Polyacrylamide–punicic acid conjugate‐based micelles for flutamide delivery in PC3 cells of prostate cancer: synthesis,characterisation and cytotoxicity studies

The aim of the present study was to synthesize a novel biopolymeric micelle based on punicic acid (PA) and polyacrylamide (PAM) for carrying chemotherapeutic drugs used in prostate cancer treatment. A polymer composite micelle was prepared by chemical conjugation between PAM and PA. The micelles were prepared by self‐assembly via film casting followed by ultrasonication method. The successful production of PAMPA copolymeric micelles was confirmed using FTIR, 1H‐NMR, and TEM. Then, flutamide was loaded in the designed nanomicelles and they were characterized. The cell cytotoxicity of the micelles was studied on PC3 cells of prostate cancer. The prepared nanomicelles showed the particle size of 88 nm, PDI of 0.246, zeta potential of −9 mV, drug loading efficiency of 94.5%, drug release of 85.6% until 10 hours in pH 7.4 and CMC of 74.13 μg/ml. The cell viability in blank nanocarriers was about 70% in PC3 cells at concentration of 25 μM. More significant cytotoxic effects were seen for flutamide loaded micelles at this concentration compared to the free drug. The results suggest that the PAMPA co‐polymeric nanomicelles can be utilized as an effective carrier to enhance the cytotoxic effects of flutamide in prostate cancer.Inspec keywords: nanoparticles, cellular biophysics, drugs, biomedical materials, drug delivery systems, colloids, hydrophilicity, pH, transmission electron microscopy, particle size, cancer, casting, toxicology, electrokinetic effects, polymer blends, proton magnetic resonance, nanomedicine, self‐assembly, nanofabrication, Fourier transform infrared spectraOther keywords: PC3 cells, chemotherapeutic drugs, prostate cancer treatment, polymer composite micelle, chemical conjugation, proton nuclear magnetic resonance, cell cytotoxicity, prepared nanomicelles, drug loading efficiency, drug release, critical micelle concentration, cell viability, cytotoxic effects, flutamideloaded micelles, flutamide delivery, polyacrylamide‐punicic acid conjugate‐based micelles, PAMPA copolymeric nanomicelles, biopolymeric micelle, PAM‐punicic acid copolymer copolymeric micelles, hydrophilic shell, self‐assembly, film casting, ultrasonication method, Fourier transform infrared spectra, transmission electron microscopy, particle size, polydisperity index, zeta potential, pH, blank nanocarriers, time 10.0 hour     

Preparation and evaluation of self-assembly Soluplus®-sodium cholate-phospholipid ternary mixed micelles of docetaxel

Abstract

Ternary mixed micelles constituted of Soluplus^®, sodium cholate, and phospholipid were prepared as nano-delivery system of the anticancer drug, docetaxel. The formulation of docetaxel-loaded ternary mixed micelles (DTX-TMMs) with an optimized composition (Soluplus^®/sodium cholate/phospholipid= 3:2:1 by weight) were obtained. The main particle size of DTX-TMMs was 76.36?±?2.45?nm, polydispersity index (PDI) was 0.138?±?0.039, and the zeta potential was ?8.46?±?0.55?mv. The encapsulation efficiency was 94.24?±?4.30% and the drug loading was 1.25%. The critical micelle concentration value was used to assess the ability of carrier materials to form micelles. The results indicated that the addition of Soluplus^® to sodium cholate-phospholipid mixed micelles could reduce the critical micelle concentration and improve the stability. In vitro release studies demonstrated that compared with DTX-Injection group, the DTX-TMMs presented a controlled release property of drugs. In vivo pharmacodynamics results suggested that DTX-TMMs had the most effective inhibitory effect on tumor proliferation and had good biosafety. In addition, the relative bioavailability of mixed micelles was increased by 1.36 times compared with the DTX-Injection in vivo pharmacokinetic study indicated that a better therapeutic effect could be achieved. In summary, the ternary mixed micelles prepared in this study are considered to be promising anticancer drug delivery systems.     

