Search Results (35)

Background/Objectives: Proteolysis-targeting chimeras (PROTACs) have shown significant potential in the treatment of intractable diseases. However, their clinical applications are limited by poor water solubility and permeability. In this study, the cyclodextrin inclusion method was employed for the first time to prepare the PROTAC-CD complex with the aim of improving the dissolution of a PROTAC drug (LC001). Methods: Initially, sulfobutyl ether-β-cyclodextrin (SBE-β-CD) was selected to improve the solubility of LC001. The polymer TPGS was screened based on the phase solubility method to enhance the efficiency of complexation and solubilization capacity, and its ratio with SBE-β-CD was optimized. The ternary complex was prepared by lyophilization with an SBE-β-CD/TPGS molar ratio of 1:0.03. Differential scanning calorimetry, powder X-ray diffraction, and scanning electron microscopy results confirmed the formation of an amorphous complex. Fourier-transform infrared and molecular docking simulations indicated the formation of hydrogen bond interactions between components. Results: The results showed that the ternary complexes significantly improved the dissolution rate and release amount of LC001 in PBS (pH 6.8) and were unaffected by changes in gastric pH compared to the binary complexes and physical mixtures. The lack of crystal structure in the lyophilized particles and the formation of nano aggregates in solution may be the reasons for the improved dissolution of the ternary complex. Conclusions: In conclusion, the addition of TPGS to the LC001-SBE-β-CD binary system has a synergistic effect on improving the solubility and dissolution of LC001. This ternary complex is a promising formulation for enhancing the dissolution of LC001. Full article

Background: D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), an amphiphilic derivative of natural vitamin E, functions as both a drug efflux inhibitor and a protector against enzymatic degradation and has been widely incorporated into nano-formulations for drug design and delivery. Objective: This systematic review evaluates TPGS-based organic nanocarriers, emphasizing their potential to enhance bioavailability of active compounds which include drugs and phytochemicals, improve pharmacokinetic profiles, and optimize therapeutic outcomes, eventually overcoming the limitations of conventional oral active compounds delivery. Search strategy: Data collection was carried out by entering key terms (TPGS) AND (Micelle OR Liposome OR Nanoparticle OR Nanotube OR Dendrimer OR Niosome OR Nanosuspension OR Nanomicelle OR Nanocrystal OR Nanosphere OR Nanocapsule) AND (Oral Bioavailability) into the Scopus database. Inclusion criteria: Full-text articles published in English and relevant to TPGS, which featured organic materials, utilized an oral administration route, and included pharmacokinetic study, were included to the final review. Data extraction and analysis: Data selection was conducted by two review authors and subsequently approved by all other authors through a consensus process. The outcomes of the included studies were reviewed and categorized based on the types of nanocarriers. Results: An initial search of the database yielded 173 records. After screening by title and abstract, 52 full-text articles were analyzed. A total of 21 papers were excluded while 31 papers were used in this review. Conclusions: This review concludes that TPGS-based organic nanocarriers are able to enhance the bioavailability of various active compounds, including several phytochemicals, leveraging TPGS’s amphiphilic nature, inhibition of efflux transporters, protection against degradation, and stabilization properties. Despite using the same excipient, variability in particle size, zeta potential, and encapsulation efficiency among nanocarriers indicates the need for tailored formulations. A comprehensive approach involving the development and standardized comparison of diverse TPGS-incorporated active compound formulations is essential to identify the optimal TPGS-based nanocarrier for improving a particular active compound’s bioavailability. Full article

