ABSTRACT
Cholesteryl hemisuccinate (CHS)-conjugated chitosan (CS)-based self-assembled nanoparticles (NPs) were developed for enhancing the intracellular uptake of docetaxel in multidrug resistance (MDR)-acquired cancer cells. CHS-CS was successfully synthesized and self-aggregation, particle size, zeta potential, drug entrapment efficiency, and in vitro drug release of docetaxel-loaded CHS-CS NPs were tested. The optimized NPs had a mean hydrodynamic diameter of 303 nm, positive zeta potential of 21.3 mV, and spherical shape. The in vitro release of docetaxel from the optimized CHS-CS NPs in different pH medium (pH 6.0 and 7.4) revealed that the release was improved in a more acidic condition (pH 6.0), representing a tumor cell's environment. The superior MDR-overcoming effect of docetaxel-loaded CHS-CS NPs, compared with docetaxel solution, was verified in anti-proliferation and cellular accumulation studies in MDR-acquired KBV20C cells. Thus, CHS-CS NPs could be potentially used for overcoming the MDR effect in anticancer drug delivery.
ABSTRACT
In this study, a redox-sensitive chitosan derivative with modifications by cholesterol, sulfhydryl, and mPEG (mPEG-CS(SH)-CHO) was successfully synthesized and characterized. Due to its amphiphilicity, the conjugate could spontaneously form micelles in an aqueous environment. The optimized paclitaxel (PTX)-loaded mPEG-CS(SH)-CHO micelles, with a mean diameter of 158 nm, zeta potential of +26.9 mV, drug loading of 11.7%, and entrapment efficiency of 88.3%, were successfully prepared. The results of an XRD study demonstrated that PTX was loaded in the core of the micelles in a non-crystalline state. Inspiringly, the PTX-loaded micelles possessed excellent anticancer effect but low toxicity to the body. It can be concluded that the mPEG-CS(SH)-CHO micellar system is a promising drug delivery carrier for the controlled release of PTX.
Subject(s)
Antineoplastic Agents/administration & dosage , Drug Delivery Systems , Hyaluronic Acid/chemistry , Micelles , Neoplasms/drug therapy , Neoplasms/metabolism , Oxidation-Reduction , Paclitaxel/administration & dosage , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Disulfides/chemistry , Hemolysis , Humans , In Vitro Techniques , MCF-7 Cells , Mice , Microscopy, Electron, Transmission , Polyethylene Glycols/chemistry , Polymers/chemistry , Rabbits , Tetrazolium Salts/chemistry , Thiazoles/chemistry , X-Ray DiffractionABSTRACT
Tumor-targeting micelles for the delivery of paclitaxel (PTX) were developed based on folic acid and α-tocopherol succinate conjugated hyaluronic acid (FA-HA-TOS). The conjugate FA-HA-TOS was synthesized by an esterification reaction and was characterized by proton nuclear magnetic resonance (1H NMR) and Fourier transform infrared (FT-IR) analysis. The conjugate self-assembles into nanosized micelles in aqueous medium with a critical micellar concentration (CMC) of 1.12 × 10-2 mg/mL. The FA-HA-TOS micelles demonstrated high drug loading and entrapment efficiency for PTX, with respective values of 21.37% and 90.48%. The physicochemical properties of the micelles were measured by DLS, TEM and XRD. Moreover, in vitro and in vivo evaluations were performed to demonstrate the superior antitumor activity of the PTX-loaded micelles. It was suggested that the FA-HA-TOS micelle system represents a promising nanocarrier for targeted delivery of PTX.
Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Drug Delivery Systems , Paclitaxel/pharmacology , alpha-Tocopherol/chemistry , Animals , Antineoplastic Agents, Phytogenic/chemistry , Cell Proliferation/drug effects , Cell Survival/drug effects , Drug Screening Assays, Antitumor , Folic Acid/chemistry , Humans , Hyaluronic Acid/chemistry , MCF-7 Cells , Male , Mice , Mice, Inbred Strains , Micelles , Molecular Structure , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/pathology , Paclitaxel/chemistry , Particle Size , Tumor Cells, CulturedABSTRACT
The present investigation aimed to develop a tumor-targeting drug delivery system for paclitaxel (PTX). The hydrophobic deoxycholic acid (DA) and active targeting ligand folic acid (FA) were used to modify water-soluble chitosan (CS). As an amphiphilic polymer, the conjugate FA-CS-DA was synthesized and characterized by Proton nuclear magnetic resonance (¹H-NMR) and Fourier-transform infrared spectroscopy (FTIR) analysis. The degree of substitutions of DA and FA were calculated as 15.8% and 8.0%, respectively. In aqueous medium, the conjugate could self-assemble into micelles with the critical micelle concentration of 6.6 × 10-3 mg/mL. Under a transmission electron microscope (TEM), the PTX-loaded micelles exhibited a spherical shape. The particle size determined by dynamic light scattering was 126 nm, and the zeta potential was +19.3 mV. The drug loading efficiency and entrapment efficiency were 9.1% and 81.2%, respectively. X-Ray Diffraction (XRD) analysis showed that the PTX was encapsulated in the micelles in a molecular or amorphous state. In vitro and in vivo antitumor evaluations demonstrated the excellent antitumor activity of PTX-loaded micelles. It was suggested that FA-CS-DA was a safe and effective carrier for the intravenous delivery of paclitaxel.
Subject(s)
Carcinoma, Hepatocellular/drug therapy , Deoxycholic Acid/chemistry , Drug Carriers/chemical synthesis , Folic Acid/chemistry , Liver Neoplasms/drug therapy , Paclitaxel/administration & dosage , Animals , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Chitosan/chemistry , Drug Carriers/chemistry , Female , Humans , Injections, Intravenous , MCF-7 Cells , Mice , Micelles , Neoplasm Transplantation , Paclitaxel/chemistry , Paclitaxel/pharmacology , Particle Size , Xenograft Model Antitumor AssaysABSTRACT
Amphiphilic polymer of α-tocopherol succinate modified glycol chitosan (TS-GC) was successfully constructed by conjugating α-tocopherol succinate to the skeleton of glycol chitosan and characterized by Fourier-transform infrared (FT-IR) and proton nuclear magnetic resonance (¹H-NMR). In aqueous milieu, the conjugates self-assembled to micelles with the critical aggregation concentration of 7.2 × 10−3 mg/mL. Transmission electron microscope (TEM) observation and dynamic light scattering (DLS) measurements were carried out to determine the physicochemical properties of the micelles. The results revealed that paclitaxel (PTX)-loaded TS-GC micelles were spherical in shape. Moreover, the PTX-loaded micelles showed increased particle sizes (35 nm vs. 142 nm) and a little reduced zeta potential (+19 mV vs. +16 mV) compared with blank micelles. The X-ray diffraction (XRD) spectra demonstrated that PTX existed inside the micelles in amorphous or molecular state. In vitro and in vivo tests showed that the PTX-loaded TS-GC micelles had advantages over the Cremophor EL-based formulation in terms of low toxicity level and increased dose, which suggested the potential of the polymer as carriers for PTX to improve their delivery properties.
Subject(s)
Chitosan/chemistry , Drug Delivery Systems , Micelles , Paclitaxel/administration & dosage , Polymers/chemistry , Animals , Antineoplastic Agents/pharmacology , Chitosan/chemical synthesis , Female , Glycerol/analogs & derivatives , Glycerol/pharmacology , Humans , Injections, Intravenous , MCF-7 Cells , Male , Mice , Particle Size , Polymers/chemical synthesis , Proton Magnetic Resonance Spectroscopy , Rabbits , Spectroscopy, Fourier Transform Infrared , Static Electricity , X-Ray Diffraction , alpha-Tocopherol/analogs & derivatives , alpha-Tocopherol/chemical synthesis , alpha-Tocopherol/chemistryABSTRACT
In this study, we designed and developed a new drug delivery system of multifunctional composite microcapsules for oral administration of insulin. Firstly, in order to enhance the encapsulation efficiency, insulin was complexed with functional sodium deoxycholate to form insulin-sodium deoxycholate complex using hydrophobic ion pairing method. Then the complex was encapsulated into poly(lactide-co-glycolide) (PLGA) nanoparticles by emulsion solvent diffusion method. The PLGA nanoparticles have a mean size of 168 nm and a zeta potential of -29.2 mV. The encapsulation efficiency was increased to 94.2% for the complex. In order to deliver insulin to specific gastrointestinal regions and reduce the burst release of insulin from PLGA nanoparticles, hence enhancing the bioavailability of insulin, enteric targeting multifunctional composite microcapsules were further prepared by encapsulating PLGA nanoparticles into pH-sensitive hydroxypropyl methyl cellulose phthalate (HP55) using organic spray-drying method. A pH-dependent insulin release profile was observed for this drug delivery system in vitro. All these strategies help to enhance the encapsulation efficiency, control the drug release, and protect insulin from degradation. In diabetic fasted rats, administration of the composite microcapsules produced a great enhancement in the relative bioavailability, which illustrated that this formulation was an effective candidate for oral insulin delivery.