Co-delivery of paclitaxel and α-tocopherol succinate by novel chitosan-based polymeric micelles for improving micellar stability and efficacious combination therapy

The aim of this study was to develop chitosan derivative polymeric micelles for co-delivery of paclitaxel (PTX) and α-tocopherol succinate (α-TS) to the cancer cells to improve the therapeutic efficiency and reduce side effects of PTX. In this study, amphiphilic tocopheryl succinate-grafted chitosan oligosaccharide was synthesized and physically loaded by PTX and α-TS with entrapment efficiency of 67.9% and 73.2%, respectively. Physical incorporation of α-TS into the micelles increased the hydrophobic interaction between PTX and the micelles core, which improved micelle stability, reduced the micelle size and also sustained the PTX release from the micelles. The mean particle size and zeta potential of αTS/PTX-loaded micelles were about 133?nm and +25.2?mV, respectively, and PTX release was completed during 6–9?d from the micelles. Furthermore, the cytotoxicity of α-TS/PTX-loaded micelles against human ovarian cancer cell line cancer cell in vitro was higher than that of PTX-loaded micelles and the free drug solution. Half maximal inhibitory concentration values of PTX after 48-h exposure of the cells to the PTX-loaded micelles modified and unmodified with α-TS were 110 and 188?ng/ml, respectively.     

Synthesis,in vitro characterization,and anti-tumor effects of novel polystyrene-poly(amide-ether-ester-imide) co-polymeric micelles for delivery of docetaxel in breast cancer in Balb/C mice

Objective: The goal of the present work was to make novel co-polymeric micellar carriers for the delivery of docetaxel (DTX).

Significance: Co-polymeric micelles can not only solubilize DTX and eliminate the need for toxic surfactants to dissolve it, but also cause passive targeting of the drug to the tumor and reduce its toxic side effects.

Methods: Poly(styrene-maleic acid) (SMA) was conjugated to poly (amide-ether-ester-imide)-poly ethylene glycol (PAEEI-PEG). Copolymer synthesis was proven by Fourier transform infrared (FTIR) and ¹H-nuclear magnetic resonance (¹H-NMR). The SMA-PAEEI-PEG micelles loaded with DTX were prepared and their critical micelle concentration (CMC), zeta potential, particle size, entrapment efficiency, and their release efficiency were studied. MCF-7 and MDA-MB231 breast cancer cells were used to evaluate the cellular uptake and cytotoxicity of the micelles. The antitumor activity of the DTX-loaded nanomicelles was measured in Balb/c mice.

Results: The FTIR and HNMR spectroscopy confirmed successful conjugation of SMA and PAEEI-PEG. The drug loading efficiency was in the range of 34.01–72.75% and drug release lasted for 120?h. The CMC value of the micelles was affected by the SMA/PAEEI-PEG ratio and was in the range of 29.85–14.28?µg/ml. The DTX-loaded micelles showed five times more cytotoxicity than the free drug. The DTX loaded micelles were more effective in tumor growth suppression in vivo and the animals showed an enhanced rate of survival.

Conclusion: The results show that the SMA-PAEEI-PEG micelles of DTX could potentially provide a suitable parenteral formulation with more stability, higher cytotoxicity, and improved antitumor activity.     

