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Purpose: To synthesize and characterize an effective macromolecular magnetic resonance imaging (MRI) contrast agent based on oligoethylenimine-grafted chitosan with targeting capability., Materials and Methods: In this study we synthesized and characterized oligoethylenimine-grafted chitosan copolymers, followed by conjugating with Gd-DTPA and folic acid. The toxicity was evaluated by WST assay, and in vitro MRI studies were performed in comparison with Gd-DTPA. Finally, the contrast enhancement of the new macromolecular MRI contrast agent was then evaluated in the mice bearing KB xenografts., Results: Compared to Gd-DTPA (4.3 mM(-1) s(-1) ), this macromolecular contrast agent (mCA) exhibited much higher T1 relaxivity (14.4 mM(-1) s(-1) ), up to 3.3 times higher. Meanwhile, the WST assay illustrated that the viability of KB cells remained at 90% even when the Gd concentration was 1 mM. During the in vivo study, the image contrast produced by FA-mCA was higher than one produced by mCA, up to 2.5 times higher., Conclusion: Our results showed this macromolecular contrast agent has potential for developing sensitive and biocompatible MRI probe with targeting capability. J. Magn. Reson. Imaging 2016;44:23-29., (© 2015 Wiley Periodicals, Inc.)

A series of melphalan-O-carboxymethyl chitosan (Mel-OCM-chitosan) conjugates with different spacers were prepared and structurally characterized. All conjugates showed satisfactory water-solubility (160-217 times of Mel solubility). In vitro drug release behaviors by both chemical and enzymatic hydrolysis were investigated. The prodrugs released Mel rapidly within papain and lysosomal enzymes of about 40-75%, while released only about 4-5% in buffer and plasma, which suggested that the conjugates have good plasma stability and the hydrolysis in both papain and lysosomes occurs mostly via enzymolysis. It was found that the spacers have important effect on the drug content, water solubility, drug release properties and cytotoxicity of Mel-OCM-chitosan conjugates. Cytotoxicity studies by MTT assay demonstrated that these conjugates had 52-70% of cytotoxicity against RPMI8226 cells in vitro as compared with free Mel, indicating the conjugates did not lose anti-cancer activity of Mel. Overall these studies indicated Mel-OCM-chitosan conjugates as potential prodrugs for cancer treatment., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

In this work, an amphiphilic polymeric prodrug Cis-3-(9H-purin-6-ylthio)-acrylic acid-graft-carboxymethyl chitosan (PTA-g-CMCS) was designed and synthesized. In aqueous solution, this grafted polymer can self-assemble into spherical micelles with a size ranging from 104 to 285 nm and zeta potential ranging from -12.3 to -20.1 mV. For the release study, less than 24% of 6-Mercaptopurine (6-MP) was released from PTA-g-CMCS1 in the media containing 2 and 100 μM glutathione (GSH), whereas 37%, 54% and 75% of 6-MP was released from the media with GSH of 1, 2 and 10mM, respectively. Besides, pH and drug content of the polymeric prodrug only presented slight influence on the 6-MP release. MTT assay demonstrated that this system had higher inhibition ratio on HL-60 cells (human promyelocytic leukemia cells) in the presence of GSH and lower cytotoxicity on mouse fibroblast cell line (L929). Therefore, this nano-sized system is glutathione-dependent, and it can be employed as a potential carrier for the controlled release of 6-MP., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Through incorporating lactobionic acid (LA) bearing a galactose group to N-succinyl-chitosan-graft-polyethylenimine (NSC-g-PEI), NSC-g-PEI-LA copolymers were synthesized as gene vectors with hepatocyte targeting properties. The molecular weight and composition of NSC-g-PEI-LA copolymers were characterized using gel permeation chromatography (GPC) and (1)H nuclear magnetic resonance spectroscopy ((1)H NMR) respectively. Agarose gel electrophoresis assays showed good DNA binding ability of NSC-g-PEI-LA, and the particle size of the NSC-g-PEI-LA/DNA complexes were between 150 and 400 nm as determined by a Zeta sizer. The NSC-g-PEI-LA/DNA complexes observed by scanning electron microscopy (SEM) exhibited a compact and spherical morphology. The zeta potentials of these complexes were increased with the weight ratio of NSC-g-PEI-LA/DNA. NSC-g-PEI-LA has a lower cytotoxicity than PEI (25 kDa) and the toxicity decreased with increasing substitution of LA. The transfection efficiency of different complexes was evaluated by luciferase assay. Compared with PEI (25 kDa) and NSC-g-PEI/DNA, NSC-g-PEI-LA showed good transfection activity and cell specificity to HepG2 cells. The results suggested that NSC-g-PEI-LA has the potential to be used as a safe and effective targeting gene vector.