Subject(s)
Capsules/chemistry , Diabetes Mellitus, Experimental/drug therapy , Insulin/administration & dosage , Nanoparticles/chemistry , Administration, Oral , Animals , Drug Liberation , Insulin/pharmacokinetics , Insulin/therapeutic use , Lactic Acid/chemistry , Male , Methylcellulose/analogs & derivatives , Methylcellulose/chemistry , Polyglycolic Acid/chemistry , Polylactic Acid-Polyglycolic Acid Copolymer , Rats , Rats, WistarABSTRACT
OBJECTIVE: To preliminarily develop a surfactant-free, polymeric solid dispersion (PSD) of paclitaxel suitable for oral administration. METHODS: A co-solvent quench method was applied to screen the proper polymer matrix of the PSD which were prepared in a liquid system using a quasi-emulsion solvent diffusion method (QESDM). Three dissolution experiments and two in vivo tests in rats were used to explain the differences among the formulations. RESULTS: The theoretical solubility ratio of amorphous/crystalline PTX was 92.6 (37 °C). Hydroxypropyl methylcellulose acetate succinate (HPMCAS) was chosen as the polymer carrier of the PSD and a porous silicon dioxide [called white carbon black (WCB)] was selectable to be used to further adjust the dissolution rate. The absolute oral bioavailability (AOB, 20 mg/kg) of the three formulas [HPMCAS/paclitaxel/WCB = 4/1/0 (F1), 8/1/0 (F2) and 4/1/4 (F3), w/w/w] were 11.8, 13.6 and 25.6%, respectively. The AOB of F3 is nearly seven times higher than that (3.8%) of paclitaxel material (a control). The advantage of higher HPMCAS/paclitaxel ratio of F2 in a dissolution test was not reflected in the first in vivo test due to the relatively higher dose of polymer which could not be effectively dissolved under the limitation of intestinal environment. This was deduced from the dissolution tests and was finally validated when the oral dose of PTX (and thus polymer) was reduced. The relevant AOBs (10 mg/kg) were 10.4, 20.8 and 19.6%, respectively. CONCLUSION: The PSD is a promising formulation strategy and the QESDM is a practical preparation method to implement such formulation design.
Subject(s)
Chemistry, Pharmaceutical/methods , Emulsions/chemical synthesis , Paclitaxel/chemical synthesis , Polymers/chemical synthesis , Solvents/chemical synthesis , Administration, Oral , Animals , Biological Availability , Diffusion , Emulsions/administration & dosage , Emulsions/pharmacokinetics , Male , Paclitaxel/administration & dosage , Paclitaxel/pharmacokinetics , Polymers/administration & dosage , Polymers/pharmacokinetics , Rats , Rats, Sprague-Dawley , Solvents/administration & dosage , Solvents/pharmacokineticsABSTRACT
In our previous study, α-tocopherol succinate modified chitosan (CS-TOS) was synthesized and encapsulated paclitaxel (PTX) to form micelles. Preliminary study revealed that the CS-TOS was a potential micellar carrier for PTX. In this study, some further researches were done using Taxol formulation as the control to evaluate the micelle system deeply. In vitro cell experiments demonstrated that the cytotoxic effect of PTX-loaded CS-TOS micelles against MCF-7 cells was comparable with that of Taxol formulation, and the PTX-loaded micelles had excellent cellular uptake ability, which was in a time-dependent manner. The in vivo pharmacokinetic study in rats showed that the micelles prolonged the half-life and increased AUC of PTX than Taxol formulation. From biodistribution study, it was clear that for micelles, the drug concentrations in the liver and spleen were significantly higher than those of Taxol formulation, but much lower in the heart and kidney. Furthermore, the PTX-loaded micelles showed superior antitumor effect, but yielded less toxicity as indicated by the results of antitumor efficacy study and survival study in U14 tumor-bearing mice. These results suggested that CS-TOS micelles could be a potentially useful drug delivery system to improve the performance and safety of PTX.