Background/Objectives: Melanoma is a pathology that affects a large part of the population, and the currently available therapies have many limitations, including the selective targeting of the site of action. This study explores the development of curcumin (CUR)-loaded nanostructured delivery systems for topical melanoma treatment, addressing CUR’s limitations in bioavailability, solubility, and stability. Methods: Binary surfactant mixtures of Vitamin E-TPGS (TPGS) and Kolliphor ELP (ELP) were selected to form stable micelles for curcumin encapsulation. A Design of Experiments (DoE) approach was applied to optimize the surfactant ratios for enhanced drug solubilization and improved cytotoxic effects on melanoma cells. The final formulation was characterized using Fourier Transform Infrared Spectroscopy (FTIR), Differential Scanning Calorimetry (DSC), and Nuclear Magnetic Resonance (NMR) spectroscopy to confirm its properties. Results: The final formulation, TPGS30ELP15, contained 30 mM TPGS and 15 mM ELP and led to formation of nanostructures of the expected size (hydrodinamic diameter, Dh: 13.11 ± 0.01 nm; polydispersivity index, PDI = 0.371 ± 0.05), able to solubilize 5.51 ± 1.09 mM CUR. The formulation was stable for a 120-day period stored at 4 °C and room temperature in the dark. Cytotoxicity testing in A375 melanoma cells demonstrated that curcumin-loaded micelles significantly reduced cell viability compared to free curcumin. Long-term exposure (24 h) revealed that free curcumin caused an 85% reduction in cell viability, while TPGS30ELP15 resulted in a 70% reduction. Additionally, free curcumin induced a 30% increase in cytoplasmic area, indicating necrosis, whereas TPGS30ELP15 decreased the cytoplasmic area by 20%, suggesting apoptosis. Conclusions: This study demonstrates that TPGS30ELP15 nanomicelles enhance curcumin’s anticancer effects while promoting apoptosis and minimizing necrosis, which is associated with lower inflammation and tissue damage. These findings suggest that TPGS30ELP15 offers a more favorable therapeutic profile for melanoma treatment, paving the way for safer and more effective topical therapies. Full article

This study aimed to investigate the potential of polycaprolactone–vitamin E TPGS (PCL-TPGS) micelles as a delivery system for oral administration of paclitaxel (PTX). The PCL-TPGS copolymer was synthesized using ring opening polymerization, and PTX-loaded PCL-TPGS micelles (PTX micelles) were prepared via a co-solvent evaporation method. Characterization of these micelles included measurements of size, polydispersity, and encapsulation efficiency. The cellular uptake of PTX micelles was evaluated in Caco-2 cells using rhodamine 123 (Rh123) as a fluorescent probe. Moreover, an everted rat sac study was conducted to evaluate the ex vivo permeability of PTX micelles. Additionally, a comparative pharmacokinetic study of PTX micelles versus the marketed formulation, Ebetaxel^® (a Taxol generic), was performed after a single oral administration to rats. The results demonstrated that the micellar formulation significantly improved PTX solubility (nearly 1 mg/mL). The in vitro stability and release of PTX micelles in simulated gastric fluid (SGF) and simulated intestinal fluid (SIF) demonstrated that PTX micelles remained stable for up to 24 h and significantly slowed the release of PTX in both media compared to Ebetaxel^®. The in vitro cellular uptake, ex vivo intestinal permeability, and in vivo pharmacokinetic profile demonstrated that PTX micelles enhanced the permeability and facilitated a rapid absorption of the drug. Conclusively, the PCL₇₀₀₀-TPGS₃₅₀₀ micelles exhibit potential as an effective oral delivery system for PTX. Full article

NDH-4338 is a highly lipophilic prodrug comprising indomethacin and an acetylcholinesterase inhibitor. A design of experiments approach was used to synthesize, characterize, and evaluate the wound healing efficacy of optimized NDH-4338 nanosuspensions against nitrogen mustard-induced skin injury. Nanosuspensions were prepared by sonoprecipitation in the presence of a Vitamin E TPGS aqueous stabilizer solution. Critical processing parameters and material attributes were optimized to reduce particle size and determine the effect on dissolution rate and burn healing efficacy. The antisolvent/solvent ratio (A/S), dose concentration (DC), and drug/stabilizer ratio (D/S) were the critical sonoprecipitation factors that control particle size. These factors were subjected to a Box–Behnken design and response surface analysis, and model quality was assessed. Maximize desirability and simulation experiment optimization approaches were used to determine nanosuspension parameters with the smallest size and the lowest defect rate within the 10–50 nm specification limits. Optimized and unoptimized nanosuspensions were prepared and characterized. An established depilatory double-disc mouse model was used to evaluate the healing of nitrogen mustard-induced dermal injuries. Optimized nanosuspensions (A/S = 6.2, DC = 2% w/v, D/S = 2.8) achieved a particle size of 31.46 nm with a narrow size range (PDI = 0.110) and a reduced defect rate (42.2 to 6.1%). The optimized nanosuspensions were stable and re-dispersible, and they showed a ~45% increase in cumulative drug release and significant edema reduction in mice. Optimized NDH-4338 nanosuspensions were smaller with more uniform sizes that led to improved physical stability, faster dissolution, and enhanced burn healing efficacy compared to unoptimized nanosuspensions. Full article

