Mixed Polymeric Micelles Research Articles

Ciprofloxacin-Loaded Mixed Polymeric Micelles as Antibiofilm Agents.

In this work, mixed polymeric micelles (MPMs) based on a cationic poly(2-(dimethylamino)ethyl methacrylate)-b-poly(ε-caprolactone)-b-poly(2-(dimethylamino)ethyl methacrylate) (PDMAEMA29-b-PCL70-b-PDMAEMA29) and a non-ionic poly(ethylene oxide)-b-poly(propylene oxide)-b-poly(ethylene oxide) (PEO99-b-PPO67-b-PEO99) triblock copolymers, blended at different molar ratios, were developed. The key physicochemical parameters of MPMs, including size, size distribution, and critical micellar concentration (CMC), were evaluated. The resulting MPMs are nanoscopic with a hydrodynamic diameter of around 35 nm, and the ζ-potential and CMC values strongly depend on the MPM's composition. Ciprofloxacin (CF) was solubilized by the micelles via hydrophobic interaction with the micellar core and electrostatic interaction between the polycationic blocks, and the drug localized it, to some extent, in the micellar corona. The effect of a polymer-to-drug mass ratio on the drug-loading content (DLC) and encapsulation efficiency (EE) of MPMs was assessed. MPMs prepared at a polymer-to-drug mass ratio of 10:1 exhibited very high EE and a prolonged release profile. All micellar systems demonstrated their capability to detach pre-formed Gram-positive and Gram-negative bacterial biofilms and significantly reduced their biomass. The metabolic activity of the biofilm was strongly suppressed by the CF-loaded MPMs indicating the successful drug delivery and release. The cytotoxicity of empty and CF-loaded MPMs was evaluated. The test reveals composition-dependent cell viability without cell destruction or morphological signs of cell death.

Self-Assembling Lecithin-Based Mixed Polymeric Micelles for Nose to Brain Delivery of Clozapine: In-vivo Assessment of Drug Efficacy via Radiobiological Evaluation.

The research objective is to design intranasal brain targeted CLZ loaded lecithin based polymeric micelles (CLZ- LbPM) aiming to improve central systemic CLZ bioavailability. In our study, intranasal CLZ loaded lecithin based polymeric micelles (CLZ- LbPM) were formulated using soya phosphatidyl choline (SPC) and sodium deoxycholate (SDC) with different CLZ:SPC:SDC ratios via thin film hydration technique aiming to enhance drug solubility, bioavailability and nose to brain targeting efficiency. Optimization of the prepared CLZ-LbPM using Design-Expert® software was achieved showing that M6 which composed of (CLZ:SPC: SDC) in respective ratios of 1:3:10 was selected as the optimized formula. The optimized formula was subjected to further evaluation tests as, Differential Scanning Calorimetry (DSC), TEM, in vitro release profile, ex vivo intranasal permeation and in vivo biodistribution. The optimized formula with the highest desirability exhibiting (0.845), small particle size (12.23±4.76 nm), Zeta potential of (-38 mV), percent entrapment efficiency of > 90% and percent drug loading of 6.47%. Ex vivo permeation test showed flux value of 27 μg/cm².h and the enhancement ratio was about 3 when compared to the drug suspension, without any histological alteration. The radioiodinated clozapine ([131I] iodo-CLZ) and radioiodinated optimized formula ([131I] iodo-CLZ-LbPM) were formulated in an excellent radioiodination yield more than 95%. In vivo biodistribution studies of [131I] iodo-CLZ-LbPM showed higher brain uptake (7.8%± 0.1%ID/g) for intranasal administration with rapid onset of action (at 0.25 h) than the intravenous formula. Its pharmacokinetic behavior showed relative bioavailability, direct transport percentage from nose to brain and drug targeting efficiency of 170.59%, 83.42% and 117% respectively. The intranasal self-assembling lecithin based mixed polymeric micelles could be an encouraging way for CLZ brain targeting.

