Predicting Tumor Dynamics Post-Staged GKRS: Machine Learning Models in Brain Metastases Prognosis.

This study assesses the predictive performance of six machine learning models and a 1D Convolutional Neural Network (CNN) in forecasting tumor dynamics within three months following Gamma Knife radiosurgery (GKRS) in 77 brain metastasis (BM) patients. The analysis meticulously evaluates each model before and after hyperparameter tuning, utilizing accuracy, AUC, and other metrics derived from confusion matrices. The CNN model showcased notable performance with an accuracy of 98% and an AUC of 0.97, effectively complementing the broader model analysis. Initial findings highlighted that XGBoost significantly outperformed other models with an accuracy of 0.95 and an AUC of 0.95 before tuning. Post-tuning, the Support Vector Machine (SVM) demonstrated the most substantial improvement, achieving an accuracy of 0.98 and an AUC of 0.98. Conversely, XGBoost showed a decline in performance after tuning, indicating potential overfitting. The study also explores feature importance across models, noting that features like "control at one year", "age of the patient", and "beam-on time for volume V1 treated" were consistently influential across various models, albeit their impacts were interpreted differently depending on the model's underlying mechanics. This comprehensive evaluation not only underscores the importance of model selection and hyperparameter tuning but also highlights the practical implications in medical diagnostic scenarios, where the accuracy of positive predictions can be crucial. Our research explores the effects of staged Gamma Knife radiosurgery (GKRS) on larger tumors, revealing no significant outcome differences across protocols. It uniquely considers the impact of beam-on time and fraction intervals on treatment efficacy. However, the investigation is limited by a small patient cohort and data from a single institution, suggesting the need for future multicenter research.

Albumin-Based Hydrogel Films Covalently Cross-Linked with Oxidized Gellan with Encapsulated Curcumin for Biomedical Applications.

Bovine serum albumin (BSA) hydrogels are non-immunogenic, low-cost, biocompatible, and biodegradable. In order to avoid toxic cross-linking agents, gellan was oxidized with NaIO4 to obtain new functional groups like dialdehydes for protein-based hydrogel cross-linking. The formed dialdehyde groups were highlighted with FT-IR and NMR spectroscopy. This paper aims to investigate hydrogel films for biomedical applications obtained by cross-linking BSA with oxidized gellan (OxG) containing immobilized ß-cyclodextrin-curcumin inclusion complex (ß-CD-Curc) The ß-CD-Curc improved the bioavailability and solubility of Curc and was prepared at a molar ratio of 2:1. The film's structure and morphology were evaluated using FT-IR spectroscopy and SEM. The swelling degree (Q%) values of hydrogel films depend on hydrophilicity and pH, with higher values at pH = 7.4. Additionally, the conversion index of -NH2 groups into Schiff bases increases with an increase in OxG amount. The polymeric matrix provides protection for Curc, is non-cytotoxic, and enhances antioxidant activity. At pH = 5.5, the skin permeability and release efficiency of encapsulated curcumin were higher than at pH = 7.4 because of the interaction of free aldehyde and carboxylic groups from hydrogels with amine groups from proteins present in the skin membrane, resulting in a better film adhesion and more efficient curcumin release.

A Holographic-Type Model in the Description of Polymer-Drug Delivery Processes.

A unitary model of drug release dynamics is proposed, assuming that the polymer-drug system can be assimilated into a multifractal mathematical object. Then, we made a description of drug release dynamics that implies, via Scale Relativity Theory, the functionality of continuous and undifferentiable curves (fractal or multifractal curves), possibly leading to holographic-like behaviors. At such a conjuncture, the Schrödinger and Madelung multifractal scenarios become compatible: in the Schrödinger multifractal scenario, various modes of drug release can be "mimicked" (via period doubling, damped oscillations, modulated and "chaotic" regimes), while the Madelung multifractal scenario involves multifractal diffusion laws (Fickian and non-Fickian diffusions). In conclusion, we propose a unitary model for describing release dynamics in polymer-drug systems. In the model proposed, the polymer-drug dynamics can be described by employing the Scale Relativity Theory in the monofractal case or also in the multifractal one.