A novel mixed polymeric micelle for co-delivery of paclitaxel and retinoic acid and overcoming multidrug resistance: synthesis,characterization, cytotoxicity,and pharmacokinetic evaluation

In the current study, retinoic acid (RA) was conjugated to Pluronic F127 (PF127) through an esterification process. Mixed micelles were formed with tocopheryl polyethylene glycol 1000 (TPGS) for co-delivery of paclitaxel (PTX) and RA to the cancer cells. Mixed micelles of RA-PF127 and TPGS in different weight ratios (10:0, 7:3, 5:5, 3:7, 0:10 w/w) were prepared and physicochemical properties including, particle size, zeta potential, critical micelle concentration (CMC), drug loading content, entrapment efficiency, drug release, cellular uptake and in vitro cytotoxicity, were investigated in details. Furthermore, the pharmacokinetics of PTX-loaded optimized mixed micelles were evaluated in Sprague-Dawley rats and compared with Stragen^® (PTX in Cremophor EL^®). Particle sizes and zeta potentials of the drug-loaded micelles were in the range of 102.6–223.5?nm and ?5.3 to ?9.6?mV, respectively. The 7:3 and 5:5 micellar combinations had lower CMC values (0.034–0.042?mg/mL) than 0:10 (0.124?mg/mL). The entrapment efficiencies of 10:0, 7:3, and 5:5 were 53.4?±?9.3%, 61.3?±?0.5%, and 78.7?±?1.66%, respectively. The release rates of PTX from 7:3 and 5:5 mixed micelles were significantly slower than other formulations. Cytotoxicity assay demonstrated increased cytotoxic activity of PTX-loaded mixed micelles compared to free PTX. The V_d and t_1/2ß of PTX-loaded RA-PF127/TPGS (7:3) were increased by 2.61- and 1.27-fold, respectively, while the plasma area under the curve (AUC) of the micelles was 2.03-fold lower than those of Stragen^®. Therefore, these novel mixed micelles could be effectively used for delivery of PTX and RA to the cancer cells. Moreover, TPGS as part of micelle composition could enhance the therapeutic effect of PTX and reduce side effects.     

A novel drug and gene co-delivery system based on Poly(epsilon-caprolactone)-Poly(ethylene glycol)-Poly(epsilon-caprolactone) grafted polyethyleneimine micelle

In this paper, we prepared a novel cationic self-assembled micelle from poly(epsilon-caprolactone)-poly(ethyl glycol)-poly(epsilon-caprolactone) grafted polyethyleneimine (PCEC-g-PEI). The PCEC-g-PEI micelles, formed by self-assembly method, had mean particle size of ca. 82 nm and zeta potential of +22.5 mV at 37 degrees C, and could efficiently transfer pGFP into HEK293 cells in vitro. Meanwhile, as a model hydrophobic chemotherapeutic drug, honokiol was loaded into PCEC-g-PEI micelles by direct dissolution method assisted by ultrasonication. The honokiol loaded cationic PCEC-g-PEI micelles could effectively adsorb DNA onto its surface, while it could release honokiol in an extended period in vitro. This study demonstrated a novel DNA and hydrophobic chemotherapeutic drug co-delivery system.     

Design and synthesis of mixed micellar system for enhanced anticancer efficacy of Paclitaxel through its co-delivery with Naringin

Emergence of multidrug resistance (MDR) has limited the success of chemotherapeutic agents. Reversal of drugs efflux systems through combination therapy has got wider attention for increasing anticancer drugs efficacy. This study aims at co-encapsulation of Paclitaxel with Naringin in mixed polymeric micelles for enhanced anticancer activity of the drug. Drug-loaded micelles were prepared using two different amphiphilic block co-polymers and were characterized for morphology, size, zeta potential, drug encapsulation, in vitro release and stability using atomic force microscope (AFM), zetasizer, UV spectrophotometer, and FT-IR. MTT assay and fluorescence microscopy were used for in vitro cytotoxicity and cellular uptake studies. Nano-size micelles with spherical morphology and negative charge encapsulated 76.52?±?0.94% and 32.87 0.61% Paclitaxel and Naringin, respectively. The micelles were thermally stable and retained 87.05?±?0.69% and 92.88?±?2.17% Paclitaxel and Naringin upon one-month storage. Maximum drug release was achieved at fourth hour of the study for both the loaded drugs. Paclitaxel co-encapsulation with Naringin synergistically improved its intracellular uptake and 65% in vitro cytotoxicity against breast cancer cells was achieved at its lower dose of 15?µg/mL. Results suggest that co-encapsulation of Paclitaxel with Naringin in mixed micelles is an effective strategy for achieving its higher anticancer activity.     