A series of chitosan-based oligoamine polymers was synthesized from N-maleated chitosan (NMC) via Michael addition with diethylenetriamine (DETA), triethylenetetramine (TETA), tetraethylenepentamine (TEPA) and linear polyethylenimine (M(n) 423), respectively. The resulted polymers exhibited well binding ability to condense plasmid DNA to form complexes with size ranging from 200 to 600 nm when the polymer/DNA weight ratio was above 7. The polymer/DNA complexes observed by scanning electron microscopy (SEM) exhibited a compact and spherical morphology. The cytotoxicity assay showed that the synthesized polymers were less toxic than that of PEI(25 K). The gene transfection effect of resulted polymers was evaluated in 293T and HeLa cells, and the results showed that the gene transfection efficiency of these polymers was better than that of chitosan. Moreover, the transfection efficiency was dependent on the length of the oligoamine side chains and the molecular weight of the chitosan derivatives.

Low transfection efficiency and inactivation by serum are the major drawbacks for cationic polymers when used as non-viral gene vectors. Here, a series of N-succinyl-chitosan-graft-polyethylenimine (NSC-g-PEI) copolymers with different compositions were synthesized through grafting low molecular weight PEI (800 Da) to N-succinyl-chitosan. An agarose gel electrophoresis assay showed NSC-g-PEIs had good binding capability with DNA and the particle size of the NSC-g-PEI-DNA complexes was between 150 to 300 nm as determined by a Zeta sizer. In vitro transfection of NSC-g-PEI-DNA complexes for 293T, HeLa and CHO cells was investigated. It was found that the transfection efficiency of NSC-g-PEI-DNA complexes was higher than that of DNA combined PEI (25 kDa) and the transfection efficiency increased with the increasing GD of PEI. More importantly, the NSC-g-PEI-DNA complexes were stable and the transfection efficiency was not affected obviously in the presence of serum with different concentrations. In addition, NSC-g-PEIs had a lower cytotoxicity than PEI (25 kDa) and the toxicity increased with increasing GD of PEI. The NSC-g-PEI copolymers will have a good potential as efficient non-viral gene vectors in the presence of serum.

To develop chitosan-based efficient gene vectors, chitosans with different molecular weights were chemically modified with low molecular weight polyethylenimine. The molecular weight and composition of polyethylenimine grafted N-maleated chitosan (NMC-g-PEI) copolymers were characterized using gel permeation chromatography (GPC) and (1)H NMR, respectively. Agarose gel electrophoresis assay showed that NMC-g-PEI had good binding ability with DNA, and the particle size of the NMC-g-PEI/DNA complexes was 200-400 nm, as determined by a Zeta sizer. The nanosized complexes observed by scanning electron microscopy (SEM) exhibited a compact and spherical morphology. The NMC-g-PEI copolymers showed low cytotoxicity and good transfection activity, comparable to PEI (25 KDa) in both 293T and HeLa cell lines, except for NMC 50K-g-PEI. The results indicated that the molecular weight of NMC-g-PEI has an important effect on cytotoxicity and transfection activity, and low molecular weight NMC-g-PEI has a good potential as efficient nonviral gene vectors.