Nanosystems for Brain Targeting of Antipsychotic Drugs: An Update on the Most Promising Nanocarriers for Increased Bioavailability and Therapeutic Efficacy

Orally administered antipsychotic drugs are the first-line treatment for psychotic disorders, such as schizophrenia and bipolar disorder. Nevertheless, adverse drug reactions jeopardize clinical outcomes, resulting in patient non-compliance. The design formulation strategies for enhancing brain drug delivery has been a major challenge, mainly due to the restrictive properties of the blood-brain barrier. However, recent pharmacokinetic and pharmacodynamic in vivo assays confirmed the advantage of the intranasal route when compared to oral and intravenous administration, as it allows direct nose-to-brain drug transport via neuronal pathways, reducing systemic side effects and maximizing therapeutic outcomes. In addition, the incorporation of antipsychotic drugs into nanosystems such as polymeric nanoparticles, polymeric mixed micelles, solid lipid nanoparticles, nanostructured lipid carriers, nanoemulsions, nanoemulgels, nanosuspensions, niosomes and spanlastics, has proven to be quite promising. The developed nanosystems, having a small and homogeneous particle size (ideal for nose-to-brain delivery), high encapsulation efficiency and good stability, resulted in improved brain bioavailability and therapeutic-like effects in animal models. Hence, although it is essential to continue research in this field, the intranasal delivery of nanosystems for the treatment of schizophrenia, bipolar disorder and other related disorders has proven to be quite promising, opening a path for future therapies with higher efficacy.

Transcellular Transport Behavior of the Intact Polymeric Mixed Micelles with Different Polymeric Ratios.

In order to better promote the application of the polymeric mixed micelles (PMMs) in oral delivery, in addition to focusing on the improvement of micellar structural stability, it is necessary to obtain the absorption characteristics of the intact micellar particles. In this work, the transport behavior across Caco-2 cells of FS/PMMs composed of Pluronic F127 and Solutol HS15 was tracked by encapsulating an environment-responsive probe into the particles. The specific property of the probe is the water-initiated aggregation-caused quenching (ACQ) ability, by which integral particles can be identified accurately. The influence of polymeric ratios (FS) on the transcellular behavior of FS/PMMs was explored and the single pass intestinal perfusion experiment was used to further illustrate it. Moreover, pharmacokinetics parameters were detected to analyze the relationship among FS ratios, transport behavior, and pharmacokinetic parameters. FS ratios were found to hardly affect the endocytosis pathways and intracellular itinerary of FS/PMMs, but do affect the proportion of each path. FS/PMMs with high HS15 content, namely System-I, were found to primarily undergo receptor-mediated endocytosis pathway and be less susceptible to lysosomal degradation, which would lead to more absorption and higher Cmax and AUC than drug suspension. In contrast, despite System-II with high F127 content cannot contribute to drug plasma concentration, it can prolong the in vivo retention time. These findings provided evidence for the role of polymeric ratios in modulating the transcellular absorption and pharmacokinetic parameters of the drug-loaded PMMs, and would be a step forward in helping PMMs' design to enhance oral drug delivery.

Pluronics-Based Drug Delivery Systems for Flavonoids Anticancer Treatment.

This research concerns the investigation of the preparation of polymeric nanocarriers containing a flavonoid-naringenin, xanthohumol or isoxanthohumol-based on Pluronics by the thin-film formation method. The size of the formed micelles and their stability upon dilution were evaluated using Dynamic light scattering (DLS) analysis; the high values of the drug loading and the encapsulation efficiency confirmed that the proposed systems of flavonoids delivery consisting of Pluronic P123 and F127 nanomicelles could effectively distribute the drug into tumour tissues, which makes these nanocarriers ideal candidates for passive targeting of cancer cells by the enhanced permeation and retention (EPR) effect. The in vitro cytotoxicity of proposed flavonoids in the Pluronic formulations was investigated by the SRB assay with human colon cancer cells. We designed mixed polymeric micelles, which was a successful drug delivery system for the case of naringenin not being able to enhance the bioavailability and cytotoxic activity of xanthohumol and isoxanthohumol. Furthermore, it was observed that the higher amount of polymer in the formulation achieved better cytotoxic activity.

