Octadecyl Quaternized Carboxymethyl Chitosan Research Articles

Application of Paclitaxel-loaded EGFR Peptide-conjugated Magnetic Polymeric Liposomes for Liver Cancer Therapy.

Developing the methodologies that allow for safe and effective delivery of therapeutic drugs to target sites is a very important research area in cancer therapy. In this study, polyethylene glycol (PEG)-coated magnetic polymeric liposome (MPL) nanoparticles (NPs) assembled from octadecyl quaternized carboxymethyl chitosan (OQC), PEGylated OQC, cholesterol, and magnetic NPs, and functionalized with epithelial growth factor receptor (EGFR) peptide, were successfully prepared for in-vivo liver targeting. The two-step liver targeting strategy, based on both magnetic force and EGFR peptide conjugation, was evaluated in a subcutaneous hepatocellular carcinoma model of nude mouse. The results showed that EGFR-conjugated MPLs not only accumulated in the liver by magnetic force, but could also diffuse into tumor cells as a result of EGFR targeting. In addition, paclitaxel (PTX) was incorporated into small EGFR-conjugated MPLs (102.0±0.7 nm), resulting in spherical particles with high drug encapsulation efficiency (>90%). The use of the magnetic targeting for enhancing the transport of PTX-loaded EGFR-conjugated MPLs to the tumor site was further confirmed by detecting PTX levels. In conclusion, PTX-loaded EGFR-conjugated MPLs could potentially be used as an effective drug delivery system for targeted liver cancer therapy.

Liquid Crystalline Nanoparticles as an Ophthalmic Delivery System for Tetrandrine: Development, Characterization, and In Vitro and In Vivo Evaluation.

The purpose of this study was to develop novel liquid crystalline nanoparticles (LCNPs) that display improved pre-ocular residence time and ocular bioavailability and that can be used as an ophthalmic delivery system for tetrandrine (TET). The delivery system consisted of three primary components, including glyceryl monoolein, poloxamer 407, and water, and two secondary components, including Gelucire 44/14 and amphipathic octadecyl-quaternized carboxymethyl chitosan. The amount of TET, the amount of glyceryl monoolein, and the ratio of poloxamer 407 to glyceryl monoolein were selected as the factors that were used to optimize the dependent variables, which included encapsulation efficiency and drug loading. A three-factor, five-level central composite design was constructed to optimize the formulation. TET-loaded LCNPs (TET-LCNPs) were characterized to determine their particle size, zeta potential, entrapment efficiency, drug loading capacity, particle morphology, inner crystalline structure, and in vitro drug release profile. Corneal permeation in excised rabbit corneas was evaluated. Pre-ocular retention was determined using a noninvasive fluorescence imaging system. Finally, pharmacokinetic study in the aqueous humor was performed by microdialysis technique. The optimal formulation had a mean particle size of 170.0 ± 13.34 nm, a homogeneous distribution with polydispersity index of 0.166 ± 0.02, a positive surface charge with a zeta potential of 29.3 ± 1.25 mV, a high entrapment efficiency of 95.46 ± 4.13 %, and a drug loading rate of 1.63 ± 0.07 %. Transmission electron microscopy showed spherical particles that had smooth surfaces. Small-angle X-ray scattering profiles revealed an inverted hexagonal phase. The in vitro release assays showed a sustained drug release profile. A corneal permeation study showed that the apparent permeability coefficient of the optimal formulation was 2.03-fold higher than that of the TET solution. Pre-ocular retention capacity study indicated that the retention of LCNPs was significantly longer than that of the solution (p < 0.01). In addition, a pharmacokinetic study of rabbit aqueous humors demonstrated that the TET-LCNPs showed 2.65-fold higher ocular bioavailability than that of TET solution. In conclusion, a LCNP system could be a promising method for increasing the ocular bioavailability of TET by enhancing its retention time and permeation into the cornea.