The use of methotrexate (MTX), an anticancer drug for the treatment of hematologic malignancies, has been limited in the clinical application due to its poor water solubility, high clearance rate, and lack of target specificity. To solve these problems, O, N-carboxymethyl chitosan-dipeptide-MTX conjugates have been synthesized and characterized by fourier transform infrared radiation spectroscopy and proton nuclear magnetic resonance (H NMR). All polymeric conjugates showed satisfactory water solubility. The results of the study revealed that drug release and toxicity were affected by employing polymeric conjugation strategy and dipeptide spacers [glycylglycine (Gly-Gly), glycyl- l-phenylalanine (Gly-Phe), glycyl- l-tyrosine (Gly-Tyr)]. It has been found that drugs could be effectively loaded and released when polymeric prodrugs were combined with a dipeptide spacer. In conclusion, O, N-CMCS-dipeptide-MTX polymeric prodrugs could potentially be used as responsive drug delivery systems. [ABSTRACT FROM AUTHOR]

A bipolar membrane (BPM) of carboxymethyl cellulose (CMC) and chitosan (CS) with superior performance was prepared based on the macromolecules containing metal elements. A carboxymethyl cellulose cation layer was modified by copper phthalocyanine 16-carboxylic acid (CuPc(COOH)16) to improve its ion exchange capacity as well as cation transfer rate and promote water splitting at the intermediate layer. Chitosan was crosslinked with acetyl ferrocene to prepare the anion layer. A casting method was used to prepare the BPM which showed excellent physical and chemical properties after modification. To improve the compatibility of the anion-exchange layer and cation-exchange layer, polyethylene glycol (PEG) was blended with both the CMC and CS. Scanning electron microscopy (SEM) images illustrated a structure that consisted of an anion layer and a cation layer that were closely combined with each other. The swelling results implied a proper hydrophilic performance and good shape stability in an alkali solution ([OH−]≤10 mol·L−1) of the BPM. After modification, the BPM with the metal elements exhibited good thermal stability, as shown by the thermogravimetry (TG) results. Compared with the BPM that was unmodified, both the AC impedance and the working voltage were decreased sharply. Furthermore, the modified BPM exhibited higher ion penetrability which is beneficial for its wide application. [ABSTRACT FROM AUTHOR]

Abstract: Three novel diamine-modified chitosan derivatives were synthesized from N-maleyl chitosan via Michael addition reaction with 1,2-diaminoethane, 1,4-diaminobutane, and 1,6-diaminohexane, respectively. These chitosan derivatives exhibited well binding ability of condensing plasmid DNA to form complexes with size ranging from 150 to 500nm when the chitosan derivative/DNA weight ratios were above 10. The complexes observed by scanning electron microscopy (SEM) exhibited a compact and spherical morphology. The cytotoxicity of the chitosan derivatives presented a dependence on their side-chain structures. The gene transfection experiments were evaluated in 293T and HeLa cells. The data obtained demonstrated that the gene transfection efficiencies of these chitosan derivatives were better than that of chitosan, suggesting these chitosan derivatives as potential gene vectors in vitro. [Copyright &y& Elsevier]