Development of self-cooperative nanochaperones with enhanced activity to facilitate protein refolding.

Regulating protein folding including assisting de novo folding, preventing misfolding and aggregation, and facilitating refolding of proteins are of significant importance for retaining protein's biological activities. Here, we report a mixed shell polymeric micelle (MSPM)-based self-cooperative nanochaperone (self-CO-nChap) with enhanced activity to facilitate protein refolding. This self-CO-nChap was fabricated by introducing Hsp40-mimetic artificial carriers into the traditional nanochaperone to cooperate with the Hsp70-mimetic confined hydrophobic microdomains. The artificial carrier facilitates transfer and immobilization of client proteins into confined hydrophobic microdomains, by which significantly improving self-CO-nChap's capability to inhibit unfolding and aggregation of client proteins, and finally facilitating refolding. Compared to traditional nanochaperones, the self-CO-nChap significantly enhances the thermal stability of horseradish peroxidase (HRP) epicyclically under harsher conditions. Moreover, the self-CO-nChap efficiently protects misfolding-prone proteins, such as immunoglobulin G (IgG) antibody from thermal denaturation, which is hardly achieved using traditional nanochaperones. In addition, a kinetic partitioning mechanism was devised to explain how self-CO-nChap facilitates refolding by regulating the cooperative effect of kinetics between the nanochaperone and client proteins. This work provides a novel strategy for the design of protein folding regulatory materials, including nanochaperones.

Design, Fabrication and Evaluation of Stabilized Polymeric mixed micelles for Effective Management in Cancer Therapy.

Cancer is one of the most common and fatal disease, chemotherapy is the major treatment against many cancer types. The anti-apoptotic BCL-2 protein's expression was increased in many cancer types and Venetoclax (VLX; BCL-2 inhibitor) is a small molecule, which selectively inhibits this specified protein. In order to increase the clinical performance of this promising inhibitor as a repurposed drug, polymeric mixed micelles formulations approach was explored. The Venetoclax loaded polymeric mixed micelles (VPMM) were prepared by using Pluronic® F-127 and alpha tocopherol polyethylene glycol 1000 succinate (TPGS) as excipients by thin film hydration method and characteristics. The percentage drug loading capacity, entrapment efficiency and in-vitro drug release studies were performed using HPLC method. The cytotoxicity assay, cell uptake and anticancer activities were evaluated in two different cancer cells i.e. MCF-7 (breast cancer) and A-549 (lung cancer). Particle size, polydispersity index and zeta potential of the VPMM was found to be 72.88 ± 0.09nm, 0.078 ± 0.009 and -4.29 ± 0.24mV, respectively. The entrapment efficiency and %drug loading were found to be 80.12 ± 0.23% and 2.13% ± 0.14%, respectively. The IC50 of VLX was found to be 4.78, 1.30, 0.94µg/ml at 24, 48 and 72h, respectively in MCF-7 cells and 1.24, 0.68, and 0.314µg/ml at 24, 48, and 72h, respectively in A549 cells. Whereas, IC50 of VPMM was found to be 0.42, 0.29, 0.09µg/ml at 24, 48 and 72h, respectively in MCF-7 cells and 0.85, 0.13, 0.008µg/ml at 24, 48 and 72h in A549 cells, respectively, indicating VPMM showing better anti-cancer activity compared to VLX. The VPMM showed better cytotoxicity which was further proven by other assays and explained the anti-cancer activity is shown through the generation of ROS, nuclear damage,apoptotic cell death and expression of caspase-3,7, and 9 activities in apoptotic cells. The current investigation revealed that the Venetoclax loaded polymeric mixed micelles (VPMM) revealed the enhanced therapeutic efficacy against breast and lung cancer in vitro models.