Theoretical-Experimental Approach of Chitosan/Quaternized Chitosan Nanofibers' Behavior in Wound Exudate Media.

This study aimed to investigate the behavior of chitosan/quaternized chitosan fibers in media mimicking wound exudates to understand their capacities as wound dressing. Fiber analysis of the fibers using dynamic vapor sorption proved their ability to adsorb moisture up to 60% and then to desorb it as a function of humidity, indicating their outstanding breathability. Dissolution analyses showed that quaternized chitosan leached from the fibers in water and PBS, whereas only small portions of chitosan were solubilized in water. In media containing lysozyme, the fibers degraded with a rate determined by their composition and pH, reaching a mass loss of up to 47% in media of physiologic pH. Notably, in media mimicking the wound exudate during healing, they adsorbed moisture even when their mass loss due to biodegradation was high, whereas they were completely degraded in the media of normal tissues, indicating bioabsorbable dressing capacities. A mathematical model was constructed, which characterized the degradation rate and morphology changes of chitosan/quaternized chitosan fibers through analyses of dynamics in scale space, using the Theory of Scale Relativity. The model was validated using experimental data, making it possible to generalize it to the degradation of other biopolymeric systems that address wound healing.

Recent Advancements and Strategies for Overcoming the Blood-Brain Barrier Using Albumin-Based Drug Delivery Systems to Treat Brain Cancer, with a Focus on Glioblastoma.

Glioblastoma multiforme (GBM) is a highly aggressive malignant tumor, and the most prevalent primary malignant tumor affecting the brain and central nervous system. Recent research indicates that the genetic profile of GBM makes it resistant to drugs and radiation. However, the main obstacle in treating GBM is transporting drugs through the blood-brain barrier (BBB). Albumin is a versatile biomaterial for the synthesis of nanoparticles. The efficiency of albumin-based delivery systems is determined by their ability to improve tumor targeting and accumulation. In this review, we will discuss the prevalence of human glioblastoma and the currently adopted treatment, as well as the structure and some essential functions of the BBB, to transport drugs through this barrier. We will also mention some aspects related to the blood-tumor brain barrier (BTBB) that lead to poor treatment efficacy. The properties and structure of serum albumin were highlighted, such as its role in targeting brain tumors, as well as the progress made until now regarding the techniques for obtaining albumin nanoparticles and their functionalization, in order to overcome the BBB and treat cancer, especially human glioblastoma. The albumin drug delivery nanosystems mentioned in this paper have improved properties and can overcome the BBB to target brain tumors.

An Accessible Method to Improve the Stability and Reusability of Porcine Pancreatic α-Amylase via Immobilization in Gellan-Based Hydrogel Particles Obtained by Ionic Cross-Linking with Mg2+ Ions.

Amylase is an enzyme used to hydrolyze starch in order to obtain different products that are mainly used in the food industry. The results reported in this article refer to the immobilization of α-amylase in gellan hydrogel particles ionically cross-linked with Mg2+ ions. The obtained hydrogel particles were characterized physicochemically and morphologically. Their enzymatic activity was tested using starch as a substrate in several hydrolytic cycles. The results showed that the properties of the particles are influenced by the degree of cross-linking and the amount of immobilized α-amylase enzyme. The temperature and pH at which the immobilized enzyme activity is maximum were T = 60 °C and pH = 5.6. The enzymatic activity and affinity of the enzyme to the substrate depend on the particle type, and this decreases for particles with a higher cross-linking degree owing to the slow diffusion of the enzyme molecules inside the polymer's network. By immobilization, α-amylase is protected from environmental factors, and the obtained particles can be quickly recovered from the hydrolysis medium, thus being able to be reused in repeated hydrolytic cycles (at least 11 cycles) without a substantial decrease in enzymatic activity. Moreover, α-amylase immobilized in gellan particles can be reactivated via treatment with a more acidic medium.