Enhanced antithrombotic effect of hirudin by bovine serum albumin nanoparticles

The aim of this study was to design hirudin-loaded bovine serum albumin (BSA) nanoparticles to control release and improve antithrombotic effect of hirudin. BSA nanoparticles were designed as carriers for delivery of hirudin. Hirudin–BSA nanoparticles were prepared by a desolvation procedure and cross linked on the wall material of BSA. The hirudin–BSA nanoparticles were characterised by particle size distribution, zeta potential, entrapment efficiency, differential scanning calorimetry (DSC), and powder X-ray diffractometry (PXRD). The in vitro release characteristics and pharmacological availability were investigated. The morphology of hirudin–BSA nanoparticles was approximately spherical. The mean particle size was 164.1 ± 5.40 nm and the zeta potential was ?20.41 ± 0.64 mV. The mean entrapment efficiency and drug loading were 85.14% ± 4.79% and 66.38% ± 3.54%, respectively. Results from DSC and PXRD revealed that hirudin in BSA existed in an amorphous state. The release behaviours of hirudin from BSA nanoparticles in phosphate buffer solution were fitted to the bioexponential model. The in vivo result obtained after intravenous injection of hirudin–BSA nanoparticles in normal rats demonstrated that BSA nanoparticles could prolong the antithrombotic effect of hirudin in comparison with hirudin solution. These results suggest that hirudin–BSA nanoparticles may be a promising drug delivery system for thrombosis and disseminated intravascular coagulation therapy.     

Thermoreversible nanoethosomal gel for the intranasal delivery of Eletriptan hydrobromide

The objective of the current study was to formulate and characterize thermoreversible gel of Eletriptan Hydrobromide for brain targeting via the intranasal route. Ethosomes were prepared by 3² factorial design with two independent variables (concentration of soya lecithin and ethanol) and two response variables [percent entrapment efficiency and vesicle size (nm)] using ethanol injection method. Formulated ethosomes were evaluated for preliminary microscopic examination followed by percent drug entrapment efficiency, vesicle size analysis, zeta potential, polydispersibility index and Transmission electron microscopy (TEM). TEM confirms spherical morphology of ethosomes, whereas Malvern zeta sizer confirms that the vesicle size was in the range of 191 ± 6.55–381.3 ± 61.0 nm. Ethosomes were incorporated in gel using poloxamer 407 and carbopol 934 as thermoreversible and mucoadhesive polymers, respectively. Ethosomal gels were evaluated for their pH, viscosity, mucoadhesive strength, in vitro drug release and ex vivo drug permeation through the sheep nasal mucosa. Mucoadhesive strength and pH was found to be 4400 ± 45 to 5500 ± 78.10 dynes/cm² and 6.0 ± 0.3 to 6.2 ± 0.1, respectively. In-vitro drug release from the optimized ethosomal gel formulation (G4) was found to be almost 100 % and ex vivo permeation of 4980 µg/ml with a permeability coefficient of 11.94 ± 0.04 × 10^?5 cm/s after 24 h. Histopathological study of the nasal mucosa confirmed non-toxic nature of ethosomal gels. Formulated EH loaded ethosomal thermoreversible gel could serve as the better alternative for the brain targeting via the intranasal route which in turn could subsequently improve its bioavailability.     

