are re-engineered with isolated red blood cell (RBC) membranes to tailor their pharmacokinetics. The RBC membrane-coated DPPs (RBC-DPPs) were found to be biocompatible in cell-based in vitro experiments and exhibited extended blood circulation half-life. They also demonstrated unique kinetics at later time points in a mouse model compared to that of bare DPPs. Our results suggested that the incorporation of biomimicry would enable the biomimetic particles to cooperate with systems in the body such as cells and biomolecules to achieve specific biomedical goals.

Stabilization of HDAC1 via TCL1-pAKT-CHFR axis is a key element for NANOG-mediated multi-resistance and stem-like phenotype in immune-edited tumor cells.

Cancer immunoediting enriches NANOG expression in tumor cells, resulting in multi-drug resistance and stem-like phenotypes. We previously demonstrated that these NANOG-associated phenotypes are promoted through HDAC1 transcriptional upregulation. In this study, we identified that NANOG also contributes to the stabilization of HDAC1 protein through the AKT signaling pathway. NANOG-AKT axis leads to phosphor-dependent inactivation of CHFR, an E3 ligase for HDAC1 protein, and thereby inhibiting the ubiquitin-mediated degradation of HDAC1. Furthermore, AKT inhibition disrupts HDAC1 WT-mediated phenotypes but had no effect on the phenotypes mediated by HDAC1 FM, a mutant that is unable to interact with CHFR. Critically, we applied a catalytic dead mutant, HDAC1-H141A, to uncover that HDAC1 confers immune-resistance, drug-resistance and stem-like phenotype in tumor cells through its catalytic activity. Collectively, our results establish a firm molecular link in immune-edited tumor cells among NANOG, AKT, CHFR, and HDAC1, identifying HDAC1 as a molecular target in controlling NANOGHIGH immune-refractory cancer.