Mechanism study of serum extracellular nano-vesicles miR-412-3p targeting regulation of TEAD1 in promoting malignant biological behavior of sub-centimeter lung nodules.

OBJECTIVE: To investigate the impact and potential mechanisms of serum extracellular nano-vesicles (sEVs) miR-412-3p released from sub-centimeter lung nodules with a diameter of ⩽ 10 mm on the malignant biological function of micro-nodular lung cancer (mnLC). METHODS: A total of 87 participants were included and divided into a mnLC group (n= 30), a benign lung nodule (BLN) group (n= 27), and a healthy people control group (n= 30). Transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA) and Western blot (WB) were used to measure the morphological characteristics and surface markers of sEVs. In vitro analysis, real-time quantitative polymerase chain reaction (RT-qPCR), CCK-8 cell proliferation assay, clone formation assay, Transwell, stem cell sphere-forming assay, and WB assay were conducted to verify the effect of miR-412-3p/TEAD1 signaling axis on the biological function of lung cancer cells through, respectively. Further validation was conducted using the serum sEVs of the participants. RESULTS: The expression level of sEVs-miR-412-3p in the mnLC group was significantly higher than that in the BLN and healthy groups (P< 0.01). In lung cancer cell lines, miR-412-3p can negatively regulate the targeted gene TEAD1. The miR-412-3p/TEAD1 signaling axis is involved in promoting the EMT signaling pathway and regulating the malignant biological functions of lung cancer cell proliferation, migration, and stemness (P< 0.05). In addition, sEVs in the mnLC group significantly promoted lung cancer cell proliferation, migration, and stemness compared to the BLN and healthy groups, inhibited the expression of E-cadherin and TEAD1 in lung cancer cells, and promoted the expression of N-cadherin and Vimentin (P< 0.05). CONCLUSION: sEVs-miR-412-3p could promote the biological process of EMT, and lead to the occurrence of malignant biological behavior in sub-centimeter lung nodules. This provides evidence for the miR-412-3p/TEAD1 signaling axis as a potential therapeutic target for mnLC.

Terpene-based novel invasomes: pioneering cancer treatment strategies in traditional medicine.

Health care workers have faced a significant challenge because of the rise in cancer incidence around the world during the past 10 years. Among various forms of malignancy skin cancer is most common, so there is need for the creation of an efficient and safe skin cancer treatment that may offer targeted and site-specific tumor penetration, and reduce unintended systemic toxicity. Nanocarriers have thus been employed to get around the issues with traditional anti-cancer drug delivery methods. Invasomes are lipid-based nanovesicles having small amounts of terpenes and ethanol or a mixture of terpenes and penetrate the skin more effectively. Compared to other lipid nanocarriers, invasomes penetrate the skin at a substantially faster rate. Invasomes possess a number of advantages, including improved drug effectiveness, higher compliance, patient convenience, advanced design, multifunctionality, enhanced targeting capabilities, non-invasive delivery methods, potential for combination therapies, and ability to overcome biological barriers,. These attributes position invasomes as a promising and innovative platform for the future of cancer treatment. The current review provides insights into invasomes, with a fresh organizational scheme and incorporates the most recent cancer research, including their composition, historical development and methods of preparation, the penetration mechanism involving effect of various formulation variables and analysis of anticancer mechanism and the application of invasomes.

Phospholipid Free Nano-Vesicles of Brinzolamide Biopolymer Ocular Insert; Design, In vitro and In vivo Evaluation.