Amphiphilic polymer–drug conjugates based on acid-sensitive 100% hyperbranched polyacetals for cancer therapy

A new type of acid-sensitive 100% hyperbranched polyacetals (HBPA) was synthesized, which could be completely degraded into small molecules under acidic environment and avoid the accumulative toxicity in vivo. The AB₂ monomer was synthesized by 4-carboxybenzaldehyde and 2-bromoethanol. The bulk polycondensation was carried out in vacuum environment to remove water byproduct. The massive terminal aldehyde groups of HBPA were conjugated with mPEG-NH₂ and doxorubicins to form amphiphilic acid-sensitive polymer–drug conjugates (DOX-HBPA-PEG). The stability of the micelles of DOX-HBPA-PEG was evaluated by DLS at different pH value in phosphate buffer saline (PBS). The DOX release in vitro showed that the cumulative release rate was 14.51% in pH 7.4 PBS after 24 h and the cumulative release rate was 48.56% in pH 6.0 PBS after 24 h. The results of cell viability of DOX-HBPA-PEG and HBPA-PEG showed that the polymer–DOX conjugates were effective drug delivery systems. The uptake process of DOX-HBPA-PEG by A549 cells showed that the micelle was totally swallowed in 1 h later. The controllable drug release nature, stability, biocompatibility and completely degradable structures (acid-sensitive) make them to be promising drug delivery systems.     

Synthesis and characterization of three novel amphiphilic dextran self-assembled micelles as potential drug delivery system

Three types of amphiphilic dextran derivatives were synthesized via the connection of different diamine compounds between the carboxyl group of stearic acid (SA) and aldehyde group of oxidized dextran. These three amphiphilic dextran derivatives self-assemble to form polymer micelles in aqueous medium. The critical micelle concentration depended on the graft ratio of SA, which ranged from 0.0700 to 0.158 mg mL^?1. These three amphiphilic dextran micelles can form typical core–shell structures of various sizes. Curcumin (Cur) was used as a model drug, and all amphiphilic micelle dextran derivatives had excellent drug loading capacity and drug encapsulation efficiency. The in vitro drug release from amphiphilic dextran derivatives/Cur micelles could be prolonged by adjusting the type of diamine compounds and composition of Cur content. These results show the superior properties of polymer micelles and suggest that these micelles are promising carriers for drug delivery systems.     

Preparation of methotrexate-loaded, large, highly-porous PLLA microspheres by a high-voltage electrostatic antisolvent process

A high-voltage (10 kV) electrostatic antisolvent process was used to prepare methotrexate (MTX)-loaded, large, highly-porous poly-l-lactide (PLLA) microspheres. MTX solution in dimethyl sulfoxide (DMSO) and PLLA solution in dichloromethane (DCM) were homogeneously mixed, and then ammonium bicarbonate (AB) aqueous solution was added. The mixed solution was emulsified by ultrasonication with Pluronic F127 (PF127) as an emulsion stabilizer. The emulsion was electrosprayed by the specific high-voltage apparatus and dropped into a 100 mL of ethanol, which acted as an antisolvent for the solute and extracted DMSO and DCM, causing the co-precipitation of PLLA and MTX, thus forming microspheres with AB aqueous micro-droplets uniformly inlaid. The obtained MTX–PLLA microspheres were subsequently lyophilized to obtain large, highly-porous MTX–PLLA microspheres, which exhibited an identifiable spherical shape and a rough surface furnished with open pores, with a mean particle size of 25.0 μm, mass median aerodynamic diameter of 3.1 ± 0.2 μm, fine-particle fraction of 57.1 ± 1.6 %, and porosity of 81.8 %; furthermore, they offered a sustained release of MTX. X-ray diffraction and Fourier transform-infrared spectra revealed that no crystallinity or alteration of chemical structure occurred during the high-voltage electrostatic antisolvent process, which in this study was proved to have great potential for preparing highly-porous drug-loaded polymer microspheres for use in pulmonary drug delivery.     