The combination of chemotherapy and phototherapy has become a promising cancer treatment strategy. In this study, a pH/NIR dual-responsive hollow mesoporous silica nanoparticles (HMSNs) based nanocarrier for co-delivering doxorubicin hydrochloride (DOX) and indocyanine green (ICG) was developed. DOX was loaded for chemotherapy and ICG for photothermal therapy (PTT) and photodynamic therapy (PDT). This system targets the asialoglycoprotein receptor (ASGPR) in over-expressing human hepatocellular liver carcinoma cells (HepG2) by linking HMSNs and lactobionic acid (LA)-modified dialdehyde chitosan (DACS) via Schiff base bonds. It is demonstrated that HMSNs-DACS-LA have been successfully prepared through various physical characterizations. Drug release tests revealed that it had the characteristics of properties of pH/NIR dual-responsive. In vitro cellular uptake and cytotoxicity assay showed that ID@HMSNs-DACS-LA could target HepG2 cells and reduced the activity of tumor cells. Therefore, co-delivery of ICG and DOX via HMSNs-DACS-LA nanocarriers may provide a feasible strategy for tumor-targeted combined chemotherapy and phototherapy. Preparation of ID@HCL with dual-responsive and targeting function can be used for chemotherapy and phototherapy of tumor cells [Display omitted] • A dual-responsive Hollow mesoporous silica nanoparticles was designed. • Combination therapy could enhance the anti-tumor effect significantly. • Lactobionic acid could improve nanoparticle ability to target tumor cells. [ABSTRACT FROM AUTHOR]

Abstract: The liver targeting and controlled release nanoparticles based on carboxymethyl chitosan derivatives were prepared: firstly, novel thiolated lactosaminated carboxymethyl chitosan (LAC-CMC) was synthesized, its chemical structure was characterized by 1H NMR spectroscopy. Then, glycyrrhizic acid was chosen as model drug and encapsulated within thiolated LAC-CMC nanoparticles through ionic gelification. The crosslinked glycyrrhizic acid-loaded nanoparticles dissociated to release drug in the presence of glutathione (GSH) at a concentration comparable to the intracellular environment, featuring the potential ability of this system for intracellular delivery. Crosslinked nanoparticles modify the tissue distribution profile of the glycyrrhizic acid solution, the kidney excretion rate is reduced and the drug accumulation in the liver is increased. According to these results, the nanoparticles have the potential to be used as drug delivery system with hepatic targeting and controlled release properties. [Copyright &y& Elsevier]

Abstract: A series of 6-mercaptopurine-carboxymethyl chitosans (6-MP-CMC) were prepared and structurally characterized. Their in vitro drug release behaviors in the buffer solutions containing glutathione (GSH) were investigated. 6-MP-CMC did not release any 6-MP in the media without GSH and containing 2μM GSH. By comparison, the obvious 6-MP release could be observed within an hour in the media containing 2mM and 10mM GSH. And the maximum cumulative release rates were 65.1% and 74.4%, respectively. The buffer pH and the 6-MP content in 6-MP-CMC had obvious influences on the 6-MP release. At 10mM GSH, the maximum cumulative release rate at pH 5 was higher than that at pH 7.4. 6-MP-CMC in pH 7.4 PBS could self-assemble into nanoparticles. Their mean hydrodynamic diameter determined by dynamic light scattering (DLS) was 155.8±6.0nm. The particles observed by transmission electron microscopy (TEM) were spherical in shape and had the size of about 100nm. [ABSTRACT FROM AUTHOR]

Abstract: Galactose group was coupled with carboxymethyl chitosan for liver specificity. The chemical structure of lactosaminated carboxymethyl chitosan (LAC-CMC) was characterized by FT-IR and 1H NMR techniques. Glycyrrhizic acid was chosen as model drug and encapsulated within LAC-CMC nanoparticles through ionic gelification. Transmission electron microscope (TEM) and dynamic light scattering (DLS) were employed to characterize the nanoparticles for morphology and size. The effects, including LAC-CMC molecular weight (MW), glycyrrhizic acid concentration and LAC-CMC concentration on the physicochemical properties of the nanoparticles were studied. Glycyrrhizic acid release from the nanoparticles exhibited a biphasic pattern, initial burst release and consequently sustained release. Glycyrrhizic acid-loaded nanoparticles modify the tissue distribution profile of the glycyrrhizic acid solution, the kidney excretion rate is reduced and drug accumulation in the liver is increased. The experimental results show that the novel lactosaminated carboxymethyl chitosan nanoparticles may be used as a potential drug delivery system with hepatic targeting properties. [Copyright &y& Elsevier]