Subject(s)
Antineoplastic Agents, Phytogenic/administration & dosage , Antineoplastic Agents, Phytogenic/chemistry , Chitosan/chemistry , Paclitaxel/administration & dosage , Paclitaxel/chemistry , Succinic Acid/chemistry , alpha-Tocopherol/chemistry , Animals , Cell Line, Tumor , Chemistry, Pharmaceutical/methods , Drug Carriers/chemistry , Drug Delivery Systems/methods , Female , Half-Life , Humans , MCF-7 Cells , Mice , Micelles , Rats , Rats, Wistar , Tissue Distribution/physiologyABSTRACT
This study proposes a new concept of pH-sensitive poly(lactide-co-glycolide) (PLGA) nanoparticle composite microcapsules for oral delivery of insulin. Firstly, insulin-sodium oleate complex was prepared by the hydrophobic ion pairing method and then encapsulated into PLGA nanoparticles by the emulsion solvent diffusion method. In order to reduce the burst release of insulin from PLGA nanoparticles and deliver insulin to specific gastrointestinal regions, hence to enhance bioavailability of insulin, the PLGA nanoparticles were further encapsulated into Eudragit(®) FS 30D to prepare PLGA nanoparticle composite microcapsules by organic spray-drying method. The preparation was evaluated in vitro and in vivo, and the absorption mechanism was discussed. The in vitro drug release studies revealed that the drug release was pH dependent, and the in vivo results demonstrated that the formulation of PLGA nanoparticle composite microcapsules was an effective candidate for oral insulin delivery.
Subject(s)
Insulin , Lactic Acid/chemistry , Nanoparticles , Polyglycolic Acid/chemistry , Administration, Oral , Animals , Capsules/administration & dosage , Capsules/chemistry , Drug Carriers , Insulin/administration & dosage , Insulin/chemistry , Insulin/pharmacokinetics , Male , Nanoparticles/administration & dosage , Nanoparticles/chemistry , Polylactic Acid-Polyglycolic Acid Copolymer , Rats , Rats, WistarABSTRACT
This work presents new spherical nanoparticles that are fabricated from supramolecular self-assembly of therapeutic proteins for inhalation treatment. The formation involved self-assembly of insulin into nanospheres (INS) by a novel thermal induced phase separation method. Surface functional modification of INS with É-poly-L-lysine (EPL), a homopolymerized cationic peptide, was followed to form a core-shell structure (INS@EPL). Both INS and INS@EPL were characterized as spherical particles with mean diameter size of 150-250 nm. The process of transient thermal treatment did not change their biological potency retention significantly. FTIR and CD characterizations indicated that their secondary structures and biological potencies were not changed significantly after self-assembly. The in vivo investigation after pulmonary administration, including lung deposition, alveoli distribution, pharmacological effects and serum pharmacokinetics were investigated. Compared to that of INS, intratracheal administration of INS@EPL offered a pronounced and prolonged lung distribution, as well as pharmacological effects which were indicated by the 23.4% vs 11.7% of relative bioavailability. Accordingly, the work described here demonstrates the possibility of spherical supramolecular self-assembly of therapeutic proteins in nano-scale for pulmonary delivery application.