Folate-modified–chitosan-coated liposomes for tumor-targeted drug delivery

In this study, a folate-modified–chitosan-coated liposome (FCCL) was prepared for tumor-targeted drug delivery. The folate–chitosan conjugates were characterized using ¹H NMR and infrared spectrum analysis. The properties of folate–chitosan-coated liposomes (FCCLs) were studied and compared with those of traditional liposomes and chitosan-coated liposomes (CCLs). FCCLs were spherical in shape with a classic core–shell structure. Compared with conventional liposomes, FCCLs had larger size (average diameter: 182.0 nm), higher zeta potential (10.1 mV), prolonged drug release behaviors (55.76 % after 24 h), and better physical stability when stored at 25 °C, all similar to the properties of CCLs. With fluorescein as a model drug, fluorescein-loaded liposomes, CCLs, and FCCLs were prepared and their tumor targeting ability was evaluated according to the in vitro cellular uptake of fluorescein loaded nanoparticles by MCF-7 and HUVEC cells. Results demonstrated that FCCLs had a significant higher uptake by folate receptor positive cells (MCF-7) as compared to traditional liposomes and CCLs, which indicated that the FCCLs were promising nano-carriers for tumor-targeted drug delivery.     

pH-Sensitive biodegradable PMAA2-b-PLA-b-PMAA2 H-type multiblock copolymer micelles: synthesis,characterization, and drug release applications

pH-Sensitive biodegradable polymethacrylic acid-block-polylactic acid-block-polymethacrylic acid (PMAA₂-b-PLA-b-PMAA₂) H-type multiblock copolymers were synthesized by atom transfer radical polymerization. The copolymer structure and molecular weight were characterized by FT-IR, ¹H NMR, and gel permeation chromatography. The physicochemical characterization revealed that the copolymers could spontaneously form spherical core–shell micelles in aqueous solution, with critical aggregation concentration of about 19.7–32.5 mg L^?1 and the hydrodynamic diameters below 200 nm. Zeta potentials measurements disclosed that the copolymer micelles were negatively charged due to ionized carboxyl groups in various PBS solutions. The H-type block copolymer micelles exhibited pH- sensitivity, as expected; and the hydrophobic anticancer drugs, 10-hydroxycamptothecin, and paclitaxel, had faster release rate in PBS solution of pH 5.6–7.4 than in PBS of pH 1.4, which was important for applications in the therapy of small intestine cancers. The copolymer micelle aggregates were proved to be biodegradable, and the degradation rates changed with copolymer compositions and environmental media. The micelle drug formulation indicated pH-dependent cytotoxicity and was thus capable of effectively killing the intestinal cells while avoiding doing harm to stomach. The biodegradable pH-sensitive PMAA₂-b-PLA-b-PMAA₂ H-type copolymer micelles can be used as water-insoluble drug targeting release carriers for targeted treatment of intestine cancers.     

Preparation and evaluation of isoliquiritigenin-loaded F127/P123 polymeric micelles

Isoliquiritigenin (ISL) possesses a variety of pharmacological activities amid poor solubility in water which has restricted its clinical application. In this study, isoliquiritigenin-loaded F127/P123 polymeric micelles (ISL-FPM) were successfully prepared and evaluated in vitro and in vivo. The particle size, polydispersity index, and zeta potential of the selected formulation were 20.12?±?0.72?nm, 0.183?±?0.046, and ?38.31?±?0.33?mV, respectively, coupled with high encapsulation efficiency of 93.76?±?0.31%. Drug-loading test showed the solubility of ISL after formulating into micelles was 232 times higher than its intrinsic solubility. Moreover, critical micelle concentration (CMC) was tested with fluorescence probe method and turned out to be quite low, which implied high stability of ISL-FPM. Release profile in HCl (pH 1.2), double distilled water, and PBS (pH 7.4) of ISL-FPM reached over 80%, while free ISL was around 40%. Pharmacokinetic research revealed that formulated ISL-FPM significantly increased bioavailability by nearly 2.23-fold compared to free ISL. According to the results of in vitro antioxidant activity, scavenging DPPH activity of ISL was significantly strengthened when it was loaded into polymeric micelles. Altogether, ISL-FPM can act as a promising approach to improve solubility as well as enhance bioavailability and antioxidant activity of ISL.     