Tunable Polymeric Mixed Micellar Nanoassemblies of Lutrol F127/Gelucire 44/14 for Oral Delivery of Praziquantel: A Promising Nanovector against Hymenolepis nana in Experimentally-Infected Rats.

Hymenolepiasis represents a parasitic infection of common prevalence in pediatrics with intimidating impacts, particularly amongst immunocompromised patients. The present work aimed to snowball the curative outcomes of the current mainstay of hymenolepiasis chemotherapy, praziquantel (PRZ), through assembly of polymeric mixed micelles (PMMs). Such innovative nano-cargo could consolidate PRZ hydrosolubility, extend its circulation time and eventually upraise its bioavailability, thus accomplishing a nanoparadigm for hymenolepiasis tackling at lower dose levels. For consummating this goal, PRZ-PMMs were tailored via thin-film hydration technique integrating a binary system of Lutrol F127 and Gelucire 44/14. Box-Behnken design was planned for optimizing the nanoformulation variables employing Design-Expert® software. Also, in Hymenolepis nana-infected rats, the pharmacodynamics of the optimal micellar formulation versus the analogous crude PRZ suspension were scrutinized on the 1st and 3rd days after administration of a single oral dose (12.5 or 25 mg/kg). Moreover, in vitro ovicidal activity of the monitored formulations was estimated utilizing Fuchsin vital stain. Furthermore, the in vivo pharmacokinetics were assessed in rats. The optimum PRZ-PMMs disclosed conciliation between thermodynamic and kinetic stability, high entrapment efficiency (86.29%), spherical nanosized morphology (15.18 nm), and controlled-release characteristics over 24 h (78.22%). 1H NMR studies verified PRZ assimilation within the micellar core. Additionally, the in vivo results highlighted a significant boosted efficacy of PRZ-PMMs manifested by fecal eggs output and worm burden reduction, which was clearly evident at the lesser PRZ dose, besides a reversed effect for the intestinal histological disruptions. At 50 µg/mL, PRZ-PMMs increased the percent of non-viable eggs to 100% versus 47% for crude PRZ, whilst shell destruction and loss of embryo were only clear with the applied nano-cargo. Moreover, superior bioavailability by 3.43-fold with elongated residence time was measured for PRZ-PMMs compared to PRZ suspension. Practically, our results unravel the potential of PRZ-PMMs as an oral promising tolerable lower dose nanoplatform for more competent PRZ mass chemotherapy.

Microemulsions as Lipid Nanosystems Loaded into Thermoresponsive In Situ Microgels for Local Ocular Delivery of Prednisolone.

This study aimed to develop and evaluate thermoresponsive in situ microgels for the local ocular delivery of prednisolone (PRD) (PRD microgels) to improve drug bioavailability and prolong ocular drug residence time. Lipid nanosystems of PRD microemulsions (PRD-MEs) were prepared and evaluated at a drug concentration of 0.25–0.75%. PRD microgels were prepared by incorporating PRD-MEs into 10 and 12% Pluronic® F127 (F127) or combinations of 12% F127 and 1–10% Kolliphor®P188 (F68). PRD microgels were characterized for physicochemical, rheological, and mucoadhesive properties, eye irritation, and stability. Results showed that PRD-MEs were clear, miscible, thermodynamically stable, and spherical with droplet size (16.4 ± 2.2 nm), polydispersity index (0.24 ± 0.01), and zeta potential (−21.03 ± 1.24 mV). The PRD microgels were clear with pH (5.37–5.81), surface tension (30.96–38.90 mN/m), size, and zeta potential of mixed polymeric micelles (20.1–23.9 nm and −1.34 to −10.25 mV, respectively), phase transition temperature (25.3–36 °C), and gelation time (1.44–2.47 min). The FTIR spectra revealed chemical compatibility between PRD and microgel components. PRD microgels showed pseudoplastic flow, viscoelastic and mucoadhesive properties, absence of eye irritation, and drug content (99.3 to 106.3%) with a sustained drug release for 16–24 h. Microgels were physicochemically and rheologically stable for three to six months. Therefore, PRD microgels possess potential vehicles for local ocular delivery.