Subject(s)
Drug Delivery Systems , Insulin/therapeutic use , Lung/metabolism , Nanospheres/chemistry , Polylysine/chemistry , Animals , Blood Glucose/metabolism , Circular Dichroism , Diabetes Mellitus, Experimental/blood , Diabetes Mellitus, Experimental/drug therapy , Insulin/blood , Insulin/chemistry , Insulin/pharmacokinetics , Nanospheres/ultrastructure , Protein Structure, Secondary , Pulmonary Alveoli/drug effects , Pulmonary Alveoli/metabolism , Rats , Spectroscopy, Fourier Transform Infrared , Surface Properties , Sus scrofa , X-Ray DiffractionABSTRACT
Ligand grafted nanoparticles have been shown to enhance drug transport across epithelium barrier and are expected to improve drug delivery. However, grafting of these ligands to the surface of pure nanodrug, i.e., nanocrystals (NCs), is a critical challenge due to the shedding of ligands along with the stabilizer upon high dilution or dissolving of the drug. Herein, a non-sheddable nanocage-like stabilizer was designed by covalent cross-linking of poly(acrylic acid)-b-poly(methyl acrylate) on drug nanocrystal surface, and a ligand, wheat germ agglutinin (WGA), was successfully anchored to the surface of itraconazole (ITZ) NCs by covalent conjugation to the nanocage (WGA-cage-NCs). The cellular study showed that large amount of WGA-cage-NCs were adhered to Caco-2 cell membrane, and invaded into cells, resulting in a higher drug uptake than that of ordinary NCs (ONCs). After oral administration to rats, WGA-cage-NC were largely accumulated on the apical side of epithelium cells, facilitating drug diffusing across epithelium barrier. Interestingly, WGA-cage-NCs were capable of invading rat intestinal villi and reaching to lamina propria by transcytosis across goblet cells, which behaved like a foodborne pathogen, Listeria monocytogenes. The WGA-cage-NCs showed an improved oral bioavailability, which was 17.5- and 2.41-folds higher than that of coarse crystals and ONCs, respectively. To our best knowledge, this may represent the first report that a functional ligand was successfully anchored to the surface of pure nanodrug by using a cage-like stabilizer, showing unique biological functions in gastrointestinal tract and having an important significance in oral drug delivery.
Subject(s)
Intestinal Mucosa/metabolism , Listeria monocytogenes/physiology , Nanoparticles/chemistry , Absorption, Physiological/drug effects , Animals , Biological Transport/drug effects , Caco-2 Cells , Endocytosis/drug effects , Epithelial Cells/drug effects , Epithelial Cells/metabolism , Fluorescence , Humans , Intestinal Mucosa/drug effects , Intestinal Mucosa/pathology , Itraconazole/administration & dosage , Itraconazole/pharmacokinetics , Itraconazole/pharmacology , Male , Nanoparticles/ultrastructure , Particle Size , Rats, Sprague-Dawley , Static Electricity , Wheat Germ Agglutinins/chemistryABSTRACT
This review focuses on using precipitation (bottom-up) method to produce water-insoluble drug nanocrystals, and the stability issues of nanocrystals. The precipitation techniques for production of ultra-fine particles have been widely researched for last few decades. In these techniques, precipitation of solute is achieved by addition of a non-solvent for solute called anti-solvent to decrease the solvent power for the solute dissolved in a solution. The anti-solvent can be water, organic solvents or supercritical fluids. In this paper, efforts have been made to review the precipitation techniques involving the anti-solvent precipitation by simple mixing, impinging jet mixing, multi-inlet vortex mixing, the using of high-gravity, ultrasonic waves and supercritical fluids. The key to the success of yielding stable nanocrystals in these techniques is to control the nucleation kinetics and particle growth through mixing during precipitation based on crystallization theories. The stability issues of the nanocrystals, such as sedimentation, Ostwald ripening, agglomeration and cementing of crystals, change of crystalline state, and the approaches to stabilizing nanocrystals are also discussed in detail.