Co-delivery of hydrophilic and hydrophobic drugs by micelles: a new approach using drug conjugated PEG–PCLNanoparticles

Co-delivery strategy has been proposed to minimize the amount of each drug and to achieve the synergistic effect for cancer therapies. A conjugate of the antitumor drug, doxorubicin, with diblock methoxy poly (ethylene glycol)-poly caprolactone (mPEG-PCL) copolymer was synthesized by the reaction of mPEG–PCL copolymer with doxorubicin in the presence of p-nitrophenylchloroformate. The conjugated copolymer was characterized in vitro by ¹H-NMR, FTIR, DSC and GPC techniques. Then, the doxorubicin conjugated mPEG–PCL(DOX–mPEG-PCL) was self-assembled into micelles in the presence of curcumin in aqueous solution. The resulting micelles were characterized further by various techniques such as dynamic light scattering (DLS) and atomic force microscopy (AFM).The encapsulation efficiency of doxorubicin and curcumin were 82.31?±?3.32 and 78.15?±?3.14%, respectively. The results revealed that the micelles formed by the DOX–mPEG-PCL with and without curcumin have spherical structure with average size of 116 and 134?nm respectively. The release behavior of curcumin and doxorubicin loaded to micelles were investigated in a different media. The release rate of micelles consisted of the conjugated copolymer was pH dependent as it was higher at lower pH than in neutral condition. Another feature of the conjugated micelles was a sustained release profile. The cytotoxicity of micelles were evaluated by MTT (3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide, atetrazole) assay on lung cancer A549 cell lines. In vitro cytotoxicity assay showed that the mPEG–PCL copolymer did not affect the growth of A549 cells. The cytotoxic activity of the micelles against A549 cells was greater than free doxorubicin and free curcumin.     

Deoxycholic acid-grafted PEGylated chitosan micelles for the delivery of mitomycin C

Mitomycin C (MTC) was incorporated to a micelle system preparing from a polymer named deoxycholic acid chitosan-grafted poly(ethylene glycol) methyl ether (mPEG-CS-DA). mPEG-CS-DA was synthesized and characterized by ¹H nuclear magnetic resonance (¹H-NMR) and Fourier transform infrared spectroscopy. mPEG-CS-DA formed a core-shell micellar structure with a critical micelle concentration of 6.57?µg/mL. The mPEG-CS-DA micelles were spherical with a hydrodynamic diameter of about 231?nm. After poly(ethylene glycol)ylation of deoxycholic acid chitosan (CS-DA), the encapsulation efficiency and drug loading efficiency increased from 50.62% to 56.42% and from 20.51% to 24.13%, respectively. The mPEG-CS-DA micelles possessed a higher drug release rate than the CS-DA micelles. For pharmacokinetics, the area under the curve (AUC) of the mPEG-CS-DA micelles was 1.5 times higher than that of MTC injection, and these micelles can enhance the bioavailability of MTC. mPEG-CS-DA micelles reduced the distribution of MTC in almost all normal tissues and had the potential to improve the kidney toxicity caused by MTC injection.     

The in vitro therapeutic activity of betulinic acid nanocomposite on breast cancer cells (MCF-7) and normal fibroblast cell (3T3)

In the present study, magnetic nanoparticles (MNPs) were coated with chitosan (CS) polymer to form CS–MNP nanoparticles. The CS–MNP were loaded with an anticancer drug, betulinic acid (BA) to form a BA–CS–MNP nanocomposite. The prepared nanocomposite was characterized using XRD, FTIR, TGA, VSM, SEM, TEM, and zeta potential techniques. The release behavior of the BA from the nanocomposite was investigated at pH 7.4, and the study found that the release of BA followed a pseudo-second-order kinetic model. The potential cytotoxicity of free BA, MNPs, CS–MNP, and the BA–CS–MNP nanocomposite was evaluated using normal mouse fibroblast cells (3T3) and breast cancer cells (MCF-7). BA and the nanocomposite at concentrations in the range 0.781–50 μg mL^?1 did not affect the viability of normal cells during 72 h of incubation. The BA and BA–CS–MNP nanocomposite exhibited cytotoxicity in MCF-7 cells in a dose-dependent manner with IC₅₀ values of 2 and 3.6 μg mL^?1, respectively.     