Anti-Proliferative Potential of Quercetin Loaded Polymeric Mixed Micelles on Rat C6 and Human U87MG Glioma Cells.

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.

Implementing polymeric pseudorotaxanes for boosting corneal permeability and antiaspergillus activity of tolnaftate: formulation development, statistical optimization, ex vivo permeation and in vivo assessment

Fungal keratitis (FK) is a devastating ocular disease that can cause corneal opacity and blindness if not treated effectively. Tolnaftate (TOL) is a selective fungicidal drug against Aspergillus spp. which are among the most common causes of mycotic keratitis. TOL is lipophilic drug with low water solubility and permeation which act as obstacles for its clinical ocular efficacy. Hence, this study aimed to statistically optimize a novel polymeric pseudorotaxanes (PSRs) containing TOL for enhancing its ocular permeability and antifungal effect. For achieving this goal, a full 31.22 factorial design was fashioned for preparing and optimizing TOL-PSRs using film hydration technique. Three formulation variables were studied: drug amount (X1), weight ratio of Pluronics to HPβCD (X2) and Pluronic system (X3). Entrapment efficiency percent (EE%) (Y1), particle size (PS) (Y2) and zeta potential (ZP) (Y3) were set as dependent variables. The selected optimal TOL-PSRs (PSR1) showed EE% of 71.55 ± 2.90%, PS of 237.05 ± 12.80 nm and ZP of −32.65 ± 0.92 mV. In addition, PSR1 was compared to conventional polymeric mixed micelles (PMMs) and both carriers significantly increased the drug flux and resulted in higher amount permeated per unit area in 8 h compared to drug suspension. The histopathological studies assured the safety of PSR1 for ocular use. The in vivo susceptibility testing using Aspergillus niger confirmed that PSR1 displayed sustained antifungal activity up to 24 h. The obtained results revealed the admirable potential of PSR1 to be used as novel nanocarriers for promoting TOL ocular delivery.

Mixed Polymeric Micelles for Rapamycin Skin Delivery.

Facial angiofibromas (FA) are one of the most obvious cutaneous manifestations of tuberous sclerosis complex. Topical rapamycin for angiofibromas has been reported as a promising treatment. Several types of vehicles have been used hitherto, but polymeric micelles and especially those made of d-α-tocopherol polyethylene glycol 1000 succinate (TPGS) seem to have shown better skin bioavailability of rapamycin than the so far commonly used ointments. To better understand the influence of polymeric micelles on the behavior of rapamycin, we explored it through mixed polymeric micelles combining TPGS and poloxamer, evaluating stability and skin bioavailability to define an optimized formulation to effectively treat FA. Our studies have shown that TPGS improves the physicochemical behavior of rapamycin, i.e., its solubility and stability, due to a strong inclusion in micelles, while poloxamer P123 has a more significant influence on skin bioavailability. Accordingly, we formulated mixed-micelle hydrogels containing 0.1% rapamycin, and the optimized formulation was found to be stable for up to 3 months at 2–8 °C. In addition, compared to hydroalcoholic gel formulations, the studied system allows for better biodistribution on human skin.

Physicochemical Characterization and Pharmacological Evaluation of Novel Propofol Micelles with Low-Lipid and Low-Free Propofol.