The aim of this work to study the feasibility of using phospholipid free vesicles with positive charge inducer in a slowly dissolving polymer ocular insert to successfully control intraocular pressure (IOP) for an extended period. Brinzolamide (BRNZ) was chosen as a model drug and a full factorial design was assembled to investigate the drug loading effect, ratio of cholesterol to fatty moiety and the type of the fatty moiety used on the vesicle size and entrapment efficiency. Linear regression models were constructed, and optimization of the formulation compositions yielded two formulae with palmitic acid as a negatively charged vesicles and cetrimide positively charged vesicles. Both formulae were studied in term of permeation efficiency through bovine corneal membranes. Positively charged vesicles although it didn't achieve the highest flux and cumulative amount permeated per unit surface area in the experiment time course, it achieved the highest retention of drug inside the corneal tissue, so it was chosen to be incorporated in a slowly dissolving polymer ocular insert. The insert was evaluated in term content, physical evaluation, and release properties. In vivo evaluation of the casted ocular inserts was conducted in male albino rabbits against market eye drop product and IOP readings were collected for 48 hours. The positively charged sterosomes containing BRNZ and formulated in polymer ocular inserts achieved extended control of IOP of the test animals compared to the market product.

Tumor Cell-Derived Exosomal miR-191-5p Activates M2-Subtype Macrophages Through SOCS3 to Facilitate Breast Cancer.

Differential activation of macrophages is associated with poor progression of breast cancer (BC). Many reports have elucidated the important involvement of exosomes produced by cancer cells in remodeling the macrophage activation phenotype to promote tumor expansion and invasion. However, the underlying mechanisms by which exosomes secreted by BC cells facilitate macrophage M2 polarization remain enigmatic and worth exploring. In this study, quantitative real-time PCR (RT-qPCR) was used to investigate miR-191-5p expression in BC tumor tissues and cells. Cell counting kit 8 (CCK-8), transwell, and flow cytometry were applied to assess the functional role of miR-191-5p in BC. Isolated nano-vesicles were identified using transmission electron microscopy and western blotting. We also observed that miR-191-5p was significantly elevated in BC clinical samples and that inhibition of miR-191-5p hindered the growth and metastasis of BC cells. Importantly, BC cells successfully accelerated macrophage M2-like polarization by directly transferring exosomes to macrophages, resulting in increased miR-191-5p levels in macrophages. Mechanistically, exosomal miR-191-5p directly inhibited the suppressors of cytokine signaling 3 (SOCS3) expression in macrophages and aggravated macrophage M2 polarization. Similarly, si-SOCS3 transfected macrophages boosted BC cell migration and invasion in a positive feedback manner. Overall, our results manifested a pro-growth and pro-metastatic role between the two cells by elucidating the crucial role of exosomal miR-191-5p in stimulating M2 macrophage polarization and mediating communication between BC cells and macrophages. These findings opened up new horizons for the development of BC therapeutic strategies.

Advancements in Vaccine Adjuvants: The Journey from Alum to Nano Formulations.

Vaccination is a groundbreaking approach in preventing and controlling infectious diseases. However, the effectiveness of vaccines can be greatly enhanced by the inclusion of adjuvants, which are substances that potentiate and modulate the immune response. This review is based on extensive searches in reputable databases such as Web of Science, PubMed, EMBASE, Scopus, and Google Scholar. The goal of this review is to provide a thorough analysis of the advances in the field of adjuvant research, to trace the evolution, and to understand the effects of the various adjuvants. Historically, alum was the pioneer in the field of adjuvants because it was the first to be approved for use in humans. It served as the foundation for subsequent research and innovation in the field. As science progressed, research shifted to identifying and exploiting the potential of newer adjuvants. One important area of interest is nano formulations. These advanced adjuvants have special properties that can be tailored to enhance the immune response to vaccines. The transition from traditional alum-based adjuvants to nano formulations is indicative of the dynamism and potential of vaccine research. Innovations in adjuvant research, particularly the development of nano formulations, are a promising step toward improving vaccine efficacy and safety. These advances have the potential to redefine the boundaries of vaccination and potentially expand the range of diseases that can be addressed with this approach. There is an optimistic view of the future in which improved vaccine formulations will contribute significantly to improving global health outcomes.

Chlorambucil-Loaded Graphene-Oxide-Based Nano-Vesicles for Cancer Therapy.