A novel cationic nanostructured lipid carrier for improvement of ocular bioavailability: Design, optimization, in vitro and in vivo evaluation

The objective of this study was to prepare, optimize and evaluate a novel cationic nanostructured lipid carrier (CNLC) system, which can enhance the ophthalmic bioavailability of curcumin (CUR). CUR-loaded CNLC (CUR-CNLC) was prepared using a film-ultrasonic technique. A three-level Box-Behnken design was applied for optimization. The physicochemical properties, in vitro release and corneal permeation of the delivery method were evaluated. Preocular retention capacity study was conducted using a non-invasive fluorescence imaging system. Finally, a pharmacokinetic study in the aqueous humor was performed using a microdialysis technique. The optimal formulation had a mean particle size of 158.1 nm with a homogeneous distribution, a positive surface charge of 36.5 mV, a high entrapment efficiency of 99.12% and drug loading of 1.677%. Transmission electron microscope (TEM) morphology depicted a spherical morphology, and differential scanning calorimetry (DSC) indicated an imperfect crystalline lattice for the formulation. The CUR-CNLC formulation exhibited a sustained drug release and a 1.25-fold increase in in vitro corneal permeation (P < 0.05). The results from in vivo studies indicated the formulation had a high tolerance and a prolonged drug retention capacity in ocular tissues. A pharmacokinetic study of rabbit aqueous humors demonstrated a 2.36-fold increase in ocular bioavailability compared to a CUR solution (CUR-SOL, P < 0.01). The amphipathic octadecyl-quaternized carboxymethyl chitosan (QACMC) was used as a novel cationic material to prolong the residence time and improve the ocular bioavailability. Therefore, CNLC system is a promising approach for ocular delivery of CUR.

Codelivery of paclitaxel and small interfering RNA by octadecyl quaternized carboxymethyl chitosan-modified cationic liposome for combined cancer therapy.

Conventional therapeutic approaches for cancer are limited by cancer cell resistance, which has impeded their clinical applications. The main goal of this work was to investigate the combined antitumor effect of paclitaxel with small interfering RNA modified by cationic liposome formed from modified octadecyl quaternized carboxymethyl chitosan. The cationic liposome was composed of 3β-[N-(N', N'-dimethylaminoethane)-carbamoyl]-cholesterol, dioleoylphosphatidylethanolamine, and octadecyl quaternized carboxymethyl chitosan. The cationic liposome properties were characterized by Fourier transform infrared spectroscopy, dynamic light scattering and zeta potential measurements, transmission electron microscopy, atomic force microscopy, and gel retardation assay. The cationic liposome exhibited good properties, such as a small particle size, a narrow particle size distribution, a good spherical shape, a smooth surface, and a good binding ability with small interfering RNA. Most importantly, when combined with paclitaxel and small interfering RNA, the composite cationic liposome induced a great enhancement in the antitumor activity, which showed a significantly higher in vitro cytotoxicity in Bcap-37 cells than liposomal paclitaxel or small interfering RNA alone. In conclusion, the results indicate that cationic liposome could be further developed as a codelivery system for chemotherapy drugs and therapeutic small interfering RNAs.

Preparation and characterization of octadecyl quaternized carboxymethyl chitosan-mediated cationic liposomes for co-delivery of siRNA and paclitaxel

Blank cationic liposomes (CLP) formed from octadecyl quaternized carboxymethyl chitosan, dioleoyl-phosphatidylethanolamine and 3β-[N-(N′, N′-dimethylaminoethane)-carbamoyl] cholesterol were prepared by reverse phase evaporation. CLP containing paclitaxel (PTX), siRNA and PTX-siRNA complexes were prepared in the same manner. The series was characterized by dynamic light scattering, transmission electron microscopy, atomic force microscopy, gel retardation assay, high performance liquid chromatography, gas chromatography, confocal laser scanning microscopy and flow cytometry. The CLP possessed good sphericity, well-distributed particles with a size of about 80.0 nm, Zeta potential of up to 63.1 mV, siRNA loading efficiency of up to 91.6%, siRNA transfection efficiency of up to 70.74%, residual volume of trichloromethane of 5.0 μg/mL—below the minimum limit of 60 μg/mL—and an entrapment rate of PTX of 166.0 μg/mL.

Characterization and Bioactivity of Alginate-Quaternized Chitosan Microcapsules

Poly-L-lysine (PLL) can be replaced successfully by quaternized chitosan to prepare alginate-Ca microcapsules. By changing the compontent of quaternized chitosan mixture, including N-trimethylated chitosan, octadecyl quaternized carboxymethyl chitosan (OQC) and Poly(ethylene glycol) (PEG) modified OQC (PEG-OQC), different alginate-Ca microcapsules as carriers of cell transplantation can be obtained with diverse properties. Compared with alginate-PLL (AP), the mechanical strength of the alginate-quaternized chitosan (AQC) microcapsules was encouraging, and there was no apparent difference between AQC and AP microcapsules ( P < 0.05). The permeability of both microcapsules was observed in the presence of fluorescein isothiocyanate (FITC), immunoglobulin and bovine serum albumin (BSA) by fluorescent microscopy. Both microcapsules membranes were permeable to FITC, part-permeable to IgG and impermeable to larger molecule proteins such as BSA. The AQC and AP microcapsules entrapping L929 cells were cultured properly. L929 cells were retrieved from microcapsules and grew well after being recultured for 3 days.