We developed safe and stable mixed polymeric micelles with low lipids and free propofol for intravenous administration, to overcome the biological barrier of the reticuloendothelial system (RES), reduce pain upon injection, and complications of marketed propofol formulation. The propofol-mixed micelles were composed of distearoyl-phosphatidylethanolamine-methoxy-poly (ethylene glycol 2000) (DSPE mPEG2k) and Solutol HS 15 and were optimized using Box Behnken design (BBD). The optimized formulation was evaluated for globule size, zeta potential, loading content, encapsulation efficiency, pain on injection, histological evaluation, hemolysis test, in vivo anesthetic action, and pharmacokinetics, in comparison to the commercialized emulsion Diprivan. The optimized micelle formulation displayed homogenous particle sizes, and the free drug concentration in the micelles was 60.9% lower than that of Diprivan. The paw-lick study demonstrated that propofol-mixed micelles significantly reduced pain symptoms. The anesthetic action of the mixed micelles were similar with the Diprivan. Therefore, we conclude that the novel propofol-mixed micelle reduces injection-site pain and the risk of hyperlipidemia due to the low content of free propofol and low-lipid constituent. It may be a more promising clinical alternative for anesthetic.

Cannabidiol-Loaded Mixed Polymeric Micelles of Chitosan/Poly(Vinyl Alcohol) and Poly(Methyl Methacrylate) for Trans-Corneal Delivery.

Ocular drug delivery is challenging due to the very short drug residence time and low permeability. In this work, we produce and characterize mucoadhesive mixed polymeric micelles (PMs) made of chitosan (CS) and poly(vinyl alcohol) backbones graft-hydrophobized with short poly(methyl methacrylate) blocks and use them to encapsulate cannabidiol (CBD), an anti-inflammatory cannabinoid. CBD-loaded mixed PMs are physically stabilized by ionotropic crosslinking of the CS domains with sodium tripolyphoshate and spray-drying. These mixed PMs display CBD loading capacity of 20% w/w and sizes of 100–200 nm, and spherical morphology (cryogenic-transmission electron microscopy). The good compatibility of the unloaded and CBD-loaded PMs is assessed in a human corneal epithelial cell line. Then, we confirm the permeability of CBD-free PMs and nanoencapsulated CBD in human corneal epithelial cell monolayers under liquid–liquid and air–liquid conditions. Overall, our results highlight the potential of these polymeric nanocarriers for ocular drug delivery.

Encapsulation of Photothermal Nanoparticles in Stealth and pH-Responsive Micelles for Eradication of Infectious Biofilms In Vitro and In Vivo.

Photothermal nanoparticles can be used for non-antibiotic-based eradication of infectious biofilms, but this may cause collateral damage to tissue surrounding an infection site. In order to prevent collateral tissue damage, we encapsulated photothermal polydopamine-nanoparticles (PDA-NPs) in mixed shell polymeric micelles, composed of stealth polyethylene glycol (PEG) and pH-sensitive poly(β-amino ester) (PAE). To achieve encapsulation, PDA-NPs were made hydrophobic by electrostatic binding of indocyanine green (ICG). Coupling of ICG enhanced the photothermal conversion efficacy of PDA-NPs from 33% to 47%. Photothermal conversion was not affected by micellar encapsulation. No cytotoxicity or hemolytic effects of PEG-PAE encapsulated PDA-ICG-NPs were observed. PEG-PAE encapsulated PDA-ICG-NPs showed good penetration and accumulation in a Staphylococcus aureus biofilm. Penetration and accumulation were absent when nanoparticles were encapsulated in PEG-micelles without a pH-responsive moiety. PDA-ICG-NPs encapsulated in PEG-PAE-micelles found their way through the blood circulation to a sub-cutaneous infection site after tail-vein injection in mice, yielding faster eradication of infections upon near-infrared (NIR) irradiation than could be achieved after encapsulation in PEG-micelles. Moreover, staphylococcal counts in surrounding tissue were reduced facilitating faster wound healing. Thus, the combined effect of targeting and localized NIR irradiation prevented collateral tissue damage while eradicating an infectious biofilm.