Anthracycline antibiotics, namely, doxorubicin (DOX) and daunorubicin, are among the most widely used anticancer therapies, yet are notoriously associated with severe myocardial damage due to oxidative stress and mitochondrial damage. Studies have indicated the strong pharmacological properties of Berberine (Brb) alkaloid, predominantly mediated via mitochondrial functions and nuclear networks. Despite the recent emphasis on Brb in clinical cardioprotective studies, pharmaceutical limitations hamper its clinical use. A nanoformulation for Brb was developed (mMic), incorporating a cationic lipid, oleylamine (OA), into the TPGS-mixed corona of PEGylated-phosphatidylethanolamine (PEG-PE) micelles. Cationic TPGS/PEG-PE mMic with superior Brb loading and stability markedly enhanced both intracellular and mitochondria-tropic Brb activities in cardiovascular muscle cells. Sub-lethal doses of Brb via cationic OA/TPGS mMic, as a DOX co-treatment, resulted in significant mitochondrial apoptosis suppression. In combination with an intense DOX challenge (up to ~50 µM), mitochondria-protective Brb-OA/TPGS mMic showed a significant 24 h recovery of cell viability (p ≤ 0.05–0.01). Mechanistically, the significant relative reduction in apoptotic caspase-9 and elevation of antiapoptotic Bcl-2 seem to mediate the cardioprotective role of Brb-OA/TPGS mMic against DOX. Our report aims to demonstrate the great potential of cationic OA/TPGS-mMic to selectively enhance the protective mitohormetic effect of Brb to mitigate DOX cardiotoxicity. Full article

Background: Luteolin is a flavonoid compound that has been widely studied for its various anti-cancer properties and sensitization to multidrug-resistant cells. However, the limited solubility and bioavailability of Lut hindered its potential clinical use. Theoretically, the combination of this compound with vitamin E TPGS and poloxamer 407 can produce a synergistic effect to enhance tumor apoptosis and P-glycoprotein inhibition. This study aimed to develop and optimize vitamin E TPGS/Poloxamer 407 micelles loaded with luteolin through investigating certain factors that can affect the encapsulation efficiency and particle size of the micelle. Methods: A micelle was prepared using the film hydration method, and the micellar solution was lyophilized. The cake formed was analyzed. The factors investigated include the concentrations of the surfactants, ratio of vitamin E TPGS/Poloxamer 407, temperature of the hydrating solution, duration of hydration, and freezing temperature before lyophilization. The effects of these factors on the encapsulation efficiency and particle size of the micelle were also studied. The encapsulation efficiency was measured using a UV-Vis spectrophotometer, while particle size was measured using dynamic light scattering. Results: The optimized micelle was found to have 90% encapsulation efficiency with a particle size of less than 40 nm, which was achieved using a 10% concentration of surfactants at a vitamin E TPGS/Poloxamer 407 ratio of 3:1. The optimized temperature for hydrating the micellar film was 40 °C, the optimized mixing time was 1 h, and the optimized freezing temperature was −80 °C. The solubility of the luteolin-loaded micelles increased 459-fold compared to pure Lut in water. The critical micelle concentration of the vitamin E TPGS/Poloxamer 407 micelle was 0.001 mg/mL, and the release study showed that luteolin-loaded micelles exhibited sustained release behavior. The release of luteolin from a micelle was found to be higher in pH 6.8 compared to pH 7.4, which signified that luteolin could be accumulated more in a tumor microenvironment compared to blood. Conclusion: This study demonstrated that several factors need to be considered when developing such nanoparticles in order to obtain a well-optimized micelle. Full article