In this study, the authors have designed biocompatible nano-vesicles using graphene oxide (GO) for the release of chlorambucil (CHL) drugs targeting cancerous cells. The GO sheets were first sulfonated and conjugated with folic acid (FA) molecules for controlled release and high loading efficiency of CHL. The chlorambucil (CHL) drug loading onto the functionalized GO surface was performed through π-π stacking and hydrophobic interactions with the aromatic planes of GO. The drug loading and "in vitro" release from the nano-vesicles at different pH were studied. The average particle size, absorption, and loading efficiency (%) of FA-conjugated GO sheets (CHL-GO) were observed to be 300 nm, 58%, and 77%, respectively. The drug release study at different pH (i.e., 7.4 and 5.5) showed a slight deceleration at pH 7.4 over pH 5.5. The amount of drug released was very small at pH 7.4 in the first hour which progressively increased to 24% after 8 h. The rate of drug release was faster at pH 5.5; initially, 16% to 27% in the first 3 h, and finally it reached 73% after 9 h. These observations indicate that the drug is released more rapidly at acidic pH with a larger amount of drug-loading ability. The rate of drug release from the CHL-loaded GO was 25% and 75% after 24 h. The biotoxicity study in terms of % cell viability of CHL-free and CHL-loaded GO against human cervical adenocarcinoma cell line was found to have lower cytotoxicity of CHL-loaded nano-vesicles (IC50 = 18 µM) as compared to CHL-free (IC50 = 8 µM). It is concluded that a high drug-loading efficiency and controlled release with excellent biotoxicity of CHL-GO offers an excellent application in the biomedical field.

Formulation and characterization of lamotrigine nasal insert targeted brain for enhanced epilepsy treatment.

Lamotrigine. (LMT) is a triazine drug has an antiepileptic effect but with low water solubility, dissolution rate and thus therapeutic effect. Spanlastics are nano-vesicular carriers' act as site-specific drug delivery system. Intranasal route could direct the drug from nose to brain and provide a faster and more specific therapeutic effect. Therefore, this study aimed to upload lamotrigine onto nano-vesicles using spanlastic nasal insert delivery for effective epilepsy treatment via overcoming lamotrigine's low solubility and improving its bioavailability. Lamtrigine-loaded nano-spanlastic vesicles were prepared by ethanol injection method. To study different formulation factor's effect on formulations characters; particle size (PS), Zeta potential (ZP), polydispersity index (PDI), entrapment efficiency percentage (EE%) and LMT released amount after 6 h (Q6h); 2^1 and 3^1 full factorial designs were employed. Optimized formula was loaded in lyophilized nasal inserts formulation which were characterized for LMT release and mucoadhesion. Pharmacokinetics studies in plasma and brain were performed on rats to investigate drug targeting efficiency. The optimal nano-spanlastic formulation (F4; containing equal Span 60 amount (100 mg) and edge activator; Tween 80) exhibited nano PS (174.2 nm), high EE% (92.75%), and Q6h > 80%. The prepared nasal inserts (S4) containing 100 mg HPMC has a higher mucoadhesive force (9319.5 dyne/cm2) and dissolution rate (> 80% within 10 min) for rapid in vivo bio-distribution. In vivo studies showed considerable improvement brain and plasma's rate and extent absorption after intranasal administration indicating a high brain targeting efficiency. The results achieved indicate that nano-spanlastic nasal-inserts offer a promising LMT brain targeting in order to maximize its antiepileptic effect.

Bolstering the secretion and bioactivities of umbilical cord MSC-derived extracellular vesicles with 3D culture and priming in chemically defined media.