Polymeric micelles and nanomedicines: Shaping the future of next generation therapeutic strategies for infectious diseases

Despite all the advances in understanding the pathogenesis of infectious diseases and the development of novel treatments to combat them, these pathogenic disorders are among the most common reasons for hospitalizations and death worldwide.Polymeric micelles (PMs) are nano-sized drug delivery systems that in the last few years have raised special attention for optimizing the therapy of many infectious diseases, including those considered as neglected by the World Health Organization. These nanoscopic core/shell structures formed by self-assemblies of amphiphilic block copolymers represent an effective delivery system for poorly water-soluble drugs. In the last few years, many micellar formulations were studied for delivery of drugs, genes and nutraceuticals, and some of them are under clinical trials. This review will focus on the applications of polymeric single and mixed micelles for the treatment of infectious diseases and will discuss how these advancements have contributed to improve their pharmacotherapy, with a special emphasis on neglected tropical diseases. A summary of the nanomaterials used for the preparation of PMs is detailed. The current state of the art of several micellar formulations as nanocarriers of FDA-approved drugs for the therapy of many infectious diseases, including those under pre-clinical or clinical trials is provided. Finally, perspectives in the design of a more efficient pharmacotherapy to overcome the multi-drug resistance phenotype of pathogens or host cells are addressed.

Development of Curcumin-Loaded Polymeric Mixed Micelle for Skin Moisturizing Antioxidant Formulation

Abstract The aim of this study was to fabricate curcumin-loaded polymeric mixed micelle which was a new nanocarrier of therpeutic agent for skin uses. Curcumin was extracted from dried turmeric rhizomes using ethanol and recrystallized. The purity of curcumin was 79±3.6 %w/w. Six curcumin-loaded polymeric micelles (PM1-PM6) were prepared by simple dissolution method using poloxamer 407 (5% and 10%) as a main core structure. PEG-40 hydrogenated castor oil (PEG-40HCO) was incorporated at two percentages (2.5% and 5.0%) to study the effect on the nanoparticle characteristics. The average particle sizes of PM1-PM6 were in the range of 33.3±6.6 nm to 171.3±52.8 nm. The entrapment efficiency and the loading capacity of curcumin were in the range of 47.45%-77.35% and 0.048%w/w-0.078%w/w, respectively. When PEG-40HCO was incorporated in to the polymeric micelles, the particle size decreased and the entrapment efficiency increased. Thus, PM4 and PM5 were selected for further study. Moisturizing antioxidant creams containing 0.005%w/w of curcumin loaded in PM4, PM5 and curcumin simply dissolved in propylene glycol (PG) were formulated. The resulted formulations showed good spreadability and good characteristics. After being subjected to accelerated test, all of the formulations remained with characteristic color, pH and showed no phase separation. The stability data showed that the moisturizing antioxidant creams were stable for the whole 3 months after storage at accelerated temperature (45°C/75%RH). The study demonstrated that polymeric mixed micelle spontaneously encapsulated a poorly water-soluble curcumin and increased the solubility up to 250 folds. The developed moisturizing cream containing 0.005%w/w of curcumin resulted a greenish-yellow color preparation. It had tolerable physicochemical properties based on curcumin content, pH and viscosity under the harsh condition. The cream also had satisfactory antioxidant activity, which can be regarded as an effective and acceptable therapeutic or skincare products for topical uses.