Subject(s)
Nanoparticles/chemistry , Pharmaceutical Preparations/chemistry , Technology, Pharmaceutical/methods , Water , Chemical Precipitation , Chemistry, Pharmaceutical , Crystallization , Drug Stability , Equipment Design , Models, Chemical , Particle Size , Pharmaceutical Preparations/standards , Solubility , Solvents/chemistry , Water/chemistryABSTRACT
The effect of polymorphism of glycerol monostearate (GMS) on drug incorporation and release from lipid matrix particles (LMPs) was investigated using fenofibrate as a model drug. X-ray powder diffraction and differential scanning calorimetry were used to study the polymorphism change of GMS and the drug incorporation in GMS matrix. When medium-chain triglycerides (MCT) was absent, melted GMS was frozen to α-form of GMS with drug molecularly dispersed, whereas ß-form of GMS was formed with part of drug crystallized out when the ratio of GMS/MCT in the lipid matrix was 2:1 (w/w). For LMP composed of GMS/MCT (2:1, w/w) prepared, GMS was in α-form when the particles were in nanometer range, whereas GMS was in ß-form when lipid particles were in micrometer range. The model drug was molecularly dispread in α-form lipid nanoparticles, whereas part of drug was expulsed out from microparticles because of the denser crystalline packing than α-form of GMS, and caused a faster drug release from lipid microparticles than that from nanoparticles. During the storage, the transformation of GMS from α-form into the more stable ß-form promoted drug expulsion and caused drug precipitation. In conclusion, the polymorphism of GMS is an important factor determining particle stability, drug incorporation, and the release of the drug from LMP. Critical attention should be paid on the investigation as well as control of the lipid polymorphism when formulating lipid-based matrix particles.
Subject(s)
Fenofibrate/administration & dosage , Glycerol/analogs & derivatives , Hypolipidemic Agents/administration & dosage , Nanoparticles/chemistry , Stearates/chemistry , Calorimetry, Differential Scanning , Crystallization , Drug Design , Drug Stability , Fenofibrate/chemistry , Glycerol/chemistry , Hypolipidemic Agents/chemistry , Indicators and Reagents , Microscopy, Electron, Transmission , Monoglycerides , Particle Size , Solubility , X-Ray DiffractionABSTRACT
It is a challenging and important project to prolong the in vivo half life of protein and peptide drugs by physicochemical methods without new molecular entities generation. Protein crystallization provides a new strategy for improving the stability and in vivo delivery of these drugs. We show here that recombinant human interferon-alpha (rhIFN) can form spherical crystals. The physical and chemical features of the crystals were characterized, and drug dissolution was determined in vitro. The pharmacokinetics of crystallized interferon after sc injection in rabbit at 1.5 x 10(7) U x kg(-1) was compared to that of soluble form. The crystals were characterized as mono-dispersed spheres, with yield of > 80%, mean diameter size of about 16 microm and crystallinity of 23.2%. The in vitro dissolution behavior of crystallized rhIFN was featured as low initial burst release (21% within the first 2 h) and prolonged cumulative dissolution time up to 72 h without biological potency lost. After sc administration of soluble and crystallized interferon in rabbits, the peak time (T(max)) and half life (t1/2) were prolonged from (1.80 +/- 0.45) h and (1.35 +/- 0.35) h to (13.20 +/- 2.68) h and (10.68 +/- 1.97) h, respectively. The corresponding peak concentration decreased from (1 411.10 +/- 575.28) U x mL(-1) to (721.37 +/- 206.55) U x mL(-1). PK/PD analysis indicated that (96.87 +/- 20.30) % of relative bioavailability was obtained. The research results of this work will provide important academic value and application prospect for improving clinical therapeutic effect and development of biomacromolecules delivery system for protein and peptide drugs.