Preparation,characterization, and pharmacokinetics study of a novel genistein-loaded mixed micelles system

Genistein (GEN), is a natural dietary isoflavone, has been reported to show anticancer activities. However, its poor aqueous solubility and oral bioavailability limit its clinical application. We designed a novel genistein-loaded mixed micelles (GEN-M) system composed of Soluplus^® and Vitamin E d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) were prepared by organic solvent evaporation aimed to overcome the challenges of GEN’s poor solubility and then further improve its oral bioavailability. The optimized, spherical-shaped GEN-M was obtained at a ratio of 10:1 (Soluplus^®:TPGS). The mean particle size of GEN-M was 184.7?±?2.8?nm, with a narrow polydispersity index (PDI) of 0.162?±?0.002. The zeta potential value of GEN-M was ?2.92?±?0.01?mV. The micelles solutions was transparent with blue opalescence has high the entrapment efficiency (EE) and drug loading (DL) of 97.12?±?2.11 and 3.87?±?1.26%, respectively. GEN-M was demonstrated a sustained release behavior when formed micelles shown in drug release in vitro. The solubility of GEN in water increased to 1.53?±?0.04?mg/mL after encapsulation. The permeability of GEN across a Caco-2 cell monolayer was enhanced, and the pharmacokinetics study of GEN-M showed a 2.42-fold increase in relative oral bioavailability compared with free GEN. Based on these findings, we conclude that this novel nanomicelles drug delivery system could be leveraged to deliver GEN and other hydrophobic drugs.     

Cuboidal lipid polymer nanoparticles of rosuvastatin for oral delivery

The present work aimed to develop and characterize sustained release cuboidal lipid polymeric nanoparticles (LPN) of rosuvastatin calcium (ROS) by solvent emulsification-evaporation process. A three factor, two level (2³) full-factorial design was applied to study the effect of independent variables, i.e. amount of lipid, surfactant and polymer on dependent variables, i.e. percent entrapment efficiency and particle size. Optimized formulations were further studied for zeta potential, TEM, in vitro drug release and ex vivo intestinal permeability. Cuboidal nanoparticles exhibited average particle size 61.37?±?3.95?nm, entrapment efficiency 86.77?±?1.27% and zeta potential ?6.72?±?3.25?mV. Nanoparticles were lyophilized to improve physical stability and obtain free-flowing powder. Effect of type and concentration of cryoprotectant required to lyophilize nanoparticles was optimized using freeze-thaw cycles. Mannitol as cryoprotectant in concentration of 5-8% w/v was found to be optimal providing zeta potential ?20.4?±?4.63?mV. Lyophilized nanoparticles were characterized using FTIR, DSC, XRD and SEM. Absence of C=C and C–F aromatic stretch at 1548 and 1197?cm^?1, respectively, in LPN indicated coating of drug by lipid and polymer. In vitro diffusion of ROS using dialysis bag showed pH-independent sustained release of ROS from LPN in comparison to drug suspension. Intestinal permeability by non-everted gut sac model showed prolonged release of ROS from LPN owing to adhesion of polymer to mucus layer. In vivo absorption of ROS from LPN resulted in 3.95-fold increase in AUC_0–last and 7.87-fold increase in mean residence time compared to drug suspension. Furthermore modified tyloxapol-induced rat model demonstrated the potential of ROS-loaded LPN in reducing elevated lipid profile.