Synthesis and characterization of PEG-graft-quaternized chitosan and cationic polymeric liposomes for drug delivery

Poly(ethylene glycol) grafted octadecyl quaternized carboxymethyl chitosan (PEG-g-OQC) copolymers were synthesized to both improve the biocompatibility of OQC and form PEGylated cationic polymeric liposomes (CPLs), which composed of the mixture of OQC, cholesterol, and PEG-g-OQC. Structure of the copolymers was characterized by using Fourier transform infrared spectroscopy (FTIR), proton nuclear magnetic resonance spectroscopy (1H-NMR), and X-ray diffraction (XRD). The methyl tetrazolium (MTT) assay with L929 cell lines confirmed that PEGylation can decrease the cytotoxicity of OQC. PEGylated CPL nanoparticles (NPs) can be prepared by adding different weight ratio of PEG-g-OQC in the mixture. Paclitaxel was successfully incorporated into PEGylated CPLs with high drug encapsulating efficiency (>90%) and drug loading capacity (>15%). Physical stability experiment showed that paclitaxel-loaded PEGylated CPLs was stable with little change of particle size and size distribution in the condition of freeze-dried by adding mannitol or in high temperature and high pressure. Power or reagent of drug-loaded PEGylated CPLs showed a slow steady release profile for paclitaxel. These results show that PEG-g-OQC and CPLs have potential application as a drug delivery vehicle. © 2012 Wiley Periodicals, Inc. J Appl Polym Sci, 2012

Characterization of Chitosan Polymeric Ethosomes Capable of Encapsulating Hydrophobic and Hydrophilic Drugs Prepared by a Microemulsion Method

Polymeric ethosomes,formed from amphiphilic octadecyl quaternized carboxymethyl chitosan (OQCMC)with different degrees of quaternary substitution(DS),were prepared by the microemulsion(ME) method.These ethosomes could simultaneously encapsulate both the hydrophobic drug indomethacin (IMC)and the hydrophilic drug vincristine(VCR).The effects of the DS of the OQCMC and primary alcohols as cosurfactants on the phase diagram were elucidated.The prepared nanoparticles(NPs)were small((52.40±0.55)nm)and suitable as drug carriers for different drugs.The maximum drug loading efficiencies of VCR-loaded and IMC-loaded NPs were 22.7%and 20.1%,respectively.The drug loading capacities for co-delivery of VCR and IMC were 12.2%and 10.0%,respectively.OQCMC polymeric ethosomes were stable in aqueous solution and exhibited slow,steady drug release.Hydrophilic fluorescein isothiocyanate(FITC)and hydrophobic Nile Red were encapsulated by the OQCMC ME NPs and simultaneously delivered into HO8901 cells with green and red fluorescence,respectively.This co-delivery system may allow for temporally distinct classes of drugs for cancer therapy.

PEGlated magnetic polymeric liposome anchored with TAT for delivery of drugs across the blood-spinal cord barrier

Due to the existence of the blood-spinal cord barrier (BSCB), many therapeutic macromolecular agents, such as drugs, protein and gene, cannot pass through this barrier to reach the site of injury, all of which restricts the treatment of spinal cord injuries (SCI). In this study, TAT-conjugated PEGlated Magnetic polymeric liposomes (TAT-PEG-MPLs) formed from PEGlated amphiphilic octadecyl quaternized carboxymethyl chitosan (PEG-OQCMC), cholesterol (Chol), superparamagnetic nanoparticles, and transactivating-transduction protein (TAT), were prepared successfully and evaluated the properties in vitro and in vivo. The result indicated that TAT-PEG-MPLs were spherical in solution, with significantly small mean diameter (83.2 nm) and excellent magnetism (magnetization saturation values of 43.5 emu/g). In vitro experiment, the uptake of PEG-MPLs with TAT by MCF-7 cells was greater than that of the PEG-MPLs without TAT. Most importantly, in vivo experiment, a low MRI signal was observed in the T2-weighted images; Histological analysis, Cryo-TEM and flame atomic absorption spectrophotometry revealed that TAT-PEG-MPLs nanoparticles significantly accumulated around the site of the SCI even inside the nerve cells. These nanoparticles may provide a promising carrier to locate to the lesion site, deliver therapeutic macromolecular agents across the BSCB and penetrate into the nerve cells for the treatment of SCI.