Human mesenchymal stem cells (hMSCs)-derived extracellular vesicles (EVs) have been known to possess the features of the origin cell with nano size and have shown therapeutic potentials for regenerative medicine in recent studies as alternatives for cell-based therapies. However, extremely low production yield, unknown effects derived from serum impurities, and relatively low bioactivities on doses must be overcome for translational applications. As several reports have demonstrated the tunability of secretion and bioactivities of EVs, herein, we introduced three-dimensional (3D) culture and cell priming approaches for MSCs in serum-free chemically defined media to exclude side effects from serum-derived impurities. Aggregates (spheroids) with 3D culture dramatically enhanced secretion of EVs about 6.7 times more than cells with two-dimensional (2D) culture, and altered surface compositions. Further modulation with cell priming with the combination of TNF-α and IFN-γ (TI) facilitated the production of EVs about 1.4 times more than cells without priming (9.4 times more than cells with 2D culture without priming), and bioactivities of EVs related to tissue regenerations. Interestingly, unlike changing 2D to 3D culture, TI priming altered internal cytokines of MSC-derived EVs. Through simulating characteristics of EVs with bioinformatics analysis, the regeneration-relative properties such as angiogenesis, wound healing, anti-inflammation, anti-apoptosis, and anti-fibrosis, for three different types of EVs were comparatively analyzed using cell-based assays. The present study demonstrated that a combinatory strategy, 3D cultures and priming MSCs in chemically defined media, provided the optimum environments to maximize secretion and regeneration-related bioactivities of MSC-derived EVs without impurities for future translational applications.

Review on Nanomaterials and Nano-Scaled Systems for Topical and Systemic Delivery of Antifungal Drugs.

Fungal infections are human infections that topically affect the skin, mucous membranes, or more serious, invasive, and systemic diseases of the internal organs. The design and advancement of the formulation and approach of administration for therapeutic agents depend on many variables. The correlation between the formulations, mode of administration, pharmacokinetics, toxicity and clinical indication must be thoroughly studied for the successful evolution of suitable drug delivery systems. There are several NP formulations that serve as good delivery approaches for antifungal drugs. This paper covers various groups of nanoparticles utilized in antifungal drug delivery, such as phospholipid-based vesicles (nanovesicles), non-phospholipid vesicles, polymeric nanoparticles, inorganic nanoparticles and dendrimers, whereby their advantages and drawbacks are emphasized. Many in vitro or cell culture studies with NP formulations achieve an adequate high drug-loading capacity; they do not reach the clinically significant concentrations anticipated for in vivo studies. Because of this, the transfer of these nano-formulations from the laboratory to the clinic could be aided by focusing studies on overcoming problems related to nanoparticle stability, drug loading, and high production and standardization costs.

Encapsulation of Anabolic Peptide in Lipid Nano Vesicles for Osteoporosis.

BACKGROUND: Screening of critical variables, including formulation and process variables, in the development of various dosage forms facilitates the identification of the most influencing parameters, which modulate the responses, thereby helping in building the strong quality target product profile. OBJECTIVE: The objective of the present work was to screen out the most influential and critical variables for the development of an anabolic peptide encapsulated lipid nanovesicles (PTH-LNVs). METHODS: PTH-LNVs were prepared by the ethanol injection method. Taguchi standard orthogonal array L8 design was employed to assess the effect of formulation and processing variables on different response variables. Independent variables considered were drug concentration, lipid concentration, cholesterol concentration, stirring rate, and rate of injection, whereas dependent variables studied were particle size, PDI, zeta potential, % entrapment efficiency, and % drug loading. Particle size, PDI, and zeta potential were evaluated by a zeta sizer. Drug loading efficiency and % entrapment efficiency were determined by HPLC analysis. RESULTS: The ethanol injection method was employed to formulate PTH-LNVs using Taguchi standard orthogonal array L8 design. From the half-normal plot and Pareto ranking analysis, it was found that drug, lipid, and cholesterol concentration have a significant effect on responses of formulation and are hence considered critical variables during the formulation development. CONCLUSION: The presented work demonstrates the feasibility of Taguchi orthogonal array design in the screening of potential independent factors in the development of peptide encapsulated nanoformulations.

Lipid nano-vesicles for thyroid hormone encapsulation: A comparison between different fabrication technologies, drug loading, and an in vitro delivery to human tendon stem/progenitor cells in 2D and 3D culture.