Theoretical and Experimental Aspects of Sodium Diclofenac Salt Release from Chitosan-Based Hydrogels and Possible Applications.

Two formulations based on diclofenac sodium salt encapsulated into a chitosan hydrogel were designed and prepared, and their drug release was investigated by combining in vitro results with mathematical modeling. To understand how the pattern of drug encapsulation impacted its release, the formulations were supramolecularly and morphologically characterized by scanning electron microscopy and polarized light microscopy, respectively. The mechanism of diclofenac release was assessed by using a mathematical model based on the multifractal theory of motion. Various drug-delivery mechanisms, such as Fickian- and non-Fickian-type diffusion, were shown to be fundamental mechanisms. More precisely, in a case of multifractal one-dimensional drug diffusion in a controlled-release polymer-drug system (i.e., in the form of a plane with a certain thickness), a solution that allowed the model's validation through the obtained experimental data was established. The present research reveals possible new perspectives, for example in the prevention of intrauterine adhesions occurring through endometrial inflammation and other pathologies with an inflammatory mechanism background, such as periodontal diseases, and also therapeutic potential beyond the anti-inflammatory action of diclofenac as an anticancer agent, with a role in cell cycle regulation and apoptosis, using this type of drug-delivery system.

Biomaterials Based on Chitosan and Polyvinyl Alcohol as a Drug Delivery System with Wound-Healing Effects.

The excellent biological properties of chitosan (CS) together with the increased oxygen permeability of polyvinyl alcohol (PVA) were the prerequisites for the creation of a wound healing dressing that would also function as a system for L-arginine (L-arg) and caffeine (Caff) delivery. Using the freezing/thawing method, 12 hydrogels were obtained in PVA:CS polymer ratios of 90:10, 75:25, and 60:40, and all were loaded with L-arg, Caff, and the mixture of L-arg and Caff, respectively. Afterwards, an inorganic material (zeolite-Z) was added to the best polymeric ratio (75:25) and loaded with active substances. The interactions between the constituents of the hydrogels were analyzed by FTIR spectroscopy, the uniformity of the network was highlighted by the SEM technique, and the dynamic water vapor sorption capacity was evaluated. In the presence of the inorganic material, the release profile of the active substances is delayed, and in vitro permeation kinetics proves that the equilibrium state is not reached even after four hours. The synergy of the constituents in the polymer network recommends that they be used in medical applications, such as wound healing dressings.

Multi-fractal modeling of curcumin release mechanism from polymeric nanomicelles.

The physicochemical properties of "smart" or stimuli-sensitive amphiphilic copolymers can be modeled as a function of their environment. In special, pH-sensitive copolymers have practical applications in the biomedical field as drug delivery systems. Interactions between the structural units of any polymer-drug system imply mutual constraints at various scale resolutions and the nonlinearity is accepted as one of the most fundamental properties. The release kinetics, as a function of pH, of a model active principle, i.e., Curcumin, from nanomicelles obtained from amphiphilic pH-sensitive poly(2-vinylpyridine)-b-poly(ethylene oxide) (P2VP-b-PEO) tailor-made diblock copolymers was firstly studied by using the Rietger-Peppas equation. The value of the exponential coefficient, n, is around 0.5, generally suggesting a diffusion process, slightly disturbed in some cases. Moreover, the evaluation of the polymer-drug system's nonstationary dynamics was caried out through harmonic mapping from the usual space to the hyperbolic one. The kinetic model we developed, based on fractal theory, fits very well with the experimental data obtained for the release of Curcumin from the amphiphilic copolymer micelles in which it was encapsulated. This model is a variant of the classical kinetic models based on the formal kinetics of the process.

Drug-Loaded Polymeric Particulated Systems for Ophthalmic Drugs Release.