It has been seventy years since a water-soluble version of vitamin E called tocophersolan (also known as TPGS) was produced; it was approved by USFDA in 1998 as an inactive ingredient. Drug formulation developers were initially intrigued by its surfactant qualities, and gradually it made its way into the toolkit of pharmaceutical drug delivery. Since then, four drugs with TPGS in their formulation have been approved for sale in the United States and Europe including ibuprofen, tipranavir, amprenavir, and tocophersolan. Improvement and implementation of novel diagnostic and therapeutic techniques for disease are goals of nanomedicine and the succeeding field of nanotheranostics. Specifically, imaging and treating tumors with nanohybrid theranostics shows promising potential. Docetaxel, paclitaxel, and doxorubicin are examples of poorly bioavailable therapeutic agents; hence, much effort is applied for developing TPGS-based nanomedicine, nanotheranostics, and targeted drug delivery systems to increase circulation time and promote the reticular endothelial escape of these drug delivery systems. TPGS has been used in a number of ways for improving drug solubility, bioavailability improvement, and prevention of drug efflux from the targeted cells, which makes it an excellent candidate for therapeutic delivery. Through the downregulation of P-gp expression and modulation of efflux pump activity, TPGS can also mitigate multidrug resistance (MDR). Novel materials such as TPGS-based copolymers are being studied for their potential use in various diseases. In recent clinical trials, TPGS has been utilized in a huge number of Phase I, II, and III studies. Additionally, numerous TPGS-based nanomedicine and nanotheranostic applications are reported in the literature which are in their preclinical stage. However, various randomized or human clinical trials have been underway for TPGS-based drug delivery systems for multiple diseases such as pneumonia, malaria, ocular disease, keratoconus, etc. In this review, we have emphasized in detail the review of the nanotheranostics and targeted drug delivery approaches premised on TPGS. In addition, we have covered various therapeutic systems involving TPGS and its analogs with special references to its patent and clinical trials. Full article

The application of many currently evaluated macromolecular contrast agents for magnetic resonance imaging (MRI) has been limited because of their bio-incompatibility and toxicity. The aim of this study is to synthesize and characterize a new micelle-based TPGS gadolinium chelate as a biocompatible MRI contrast agent for prolonged blood circulation time and good tumor imaging contrast. The TPGS-gadolinium conjugate was prepared through the conjugation between TPGS-SA and bifunctional L-NETA-Gd chelate. The conjugate was characterized with regard to molecular weight, critical micellar concentration and particle sizes, cellular uptake, and in vitro cell MRI. Distributions of the MRI contrast agent in various organs were determined via intravenous injection of the agent into mice bearing xenograft tumors. The successfully prepared TPGS-L-NETA-Gd micelle exhibited improved cellular uptake in HepG2 cells and xenografts and high in vivo safety. Distributions of TPGS-L-NETA-Gd in mice showed enhanced cellular uptake up to 2 h after the contrast agent injection. Its in vitro and in vivo properties make it a favorable macromolecular MRI contrast agent for future in vivo imaging. Full article

Several therapeutically active molecules are poorly water-soluble, thereby creating a challenge for pharmaceutical scientists to develop an active solution for their oral drug delivery. This study aimed to investigate the potential for novel polymer-surfactant-based formulations (designated A and B) to improve the solubility and permeability of curcumin. A solubility study and characterization studies (FTIR, DSC and XRD) were conducted for the various formulations. The cytotoxicity of formulations and commercial comparators was tested via MTT and LDH assays, and their permeability by in vitro drug transport and cellular drug uptake was established using the Caco-2 cell model. The apparent permeability coefficients (Papp) are considered a good indicator of drug permeation. However, it can be argued that the magnitude of Papp, when used to reflect the permeability of the cells to the drug, can be influenced by the initial drug concentration (C₀) in the donor chamber. Therefore, Papp (suspension) and Papp (solution) were calculated based on the different values of C₀. It was clear that Papp (solution) can more accurately reflect drug permeation than Papp (suspension). Formulation A, containing Soluplus^® and vitamin E TPGs, significantly increased the permeation and cellular uptake of curcumin compared to other samples, which is believed to be related to the increased aqueous solubility of the drug in this formulation. Full article