Phosphatidylcholine (PC) vesicles loaded with Triiodothyronine (T3) were fabricated using different manufacturing methods: thin layer hydration plus sonication (TF-UF), supercritical liposome formation (SC), and microfluidic technology (MF). Vesicles obtained by MF had the lowest mean diameter (88.61 ± 44.48 nm) with a Zeta Potential of -20.1 ± 5.90 mV and loading of 10 mg/g (encapsulation efficiency: 57%). In contrast, SC vesicles showed extremely low encapsulation efficiency (<10%) probably due to T3 solubility in ethanol/carbon dioxide mixture; despite TF-UF vesicles exhibiting good size (167.7 ± 90 nm; Zp -8.50 ± 0.60 mV) and loading (10 mg/g), poor mass recovery was obtained (50% loss). MF vesicles had low cytotoxicity, and they were well enough internalized by both HeLa and human tendon stem/progenitor cells (hTSPCs). Their biological activity was also monitored in both 2D and 3D cultures of hTSPCs supplemented with therapeutical concentrations of PC/T3 nano-liposomes. 2D culture showed almost similar constitutive gene expression compared to control culture supplemented with free-T3. On the contrary, when hTPSCs 3D culture was assembled, it showed a more evident homogeneous distribution of FITC labeled vesicles within the high-density structure and a significant upregulation of cell constitutive genes, such as type I Collagen (4.8-fold; p < 0.0001) at day 7, compared to the control, suggesting that T3/PC formulation has increased T3 cytosolic concentration, thus improving cells metabolic activity. The study supported MF technology for nano-carriers fabrication and opens perspectives on the activity of PC/T3 nano-vesicles as innovative formulations for TPSCs stimulation in ECM secretion.

Spanlastics nanovesicular ocular insert as a novel ocular delivery of travoprost: optimization using Box-Behnken design and in vivo evaluation.

Currently, travoprost is a synthetic prostaglandin F2α analogue used in the treatment of glaucoma, it is delivered by eye drop solution. Due to its very low bioavailability and patient non-compliance, the objective of the current study was to enhance its bioavailability, and prolong its release Spanlastic nano-vesicles gels were designed and optimized using Box-Behnken design. The optimized spanlastic nano-vesicles gel exhibited the lowest particle size (PS), polydispersity index (PDI) and the highest zeta potential (ZP), encapsulation efficiency (EE) and mucoadhesive strength was fabricated into spanlastic nano-vesicles ocular insert by solvent casting. In vivo studies showed enhanced bioavailability of travoprost spanlastic nano-vesicles gel and ocular insert compared to the marketed eye drops (travoswix®), as proven by their higher Cmax and AUC0-∞, in addition to being nonirritant to ocular surfaces. However, spanlastic nano-vesicles ocular insert showed more prolonged effect than spanlastic nano-vesicles gel. According to our study, it can be suggested that travoprost spanlastic nano-vesicles ocular insert is a novel ocular delivery system for glaucoma treatment.

Surfactant free synthesis of cationic nano-vesicles: A safe triple drug loaded vehicle for the topical treatment of cutaneous leishmaniasis.

The basic aim of the study was to develop and evaluate the triple drug loaded cationic nano-vesicles (cNVs), where miltefosine was used as a replacement of surfactant (apart from its anti-leishmanial role), in addition to meglumine antimoniate (MAM) and imiquimod (Imq), as a combination therapy for the topical treatment of cutaneous leishmaniasis (CL). The optimized formulation was nano-sized (86.2 ±â€¯2.7 nm) with high entrapment efficiency (63.8 ±â€¯2.1% (MAM) and 81.4 ±â€¯2.3% (Imq)). In-vivo skin irritation assay showed reduced irritation potential and a decrease in the cytotoxicity of cNVs as compared to conventional NVs (having sodium deoxycholate as a surfactant). A synergistic interaction between drugs was observed against intracellular amastigotes, whereas the in-vivo antileishmanial study presented a significant reduction in the parasitic burden. The results suggested the potential of surfactant free, triple drug loaded cNVs as an efficient vehicle for the safe topical treatment of CL.