Subject(s)
Antiviral Agents/administration & dosage , Drug Delivery Systems , Interferon-alpha/administration & dosage , Animals , Antiviral Agents/chemistry , Antiviral Agents/pharmacokinetics , Biological Availability , Crystallization , Delayed-Action Preparations , Half-Life , Humans , Injections, Subcutaneous , Interferon-alpha/chemistry , Interferon-alpha/pharmacokinetics , Male , Rabbits , Recombinant Proteins/administration & dosage , Recombinant Proteins/chemistry , Recombinant Proteins/pharmacokinetics , Solubility , Surface PropertiesABSTRACT
PURPOSE: To make a comparative study on sustained delivery performance of rhIFN with random amorphous and spherical crystal-like ordered self-assemblies. METHODS: The rhIFN self-assemblies were identified in batch crystallization mode. Physico-chemical characteristics were compared, including morphology, XRD, FTIR, CD, biological potency, the dissolution behaviors in vitro and plasma pharmacokinetics in vivo. Moreover, molecular simulation was performed to better understand their binding site and mode. RESULTS: Here, we suggest that random amorphous and spherical ordered self-assemblies allow for long action without new molecular entities generation or carriers employed. By manipulating supersaturation, the ordered aggregates were self-organized at high concentration of Zn(II) (>100 mM) in pH 5.5-6.0, which was the first time that spherical semi-crystals of rhIFN can act as a depot source for the sustained delivery of biologically active proteins. The secondary structure and biological potency of rhIFN were unchanged after aggregation. Compared with that of the native rhIFN, both self-assemblies exhibited slower absorption and extended elimination profiles after s.c. administration, which were characterized as 4.75 ± 0.82 h and 10.58 ± 1.86 h of terminal half-life for random amorphous and spherical ordered self-assemblies, respectively. CONCLUSIONS: The work described here demonstrates the possibility of self-assemblies of biomacromolecules for controllable release application of therapeutic proteins.
Subject(s)
Antiviral Agents/administration & dosage , Delayed-Action Preparations/chemistry , Interferons/administration & dosage , Metals/chemistry , Animals , Antiviral Agents/chemistry , Antiviral Agents/pharmacokinetics , Antiviral Agents/pharmacology , Cell Line , Humans , Interferons/chemistry , Interferons/pharmacokinetics , Interferons/pharmacology , Ions/chemistry , Protein Structure, Secondary , Rabbits , Recombinant Proteins/administration & dosage , Recombinant Proteins/chemistry , Recombinant Proteins/pharmacokinetics , Recombinant Proteins/pharmacologyABSTRACT
PURPOSE: To develop an osmotically-driven pellet coated with polymeric film for sustained release of oxymatrine (OMT), a freely water soluble drug. METHODS: Pellet containing OMT and sodium chloride (NaCl), an osmotically active agent, were prepared by extrusion/spheronization and then coated with acrylic copolymers (Eudragit(®) RS 30 D) by the fluidized bed coating process. In vitro release and swelling behavior studies were employed to optimize and to evaluate the sustained-release behavior from the osmotically-driven pellets with film coated. Finally, in vivo evaluation in rabbits was employed to investigate the sustained plasma level of OMT and its active metabolite matrine. RESULTS: It was found that the F3 formulation, prepared with 20% NaCl and an 8% coating level, showed a continuous NaCl-induced water influx into the pellets providing a gradual sustained release of OMT for over 12 h. Finally, we confirmed that oral OMT with sustained release led to a gradual sustained plasma profile of both OMT, with a reduction in its bioavailability, and MT with an increase in the bioavailability compared with that of oral OMT with immediate release. CONCLUSIONS: The pharmaceutical parameters obtained suggested the potential usefulness of oral OMT with sustained release for the treatment of stress ulcers, as well as reducing the risk of MT-induced side effects.
Subject(s)
Acrylic Resins/administration & dosage , Alkaloids/administration & dosage , Quinolizines/administration & dosage , Stomach Ulcer/drug therapy , Stress, Psychological/complications , Alkaloids/chemistry , Alkaloids/pharmacokinetics , Animals , Delayed-Action Preparations , Male , Osmotic Pressure , Quinolizines/chemistry , Quinolizines/pharmacokinetics , Rabbits , Sodium Chloride/pharmacology , SolubilityABSTRACT
Achieving effective controllable delivery of therapeutic biomacromolecules for long action without new molecular entities generation or carriers employed offers a promising alternative and significant clinical benefit. We show here that recombinant human interferon-alpha (rhIFN) can form a three dimensional ordered structure that is featured by spherical semi-crystalline through molecular self-assembly directed by a polycationic short peptide. The phase diagrams for self-assembly were constructed to identify the optimal regions for nucleation and ordered growth, and which were followed by the physico-chemical characterization of the ordered self-assemblies, including morphology, particle size, X-ray diffraction, circular dichroism and biological potency evaluations. With varied molar ratio of the two composed biomacromolecules, the dissolution behaviors of the self-assemblies could be manipulated in vitro and in vivo. The plasma pharmacokinetics suggested that s.c. administration of self-assemblies at the specified relative proportion of rhIFN to polycationic peptide offered a significant prolonged duration time of rhIFN blood levels up to seven days. Moreover, molecular simulation was performed to better understand their binding site and mode. The work described here demonstrates the possibility of spherical ordered self-assembly of biomacromolecules for controllable delivery application of therapeutic proteins.