Doxorubicin (DOX) is an antineoplastic agent clinically employed for treating breast cancer patients. Despite its effectiveness, its inherent adverse toxic side effects often limit its clinical application. To overcome these drawbacks, lipid–polymer hybrid nanoparticles (LPNP) arise as promising nanoplatforms that combine the advantages of both liposomes and polymeric nanoparticles into a single delivery system. Alpha-tocopherol succinate (TS) is a derivative of vitamin E that shows potent anticancer mechanisms, and it is an interesting approach as adjuvant. In this study, we designed a pH-sensitive PLGA-polymer-core/TPGS-lipid-shell hybrid nanoparticle, loaded with DOX and TS (LPNP_TS-DOX). Nanoparticles were physicochemically and morphologically characterized. Cytotoxicity studies, migration assay, and cellular uptake were performed in 4T1, MCF-7, and MDA-MB-231 cell lines. Antitumor activity in vivo was evaluated in 4T1 breast tumor-bearing mice. In vitro studies showed a significant reduction in cell viability, cell migration, and an increase in cellular uptake for the 4T1 cell line compared to free DOX. In vivo antitumor activity showed that LPNP-TS-DOX was more effective in controlling tumor growth than other treatments. The high cellular internalization and the pH-triggered payload release of DOX lead to the increased accumulation of the drugs in the tumor area, along with the synergic combination with TS, culminating in greater antitumor efficacy. These data support LPNP-TS-DOX as a promising drug delivery system for breast cancer treatment. Full article

N-(2-fluorphenyl)-6-chloro-4-hydroxy-2-quinolone-3-carboxamide (R19) is a newly synthesized phosphatidylinositol 3-kinase alpha (PI3Kα) inhibitor with promising activity against cancer cells. The purpose of this study was to develop a polymeric nanoparticle (NP) formulation for R19 to address its poor aqueous solubility and to facilitate its future administration in preclinical and clinical settings. NPs were prepared by nanoprecipitation using two polymers: D-α-tocopheryl polyethylene glycol 1000 succinate (vitamin E TPGS) and the poloxamer Pluronic P123 in different ratios. Physicochemical characterization of the NPs revealed them to be around 100 nm in size with high monodispersity, a spherical morphology, and an almost neutral surface charge. The NPs achieved ~60% drug loading efficiency and sustained release of R19 for up to 96 h, with excellent colloidal stability in serum-containing cell culture media. NPs containing TPGS enhanced R19’s potency against MCF-7 and MDA-MB-231 breast cancer cells in vitro, with half-maximal inhibitory concentrations (IC₅₀) ranging between 1.8 and 4.3 µM compared to free R19, which had an IC₅₀ of 14.7–17.0 µM. The NPs also demonstrated low cytotoxicity against human dermal fibroblasts and more significant induction of apoptosis compared to the free drug, which was correlated with their cellular uptake efficiency. Our findings present a biocompatible NP formulation for the delivery of a cancer-targeted PI3Kα inhibitor, R19, which can further enhance its potency for the treatment of breast cancer and potentially other cancer types. Full article