The efficacy of Origanum majorana nanocubosomal systems in ameliorating submandibular salivary gland alterations in streptozotocin-induced diabetic rats.

Diabetes mellitus is a challenging health problem. Salivary gland dysfunction is one of its complications. Current treatments possess numerous adverse effects. Therefore, herbal extracts have emerged as a promising approach for safe and effective treatment. However, they are required in large doses to achieve the desired effect. Accordingly, Origanum majorana extract (OE) was incorporated into nano-sized systems to enhance its biological effects at lower dosages. OE was standardized against rosmarinic acid (RA) and then loaded into nano-cubosomal (NC) systems via a 23 full-factorial design. Two optimum nano-systems at different drug loads (2.08 or 1.04 mg-RA/mL) were selected and assessed in vivo to compare their effects in streptozotocin-induced diabetic rats against conventional OE (2.08 mg-RA/mL). Blood glucose was evaluated weekly. Submandibular salivary glands were processed for histopathological examination and nuclear factor-erythroid 2-related factor 2 (Nrf2), Kelch-like ECH-associated protein 1 (Keap1), and p38-MAPK gene expression analysis. NC systems were successfully prepared and optimized where the optimum systems showed nano-sized vesicles (210.4-368.3 nm) and high zeta potential values. In vivo results showed a significant lower blood glucose in all treated groups, with an exceptional reduction with NC formulations. Marked histopathological improvement was observed in all OE-treated groups, with OE-NC4 (2.08 mg-RA/mL) demonstrating the best features. This was supported by RT-PCR; where the OE-NC4 group recorded the highest mean value of Nrf2 and the least mean values of Keap1 and p38-MAPK, followed by OE-NC3 and OE groups. In conclusion, OE-loaded NC enhanced the anti-hyperglycemic effect of OE and ameliorated diabetic gland alterations compared to conventional OE. Thus, cubosomal nano-systems could be anticipated as potential carriers for the best outcome with OE.

Artificial intelligence and guidance of medicine in the bubble.

Microbubbles are nanosized gas-filled bubbles. They are used in clinical diagnostics, in medical imaging, as contrast agents in ultrasound imaging, and as transporters for targeted drug delivery. They can also be used to treat thrombosis, neoplastic diseases, open arteries and vascular plaques and for localized transport of chemotherapies in cancer patients. Microbubbles can be filled with any type of therapeutics, cure agents, growth factors, extracellular vesicles, exosomes, miRNAs, and drugs. Microbubbles protect their cargo from immune attack because of their specialized encapsulated shell composed of lipid and protein. Filled with curative medicine, they could effectively circulate through the whole body safely and efficiently to reach the target area. The advanced bubble-based drug-delivery system, integrated with artificial intelligence for guidance, holds great promise for the targeted delivery of drugs and medicines.

Topical Nano-Vesicular Spanlastics of Celecoxib: Enhanced Anti-Inflammatory Effect and Down-Regulation of TNF-α, NF-кB and COX-2 in Complete Freund's Adjuvant-Induced Arthritis Model in Rats.