Drug delivery to the anterior or posterior segments of the eye is a major challenge due to the protection barriers and removal mechanisms associated with the unique anatomical and physiological nature of the ocular system. The paper presents the preparation and characterization of drug-loaded polymeric particulated systems based on pre-emulsion coated with biodegradable polymers. Low molecular weight biopolymers (chitosan, sodium hyaluronate and heparin sodium) were selected due to their ability to attach polymer chains to the surface of the growing system. The particulated systems with dimensions of 190-270 nm and a zeta potential varying from -37 mV to +24 mV depending on the biopolymer charges have been obtained. Current studies show that particles release drugs (dexamethasone/pilocarpine/bevacizumab) in a safe and effective manner, maintaining therapeutic concentration for a longer period of time. An extensive modeling study was performed in order to evaluate the drug release profile from the prepared systems. In a multifractal paradigm of motion, nonlinear behaviors of a drug delivery system are analyzed in the fractal theory of motion, in order to correlate the drug structure with polymer. Then, the functionality of a SL(2R) type "hidden symmetry" implies, through a Riccati type gauge, different "synchronization modes" (period doubling, damped oscillations, quasi-periodicity and intermittency) during the drug release process. Among these, a special mode of Kink type, better reflects the empirical data. The fractal study indicated more complex interactions between the angiogenesis inhibitor Bevacizumab and polymeric structure.

Implementation of QbD Approach to the Analytical Method Development and Validation for the Estimation of Metformin Hydrochloride in Tablet Dosage Forms by HPLC.

The current studies entail quality by design (QbD)-enabled development of a simple, rapid, precise, accurate, and cost-effective high-performance liquid chromatographic method for estimation of metformin hydrochloride (M-HCl). Design of experiments (DoE) was applied for multivariate optimization of the experimental conditions of the HPLC method. Risk assessment was performed to identify the critical method parameters (CMPs) using Ishikawa diagram. The factor screening studies were performed using a two-factor three-levels design. Two independent factors, buffer pH and mobile phase composition, were used to design mathematical models. Central composite design (CCD) was used to study the response surface methodology and to study in depth the effects of these independent factors, thus evaluating the critical analytical attributes (CAAs), namely, retention time, peak area, and symmetry factor as the parameters of method robustness. Desirability function was used to simultaneously optimize the CAAs. The optimized and predicted data from contour diagram consisted of 0.02 M acetate buffer pH = 3/methanol in a ratio of 70/30 (v/v) as the mobile phase with a flow rate 1 mL/min. The separation was made on a Thermoscientific ODS HypersylTM chromatographic column (250 × 4.6 mm, 5 µm) with oven temperature 35 °C and UV detection at 235 nm. The optimized assay conditions were validated according to ICH guidelines. Hence, the results clearly showed that QbD approach could be successfully applied to optimize HPLC method for estimation of M-HCl. The method was applied both for the evaluation of M-HCl content in tablets, and for in vitro dissolution studies of M-HCl from conventional and prolonged-release tablets.

Update on the Use of Nanocarriers and Drug Delivery Systems and Future Directions in Cervical Cancer.

Cervical cancer represents a major health problem among females due to its increased mortality rate. The conventional therapies are very aggressive and unsatisfactory when it comes to survival rate, especially in terminal stages, which requires the development of new treatment alternatives. With the use of nanotechnology, various chemotherapeutic drugs can be transported via nanocarriers directly to cervical cancerous cells, thus skipping the hepatic first-pass effect and decreasing the rate of chemotherapy side effects. This review comprises various drug delivery systems that were applied in cervical cancer, such as lipid-based nanocarriers, polymeric and dendrimeric nanoparticles, carbon-based nanoparticles, metallic nanoparticles, inorganic nanoparticles, micellar nanocarriers, and protein and polysaccharide nanoparticles. Nanoparticles have a great therapeutic potential by increasing the pharmacological activity, drug solubility, and bioavailability. Through their mechanisms, they highly increase the toxicity in the targeted cervical tumor cells or tissues by linking to specific ligands. In addition, a nondifferentiable model is proposed through holographic implementation in the dynamics of drug delivery dynamics. As any hologram functions as a deep learning process, the artificial intelligence can be proposed as a new analyzing method in cervical cancer.