Background: Colorectal cancer is one of the most challenging cancers to treat. Exploring novel therapeutic strategies is necessary to overcome drug resistance and improve patient outcomes. Quercetin (QR) is a polyphenolic lipophilic compound that was chosen due to its colorectal anticancer activity. Nanoparticles could improve cancer therapy via tumor targeting by utilizing D-tocopheryl polyethylene glycol succinate (vitamin-E TPGS) as a surfactant in a nanoemulsion preparation, which is considered an efficient drug delivery system for enhancing lipophilic antineoplastic agents. Thus, this study aims to develop and optimize QR-loaded nanoemulsions (NE) using TPGS as a surfactant to enhance the QR antitumor activity. Method: The NE was prepared using a self-assembly technique using the chosen oils according to QR maximum solubility and TPGS as a surfactant. The prepared QR-NE was evaluated according to its particle morphology and pH. QR entrapment efficiency and QR in vitro drug release rate were determined from the selected QR-NE then we measured the QR-NE stability. The anticancer activity of the best-selected formula was studied on HT-29 and HCT-116 cell lines. Results: Oleic acid was chosen to prepare QR-NE as it has the best QR solubility. The prepared NE, which had particles size < 200 nm, maximum entrapment efficiency > 80%, and pH 3.688 + 0.102 was selected as the optimal formula. It was a physically stable formula. The prepared QR-NE enhanced the QR release rate (84.52 ± 0.71%) compared to the free drug. QR-NPs significantly improved the cellular killing efficiency in HCT-116 and HT-29 colon cancer cell lines (lower IC50, two folds more than free drug). Conclusion: The prepared QR-NE could be a promising stable formula for improving QR release rate and anticancer activity. Full article

Quercetin (Qu) is a natural flavonoid present in many commonly consumed food items and is also identified as a potential anticancer agent. The present study evaluates the Qu-loaded polymeric mixed micelles (Qu-PMMs) against C6 and U87MG glioma cell lines. The Box–Behnken Design (BBD) was employed to study the influence of independent variables such as Soluplus, Vitamin-E polyethyleneglycol-1000 succinate (E-TPGS), and poloxamer 407 concentrations on dependent variables including particle size (PS), polydispersity index (PDI), and percentage entrapment efficiency (%EE) of the prepared Qu-PMMs. The Qu-PMMs were further characterized by Fourier Transform Infrared Spectroscopy (FTIR), X-ray Diffraction (XRD), Scanning Electron Microscope (SEM), and were assessed for in vitro drug release, effect on cell viability, migration, cellular uptake, and apoptosis assays. The PS, PDI, and % EE of the optimized PMMs were 107.16 ± 1.06 nm, 0.236 ± 0.053, and 77.46 ± 1.94%, respectively. The FTIR and XRD revealed that the Qu was completely entrapped inside the PMMs. The SEM analysis confirmed the spherical shape of micelles. The in vitro cell viability study showed that the Qu-PMMs had 1.7 times higher cytotoxicity against C6 and U87MG cells than Qu pure drug (Qu-PD). Furthermore, Qu-PMMs demonstrated superior cellular uptake, inhibited migration, and induced apoptosis when tested against C6 and U87MG cells than pure Qu. Thus, the polymeric mixed micelle (PMMs) enhanced the therapeutic effect of Qu and can be considered an effective therapeutic strategy to treat Glioma. Full article

The extensive use of ophthalmic antibiotics is contributing to the appearance of resistant bacterial strains, which require prolonged and massive treatments with consequent detrimental outcomes and adverse effects. In addition to these issues, antibiotics are not effective against parasites and viruses. In this context, antiseptics could be valuable alternatives. They have nonselective mechanisms of action preventing bacterial resistance and a broad spectrum of action and are also effective against parasites and viruses. Here, we compare the in vitro antibacterial, antiameobic, and antiviral activities of six ophthalmic formulations containing antiseptics such as povidone-iodine, chlorhexidine, and thymol against Gram-positive and Gram-negative bacteria, the amoeba Acanthamoeba castellanii, and two respiratory viruses, HAdV-2 and HCoV-OC43. The results suggest that, among all the tested formulations, Dropsept, consisting of Vitamin E TPGS-based (tocopheryl polyethylene glycol succinate) in combination with the antiseptic chlorhexidine, is the one with the highest range of activities, as it works efficiently against bacteria, amoeba, and viruses. On the other hand, the solution containing PVA (polyvinyl alcohol) and thymol showed a promising inhibitory effect on Pseudomonas aeruginosa, which causes severe keratitis. Given its high efficiency, Dropsept might represent a valuable alternative to the widely used antibiotics for the treatment of ocular infections. In addition to this commercial eye drop solution, thymol-based solutions might be enrolled for their natural antimicrobial and antiamoebic effect. Full article