BACKGROUND: Rheumatoid arthritis (RA) is an autoimmune disease that underlies chronic inflammation of the synovial membrane. Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used to treat RA. However, a long list of adverse events associated with long-term treatment regimens with NSAIDs negatively influences patient compliance and therapeutic outcomes. AIM: The aim of this work was to achieve site-specific delivery of celecoxib-loaded spanlastic nano-vesicle-based delivery system to the inflamed joints, avoiding systemic administration of large doses. METHODOLOGY: To develop spanlastic nanovesicles for transdermal delivery of celecoxib, modified injection method was adopted using Tween 80 or Brij as edge activators. Entrapment efficiency, vesicle size, ex vivo permeation, and morphology of the prepared nano-vesicles were characterized. Carbopol-based gels containing the selected formulations were prepared, and their clarity, pH, rheological performance, and ex vivo permeation were characterized. Celecoxib-loaded niosomes and noisome-containing gels were developed for comparison. The in vivo efficacy of the selected formulations was evaluated in a rat model of Freund's complete adjuvant-induced arthritis. Different inflammatory markers including TNF-α, NF-кB and COX-2 were assessed in paw tissue before and after treatment. RESULTS: The size and entrapment efficiency of the selected spanlastic nano-vesicle formulation were 112.5 ± 3.6 nm, and 83.6 ± 2.3%, respectively. This formulation has shown the highest transdermal flux and permeability coefficient compared to the other investigated formulations. The spanlastics-containing gel of celecoxib has shown transdermal flux of 6.9 ± 0.25 µg/cm2/hr while the celecoxib niosomes-containing gel and unprocessed celecoxib-loaded gel have shown 5.2 ± 0.12 µg/cm2/hr and 0.64 ± 0.09 µg/cm2/hr, respectively. In the animal model of RA, the celecoxib-loaded spanlastics-containing gel significantly reduced edema circumference and significantly suppressed TNF-α, NF-кB and COX-2 levels compared to the niosomes-containing gel, the marketed diclofenac sodium gel, and unprocessed celecoxib-loaded gel. CONCLUSION: The spanlastic nano-vesicle-containing gel represents a more efficient site-specific treatment for topical treatment of chronic inflammation like RA, compared to commercial and other conventional alternatives.

Synthesis of lactobionic acid based bola-amphiphiles and its application as nano-carrier for curcumin delivery to cancer cell cultures in-vitro.

Curcumin is highly effective against various types of cancers; however, its low aqueous solubility, high metabolism and non-specificity hinder its efficacy. This study reports the synthesis of three lactobionic acid containing bola-amphiphiles and their investigation for curcumin nano-vesicular delivery into cancer cells. Synthesized bola-amphiphiles were capable of forming nano-vesicles and curcumin loading in a lipophilicity dependent manner. Bola-amphiphile with higher lipophilicity (C12) caused 89.55 ± 5.52% drug encapsulation in its spherical shape nano-vesicles (195.90 ± 0.83 nm). Bola-amphiphile resulting increased curcumin encapsulation with minimum vesicles size was further investigated for cellular uptake and in-vitro anticancer activity. Anticancer activity of curcumin significantly increased against the tested cancer cells upon loading in bola-amphiphile nano-vesicles. Furthermore, nano-vesicular drug delivery of curcumin enhanced its cellular uptake even at the lowest concentration of 1.25 µg/mL.It is concluded that the synthesized bola-amphiphile based nano-vesicles can efficiently deliver curcumin to the tested cancer cells and needs to be tested for established anticancer drugs against different cancer cell lines for effective treatment of cancer.

Detection of Disease-Specific Parent Cells Via Distinct Population of Nano-Vesicles by Machine Learning.

BACKGROUND: The diagnosis and prognosis of pathological conditions, such as age-related macular degeneration (AMD) and cancer still need improvement. AMD is primarily caused due to the dysfunction of retinal pigment epithelium (RPE), whereas endothelial cells (ECs) play one of the major roles in angiogenesis; an important process which occurs in malignant progression of cancer. Several reports suggested the augmented release of nano-vesicles under pathological conditions, including from RPE as well as cancer-associated ECs, which take part in various biological processes, including intercellular communication in disease progression. Importantly, these nano-vesicles are around 30-1000 nm and carry the fingerprint of their initiating parent cells (IPCs). Therefore, these nano-vesicles could be utilized as the diagnostic tool for AMD and cancer, respectively. However, the analysis of nano-vesicles for biomarker study is confounded by their extensive heterogeneous nature. METHODS: To confront this challenge, we utilized artificial intelligence (AI) based machine learning (ML) algorithms such as support vector machine (SVM) and decision tree model on the dataset of nano-vesicles from RPE and ECs cell lines with low dimensionality. RESULTS: Overall, Gaussian SVM demonstrated the highest prediction accuracy of the IPCs of nano-vesicles, among all the chosen SVM classifiers. Additionally, the bagged tree showed the highest prediction among the chosen decision tree-based classifiers. CONCLUSION: Therefore, the overall bagged tree showed the best performance for the prediction of IPCs of nanovesicles, suggesting the applicability of AI-based prediction approach in diagnosis and prognosis of pathological conditions, including non-invasive liquid biopsy via various biofluids-derived nano-vesicles.