Subject(s)
Interferon-alpha/chemistry , Peptides/chemistry , Polyamines/chemistry , Recombinant Proteins/chemistry , Circular Dichroism , Enzyme-Linked Immunosorbent Assay , Humans , Polyelectrolytes , X-Ray DiffractionABSTRACT
A two-phase delivery system involving local injections of solid lipid nanoparticles (SLNs) -loaded hydrogel was developed using 2-methoxyestradiol as a model anticancer drug. This approach improves the effectiveness of conventional treatments for subcutaneous tumors and avoids that solid lipid nanoparticles are rapidly cleared from the circulation following systemic administration. The specific aim of the study presented in this article was to investigate the in vivo release, delivery and antitumor effects of 2-ME SLNs entrapped in a hydrogel. The results indicated that the hydrogel could deliver fluorescence-marked SLNs to tumor masses and cancer cells, exhibiting a controlled release of 2-ME SLNs over 46 days following a zero-order model. After treatment with the 2-ME SLN-loaded hydrogel, BALB/c mice that had been inoculated with syngeneic 4T1 breast cancer cells displayed significantly more tumor growth suppression for at least 21 days than those treated with a hydrogel containing the free drug, which was consistent with the in vitro cytotoxicity of 2-ME SLNs. This experiment demonstrated the efficacy of the hydrogel as a depot of 2-ME SLNs. Additionally, the mice treated with the hydrogel did not exhibit a loss of body weight or abnormal levels of white blood cells compared to the control group. These experiments demonstrated the potential value of 2-ME SLN hydrogel local injections as a safer and more effective method for the chemotherapy of subcutaneous tumors.
Subject(s)
Antineoplastic Agents/administration & dosage , Body Temperature Regulation , Estradiol/analogs & derivatives , Hydrogels/administration & dosage , Nanoparticles/administration & dosage , 2-Methoxyestradiol , Animals , Body Temperature Regulation/drug effects , Body Temperature Regulation/physiology , Cell Line, Tumor , Cell Survival/drug effects , Cell Survival/physiology , Delayed-Action Preparations/administration & dosage , Estradiol/administration & dosage , Female , Mice , Mice, Inbred BALB C , Xenograft Model Antitumor Assays/methodsABSTRACT
The amorphous-to-crystalline transformation of nitrendipine was investigated using Raman spectroscopy and X-ray powder diffraction (XRPD). The nucleation and growth rate of crystalline nitrendipine in a medium containing poly (vinyl alcohol) (PVA) and polyethylene glycol (PEG 200) were quantitatively determined using image analysis based on polarized light microscopy. The findings from the image analysis revealed that the transformation process occurred through the dissolution of amorphous drug precipitate followed by the nucleation and growth of the crystalline phase with the amorphous precipitate acting as a reservoir for maintaining the supersaturation. The rates of nucleation and crystal growth of nitrendipine decreased with an increase in PEG 200 concentration in organic phase from 0% to 75% (v/v). Increasing the PVA concentration in water phase from 0.1% to 1.0% (w/w) also decreased the rates of nucleation and crystal growth, however, an increase in PVA concentration from 1.0% to 2.0% (w/w) did not result in a further decrease in the rates of nucleation and crystal growth. An increase in drug concentrations in the organic phase from 10 mg/ml to 30 mg/ml led to faster nucleation rates. However, a further increase in drug concentration to 100mg/ml decelerated the growth of nitrendipine crystals. Combining image analysis of polarized light micrographs together with Raman spectroscopy and XRPD provided an in-depth insight into solid state transformations in amorphous nitrendipine suspensions.