Infectious Inflammatory Processes and the Role of Bioactive Agent Released from Imino-Chitosan Derivatives Experimental and Theoretical Aspects.

The paper focuses on the development of a multifractal theoretical model for explaining drug release dynamics (drug release laws and drug release mechanisms of cellular and channel-type) through scale transitions in scale space correlated with experimental data. The mathematical model has been developed for a hydrogel system prepared from chitosan and an antimicrobial aldehyde via covalent imine bonds. The reversible nature of the imine linkage points for a progressive release of the antimicrobial aldehyde is controlled by the reaction equilibrium shifting to the reagents, which in turn is triggered by aldehyde consumption in the inhibition of the microbial growth. The development of the mathematical model considers the release dynamic of the aldehyde in the scale space. Because the release behavior is dictated by the intrinsic properties of the polymer-drug complex system, they were explained in scale space, showing that various drug release dynamics laws can be associated with scale transitions. Moreover, the functionality of a Schrödinger-type differential equation in the same scale space reveals drug release mechanisms of channels and cellular types. These mechanisms are conditioned by the intensity of the polymer-drug interactions. It was demonstrated that the proposed mathematical model confirmed a prolonged release of the aldehyde, respecting the trend established by in vitro release experiments. At the same time, the properties of the hydrogel recommend its application in patients with intrauterine adhesions (IUAs) complicated by chronic endometritis as an alternative to the traditional antibiotics or antifungals.

Impact of the Liquid Crystal Order of Poly(azomethine-sulfone)s on the Semiconducting Properties.

Organic semiconductors are an attractive class of materials with large application in various fields, from optoelectronics to biomedicine. Usually, organic semiconductors have low electrical conductivity, and different routes towards improving said conductivity are being investigated. One such method is to increase their ordering degree, which not only improves electrical conduction but promotes cell growth, adhesion, and proliferation at the polymer-tissue interface. The current paper proposes a mathematical model for understanding the influence of the ordering state on the electrical properties of the organic semiconductors. To this end, a series of aromatic poly(azomethine)s were prepared as thin films in both amorphous and ordered states, and their supramolecular and electrical properties were analyzed by polarized light microscopy and surface type cells, respectively. Furthermore, the film surface characteristics were investigated by atomic force microscopy. It was established that the manufacture of thin films from mesophase state induced an electrical conductivity improvement of one order of magnitude. A mathematical model was developed in the framework of a multifractal theory of motion in its Schrodinger representation. The model used the order degree of the thin films as a fractality measure of the physical system's representation in the multifractal space. It proposed two types of conductivity, which manifest at different ranges of fractalization degrees. The mathematical predictions were found to be in line with the empirical data.

Prospects and Challenges of the Drug Delivery Systems in Endometriosis Pain Management: Experimental and Theoretical Aspects.

Endometriosis is considered a serious public health issue because of the large number of females affected by this illness. Chronic pain management in patients with endometriosis demands new strategies to increase the life quality of these patients. The development of drug delivery systems represents a new approach in pain treatment among endometriosis patients. Diclofenac sodium, one of the most utilized nonsteroidal anti-inflammatory drugs (NSAID), has its own limitations when being used in formulas such as oral, parental, or local applications. In this paper, a series of four drug release formulations based on chitosan, 2-hydroxy-5-nitrobenzaldehyde, and diclofenac sodium salt were prepared in view of the investigation of the drug release ability. The formulations were analyzed from a morphological and supramolecular point of view by scanning electron microscopy and polarized light microscopy. The in vitro drug release ability was investigated by mimicking a physiologic environment. A mathematical model, using the fractal paradigm of motion, is utilized to explain the behaviors of the drug delivery system presented in this paper. These results suggest a great potential of the proposed drug delivery system, based on chitosan and 2-hydroxy-5-nitrobenzaldehyde to improve the diclofenac sodium salt bioavailability, and it may represent a future treatment formula for endometriosis pain.