Novel Enhanced Therapeutic Efficacy of Dapoxetine HCl by Nano-Vesicle Transdermal Gel for Treatment of Carrageenan-Induced Rat Paw Edema.

The aim of this was to develop a well-balanced, replaceable, and patient non-infringing innovative transdermal drug delivery system "nano-vesicle transdermal gel" (NVTG) approaches for inhibiting inflammation. To consummate this objective, we developed a skin permeation nanogel system containing surface active agent along with ethanol. Carbopol 971p, hydroxypropyl methyl cellulose (HPMC K15M), and chitosan were used to fabricate the nanogels. The nanogel system was evaluated for pH, content uniformity, spreadability, rheological studies, in vitro skin permeation, and drug release. Carbapol 971p with the desired in vitro skin permeation was utilized to investigate skin irritation test and effects on inflammation using acute inflammatory paw edema models. Moreover, in vivo pharmacokinetic study was assessed. pH of this nanogels was found within the range of 6.1-7.2, whereas the viscosity was found 310.13 to 6361 cps. The ex vivo skin permeation gels showed permeation flux range, 5.9 ± 0.80 to 17.92 ± 1.13 µg/cm2 h. The highest permeation flux (17.92 ± 1.13 µg/cm2 h) was observed, which was 3.14-folds higher than that of the plain DH gel (10.72 ± 0.84 µg/cm2 h. Additionally, from toxicological study, no obvious signs of toxicity such as skin irritation (of laboratory rats) were identified. The in vivo anti-inflammatory behavior in carrageenan-induced rats showed comparatively higher inhibition of rat paw edema swelling by the prepared nanogel compared to that of the plain DH gel and marketed ibuprofen over 6 h. The amount of drug accumulated in the skin after topical application was much higher than oral application. In conclusion, developed NVTG formulation loaded with dapoxetine HCl (DH) offers new opportunities for creating novel therapeutic modality for inflammation patients with fewer adverse effects.

Tailoring novel soft nano-vesicles 'Flexosomes' for enhanced transdermal drug delivery: Optimization, characterization and comprehensive ex vivo - in vivo evaluation.

The transdermal route is a convenient non-invasive way for drug delivery, however, the hydrophobic compact nature of stratum corneum (SC) forms an obstacle hindering the diffusion of drugs particularly hydrophilic ones. Hence, the purpose of this study was to develop novel soft nano-vesicles, entitled Flexosomes, amalgamating two penetration enhancers, ethanol and one edge activator (EA) from various types and different hydrophilic-lipophilic balances. The tailored vesicles were loaded with tropisetron hydrochloride (TRO), a potent highly-soluble anti-emetic, and compared with ethosomes. Aiming to preclude the formation of rigid non-deformable mixed micelles, all critical parameters; EA type, phosphatidylcholine-to-EA molar ratio, and cholesterol concentration, were optimized proving their influences on vesicle-to-micelle transitions. The prepared formulations were characterized in terms of visual inspection, particle size, polydispersity, zeta potential, turbidity measurements, entrapment efficiency, and vesicle morphology. The permeation mechanisms were assessed by differential scanning calorimetry on isolated SC. The modified vesicles, based on ethanol and either vitamin E or PEGylated castor oil derivatives exhibited the highest transdermal fluxes confirmed by a deeply tracking to dermis using confocal laser microscopy. Both vesicles demonstrated higher bioavailability relative to ethosomes, topical and oral aqueous solutions. The findings endorsed the effectiveness of tailored nano-vesicles in boosting TRO skin transport suggesting their applicability with various drug entities for enhanced transdermal delivery.