Development of monodispersed and functional magnetic polymeric liposomes via simple liposome method

We are reporting a simple and rapid method to prepare superparamagnetic, controlled size, and monodispersed magnetic cationic polymeric liposomes (MCPL) by octadecyl quaternized carboxymethyl chitosan (OQCMC) and cholesterol. The whole process is only about 25 min with simple thin-film dispersion and solvent evaporation method. Hydrophilic magnetic nanoparticles (LM) and hydrophobic magnetic nanoparticles (BM) can be encapsulated into these cationic polymeric liposomes, simultaneously or respectively. A model hydrophobic drug indomethacin can be successfully filled in MCPL with high drug loading capacity 22%. MCPL encapsulating BM also showed strong DNA (pEGFP) binding ability. Drug-loaded MCPL have a long and controlled sustained release profile by changing the number of polymeric lipid layer. These functional MCPL nanospheres can be allowed to serve as ideal candidates for many biomedical applications. A simple and rapid liposome method was reported to prepare superparamagnetic, controlled size, and monodispersed magnetic cationic polymeric liposomes (MCPL) by polymeric surfactant, octadecyl quaternized carboxymethyl chitosan (OQCMC), and cholesterol. Hydrophilic Fe3O4 ferrofluid and hydrophobic magnetic nanoparticles can be encapsulated into these cationic polymeric liposomes, simultaneously or respectively. Hydrophobic drug indomethacin can be encapsulated into this MCPL with high encapsulating efficiency and with controlled release profile by changing the number of polymeric lipid layer.

Characterization of Novel Multifunctional Cationic Polymeric Liposomes Formed from Octadecyl Quaternized Carboxymethyl Chitosan/Cholesterol and Drug Encapsulation

The design and construction of effective delivery vectors for drugs is very important. We have discovered that octadecyl quaternized carboxymethyl chitosan (OQCMC) in combination with cholesterol (Chol) could form stable vesicles with structure similar to that of conventional liposomes prepared from phosphatidylcholine/cholesterol (PC/Chol). Compared to conventional liposomes, our polymeric liposomes formed by OQCMC/Chol have many excellent features, such as good physical and thermal stability, excellent solubility in water, and high effectiveness in drug encapsulation. Trans-activating transcriptional activator protein (TAT peptide) could be connected on the surface of cationic polymeric liposomes by using cross-linking reagent N-hydroxysuccinimidyl-3-(2-pyridyldithio) propionate (SPDP). Also, oil-soluble magnetic nanoparticles were used to verify the bilayer structure of the polymeric liposomes and their ability to solublize hydrophobic materials. Using different preparation methods, OQCMC/Chol could easily be made into nanoscale particles by encapsulating both hydrophilic and hydrophobic components. We have successfully prepared polymeric liposomes encapsulating quantum dots (QDs), superparamagnetic nanoparticles, or both. Vincristine was also encapsulated in the polymeric liposomes with high drug encapsulation efficiency (90.1%). Vincristine-loaded magnetic polymeric liposomes were stable in aqueous solution and exhibited slow, steady release action over 2 weeks under physiologic pH (7.4). This allows the use of multifunctional cationic polymeric liposomes, such as those developed here from modified chitosan, in various applications such as cancer diagnosis and treatment.

Synthesis, Structure and Properties of Novel Quaternized Carboxymethyl Chitosan with Drug Loading Capacity

A modified approach to prepare novel amphipathic octadecyl-quaternized carboxymethyl chitosan (QACMC) was reported, in which carboxymethyl chitosan (CMC), prepared from chitosan, was made to react with glycidyl octadecyl dimethylammonium chloride; thus, the octadecyl quaternary ammonium group was introduced into CMC. The structure and thermal properties of these derivatives were characterized by Fourier transform infrared spectroscopy (FTIR), proton nuclear magnetic resonance spectroscopy ( 1H-NMR), X-ray diffraction (XRD), and differential scanning calorimetry (DSC). The crystalline properties of QACMC were perfect, and it had a high degree of crystallinity. All the chitosan derivatives had good thermal stability when the temperature was lower than 200 °C. The moisture-absorption and retention abilities of QACMC were lower than that of hyaluronic acid (HA) and CMC. The carboxymethyl and quaternary ammonium groups did not show a synergistic effect, and the effects of both the molar mass and the hydrophobic side chains of long alkyl moieties were important. Minocycline hydrochloride was successfully incorporated into QACMC polymeric micelles with a remarkably high efficiency (10.9%, mass fraction). QACMC promises to be a high-potential delivery vector for lipophilic drugs.