Polysaccharides-Based Complex Particles' Protective Role on the Stability and Bioactivity of Immobilized Curcumin.

The curcumin degradation represents a significant limitation for its applications. The stability of free curcumin (FC) and immobilized curcumin in complex particles (ComPs) based on different polysaccharides was studied under the action of several factors. Ultraviolet-visible (UV-VIS) and Fourier-transform infrared (FTIR) spectroscopy proved the FC photodegradation and its role as a metal chelator: 82% of FC and between 26% and 39.79% of curcumin within the ComPs degraded after exposure for 28 days to natural light. The degradation half-life (t1/2) decreases for FC when the pH increases, from 6.8 h at pH = 3 to 2.1 h at pH = 9. For curcumin extracted from ComPs, t1/2 was constant (between 10 and 13 h) and depended on the sample's composition. The total phenol (TPC) and total flavonoids (TFC) content values increased by 16% and 13%, respectively, for FC exposed to ultraviolet light at λ = 365 nm (UVA), whereas no significant change was observed for immobilized curcumin. Antioxidant activity expressed by IC50 (µmoles/mL) for FC exposed to UVA decreased by 29%, but curcumin within ComPs was not affected by the UVA. The bovine serum albumin (BSA) adsorption efficiency on the ComPs surface depends on the pH value and the cross-linking degree. ComPs have a protective role for the immobilized curcumin.

Study on Acute Toxicity of Amiodarone New Complexes With Cyclodextrin.

Amiodarone low solubility and high permeability is the limiting step for its bioavailability, therefore new formulations are needed to improve the solubility of amiodarone either to increase its oral bioavailability or to reduce its toxic effects. Complexation of amiodarone with cyclodextrin results in improved dissolution rate, solubility, and allows for a more controlled drug release. We characterized the acute toxicity of a new amiodarone 2-hydroxypropyl-ß-cyclodextrin complex (AMD/HP-ß-CD) as powdered form and as a matrix based on Kollidon® and chitosan, administered intraperitoneally in laboratory animals. There were developed two formulations of matrix: one containing only pure AMD as a control sample (Fc) and one containing the inclusion complex with the optimal solubility (F). AMD was equitoxic with HP-ß-CD after intraperitoneal administration (289.4 mg/kg for AMD and 298.3 mg/kg for AMD/HP-ß-CD), with corresponding histopathological changes. The matrix based formulations presented higher LD50 values for acute toxicity, of 347.5 mg/kg for Fc and 455.6 mg/kg for F10, conducting to the idea of a safer administration because KOL and CHT matrix modified the solubility and controlled the AMD release. The LD50 is 1.5 higher for AMD/HP-ß-CD included in a KOL and CHT based matrix compared to the pure AMD, administered intraperitoneally.

Magnolol and Honokiol: Two Natural Compounds with Similar Chemical Structure but Different Physicochemical and Stability Properties.

Magnolia spp. extracts are known for their use in traditional Korean, Chinese, and Japanese medicine in the treatment of gastrointestinal disorders, anxiety, and allergies. Among their main components with pharmacological activity, the most relevant are magnolol and honokiol, which also show antitumoral activity. The objectives of this work were to study some physicochemical properties of both substances and their stability under different conditions of temperature, pH, and oxidation. Additionally, liposomes of honokiol (the least stable compound) were formulated and characterized. Both compounds showed pH-dependent solubility, with different solubility-pH profiles. Magnolol showed a lower solubility than honokiol at acidic pH values, but a higher solubility at alkaline pH values. The partition coefficients were similar and relatively high for both compounds (log Po/w ≈ 4.5), indicating their lipophilic nature. Honokiol was less stable than magnolol, mainly at neutral and basic pH values. To improve the poor stability of honokiol, it was suitably loaded in liposomes. The obtained liposomes were small in size (175 nm), homogeneous (polydispersity index = 0.17), highly negatively charged (-11 mV), and able to incorporate high amounts of honokiol (entrapment efficiency = 93.4%). The encapsulation of honokiol in liposomes increased its stability only at alkaline pH values.