Anti-breast cancer activity of novel compounds loaded in polymeric mixed micelles: Characterization and in vitro studies

We designed and synthesized three new compounds against breast cancer. The first, N-(2-hydroxyphenyl)-2-propylpentanamide (HO-AAVPA), aims to target histone deacetylase. The other two compounds, (3aS, 4R, 9bR)-4-(6-bromobenzo[d][1,3]dioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-carboxylic (E)-N,N′-diisopropylcarbamimidic anhydride (ISOUREA) and (3aS, 4R, 9bR)-4-(6-bromobenzo[d][1,3]dioxol-5-yl)-5-(tert-butoxycarbonyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-carboxylic acid (G1-PABA-BOC) designed to bind to the G protein-coupled estrogen receptor. To increase the water solubility of the designed molecules, we used mixed polymeric micelles of triblock copolymer P123 and F127 as nanocarriers. We determined the water solubility, encapsulation efficiency (EE%), drug loading coefficient (DL%) and in vitro release profile of each drug loaded in the mixed polymeric micelles. We also studied the morphology and size of loaded micelles with each of the individual drugs in binary mixtures by cryo-transmission electron microscopy and dynamic light scattering. The results showed that the micelles had a spherical morphology with a size between 23 and 38 nm. The topography of the loaded micelles was studied by atomic force microscopy, and the changes in the surface were found to depend on the type of drug loaded into the mixed polymeric micelle. Finally, all solutions were tested on MDA-MB-231 and MCF-7 cancer cell lines, finding antiproliferative properties for all loaded micelles in both cancer cell lines. The IC50 for the HO-AAVPA/G1-PABA-BOC mixture loaded in the micelles, was lower than the corresponding value of the compounds tested by themselves on MCF-7 cell line. We conclude that the mixed polymeric micelles are able to solubilize large quantities of the highly hydrophobic drugs used in this work and improve their antiproliferative properties.

Formulation and performance evaluation of polymeric mixed micelles encapsulated with baicalein for breast cancer treatment

The present study is aimed to formulate baicalein-loaded mixed micelles to enhance the solubility and oral bioavailability. Baicalein encapsulated D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) and pluronic F127 (F127) combined micelles were prepared and investigated for anticancer effect. The optimized formulation contains 25.04 ± 0.24 nm mean particle size of micelles with a zeta potential value of −4.01 ± 0.5 mV. The calculated entrapment efficiency percentage of baicalein within the micellar structure was 83.43 ± 0.13% and the in vitro release of baicalein from micelles displayed a sustained release profile at pH 7.4. The incorporation of baicalein within micelles core was also confirmed by FTIR analysis of formulation, which hardly represents the characteristic peak of baicalein, indicating successful entrapment of the drug. In vitro cell culture experiments revealed baicalein-loaded micelles significantly enhanced cellular uptake and cytotoxicity against MDAMB-231 cell lines in comparison to free baicalein. Additionally, as compared to free baicalein, baicalein micelles demonstrated greater apoptosis-inducing potential while the results of the cell cycle study exhibited arrest of cells at the G0/G1 phase of the cell cycle. Results of ROS (reactive oxygen species) and MMP (mitochondrial membrane potential) assay revealed the ROS-dependent mitochondrial-mediated apoptosis pathway utilized by developed formulation to inhibit cell proliferation. Thus, the developed nano micelles can serve as a potent carrier system for baicalein against breast cancer.

Development of dexamethasone-loaded mixed polymeric micelles for nasal delivery

Our study aimed to formulate a novel dexamethasone (DXM)-loaded, mixed polymeric micelle-based drug delivery system, focusing on the auspicious nose-to-brain pathway, as a key delivery route to treat central nervous system (CNS) associated diseases. Polymeric micelles might be a solution to deliver drugs to the place of action compared to conventional formulations. Due to low Z-average (89.92 ± 2.7 nm), a polydispersity index of 0.216 ± 0.014 and high surface polarity (52.23%), a significant increase in water solubility (14-fold) was experienced. This increase resulted in favourable dissolution profile at nasal and axonal conditions with high in vitro permeability value (14.6×10−6 cm/s) on polar brain (porcine) lipid extract. Modified Side-bi-side® type diffusion study confirmed rapid and efficient passive diffusion through the nasal mucosa contributed by strong mucoadhesive properties. The final formulation met all the requirements of a nasal drug delivery system with rapid onset of action, meaning DXM can reach the CNS and there it can exert its beneficial effects in pathological conditions.