Topical formulations containing aptamer-functionalized nanocapsules loaded with 5-fluorouracil - An innovative concept for the skin cancer therapy.

New topical gel formulations based on sodium alginate and hyaluronic acid containing AS1411 aptamer-functionalized polymeric nanocapsules loaded with an antitumoral drug (5-Fluorouracil) were designed as an innovative approach for the skin cancer treatment. Several important analyses were used to characterize these obtained topical gel formulations, namely: rheological tests, permeation assays across Strat-M® artificial membrane, ex-vivo permeation assays across chicken skin membrane, haemolysis tests, skin irritation tests, in vitro cytotoxicity assay on human basal carcinoma cells and in vivo tests. Rheological tests revealed that apparent viscosity decreases with the increase of the shear rate, for analyzed samples, which demonstrates a shear thinning behavior. Low levels of hemolysis values which ranged between 0.03 and 0.55% suggested that the tested formulations did not induce red blood cell lysis.. The gel formulations containing nanocapsules loaded with 5-FU proved to be non-irritant. Furthermore, by study the ex-vivo diffusion properties across the chicken skin membrane, it was proved that nanoencapsulation enhance the permeability properties of 5-FU. In vitro cytotoxicity assay on TE 354.T (ATCC® CRL-7762™) human basal carcinoma cell line showed that the obtained formulations loaded with 5-Fluorouracil manifest an important cytotoxic effect. Finally, the presence of Langerhans CD68 cells-positive in the epidermis and epithelial sheath of dermal hair follicles suggests a specific activation, migration and retrieval of nanoparticles by these cells. Following the results obtained in this study we can appreciate that the obtained topical gel formulations have a favourable biosafety and good antitumor effects which makes them attractive for skin cancer treatment.

Drug Delivery System Based on pH-Sensitive Biocompatible Poly(2-vinyl pyridine)-b-poly(ethylene oxide) Nanomicelles Loaded with Curcumin and 5-Fluorouracil.

Smart polymeric micelles (PMs) are of practical interest as nanocarriers for the encapsulation and controlled release of hydrophobic drugs. Two hydrophobic drugs, naturally-based curcumin (Cur) and synthetic 5-fluorouracil (5-FU), were loaded into the PMs formed by a well-defined pH-sensitive poly(2-vinyl pyridine)-b-poly(ethylene oxide) (P2VP90-b-PEO398) block copolymer. The influence of the drug loading on the micellar sizes was investigated by dynamic light scattering (DLS) and it appears that the size of the PMs increases from around 60 to 100 nm when Cur is loaded. On the contrary, the loading of the 5-FU has a smaller effect on the micellar sizes. This difference can be attributed to higher molar mass of Cur with respect to 5-FU but also to higher loading efficiency of Cur, 6.4%, compared to that of 5-FU, 5.8%. In vitro drug release was studied at pH 2, 6.8, and 7.4, and it was observed that the pH controls the release of both drugs. At pH 2, where the P2VP sequences from the "frozen-in" micellar core are protonated, the drug release efficiencies exceed 90%. Moreover, it was demonstrated, by in vitro assays, that these PMs are hemocompatible and biocompatible. Furthermore, the PMs protect the Cur against the photo-degradation, whereas the non-ionic PEO corona limits the adsorption of bovine serum albumin (BSA) protein on the surface. This study demonstrates that these pH-sensitive PMs are suitable for practical utilization as human-safe and smart, injectable drug delivery systems.