Xiqun Jiang

Synthesis and characterization of chitosan-poly(acrylic acid) nanoparticles.

Chitosan (CS)-poly(acrylic acid) (PAA) complex nanoparticles, which are well dispersed and stable in aqueous solution, have been prepared by template polymerization of acrylic acid (AA) in chitosan solution. The physicochemical properties of nanoparticles were investigated by using size exclusion chromatography, FT-IR, dynamic light scattering, transmission electron microscope and zeta potential. It was found that the molecular weight of PAA in nanoparticles increased with the increase of molecular weight of CS, indicating that the polymerization of acrylic acid in the chitosan solution was a template polymerization. It was also found that the prepared nanoparticles carried a positive charge and showed the size in the range from 50 to 400 nm. The surface structure and zeta potential of nanoparticles can be controlled by different preparation processes. The experiment of in vitro silk peptide (SP) release showed that these nanoparticles provided a continuous release of the entrapped SP for 10 days, and the release behavior was influenced by the pH value of the medium.

Preparation and drug release behaviors of nimodipine-loaded poly(caprolactone) poly(ethylene oxide) polylactide amphiphilic copolymer nanoparticles

Amphiphilic block copolymers, poly(caprolactone)-poly(ethylene glycol)-poly(lactide) (PCELA), were synthesized by ring opening polymerization of caprolactone and lactide initiated with the hydroxyl groups of poly(ethylene glycol) (PEG). These copolymers could form micelle-like nanoparticles due to their amphiphilic characteristic. From the observation of transmission electron microscopy (TEM), the nanoparticles exhibited a regular spherical shape with core-shell structure. The critical micelle concentrations (CMC) of these nanoparticles in water were decreased as molecular weight of PEG decreased. The particle sizes obtained by dynamic light scattering of these nanoparticles were in the range of 100-200 nm, and increased as the hydrophobic property of the nanoparticles increased. Nimodipine as a model drug was loaded in these nanoparticles to investigate the drug release behavior. It was found that the chemical composition of the nanoparticles was a key factor in controlling nanoparticle size, nanoparticle yields, drug-entrapment efficiency, and drug release behavior. When the PEG content is about 2% (wt), the release profile of PCELA nanoparticles appeared to follow zero-order kinetics.

Cellular uptake, antitumor response and tumor penetration of cisplatin-loaded milk protein nanoparticles.

The casein nanoparticles cross-linked by transglutaminase were prepared, and cisplatin (CDDP), as a model antitumor drug, was loaded into the casein nanoparticles. These nanoparticles were characterized by dynamic light scattering (DLS), transmission electron microscopy (TEM), and zeta potential. The uptake and penetration of nanoparticles in 2- and 3-dimensional SH-SY5Y cells were examined at 37 °C and 4 °C. The in vivo biodistribution of the nanoparticles was investigated using near-infrared fluorescence (NIRF) imaging and ion-coupled plasma mass spectrometry (ICP-MS). The antitumor effect of CDDP-loaded nanoparticles was evaluated on hepatic H22 tumor-bearing mice model via intravenous administration. It is found that the obtained nanoparticles showed spherical shape with the size of 257 nm, and drug loading content of 10%. These CDDP-loaded casein nanoparticles have the extraordinary capabilities to penetrate cell membrane barriers, target tumor and inhibit tumor growth. The tumor growth inhibition of CDDP-loaded nanoparticles is 1.5-fold higher than that of free CDDP. Further, the penetration examination of the CDDP-loaded casein nanoparticles in the tumor tissue demonstrated that the nanoparticles had the ability to penetrate the tumor and deliver CDDP to the tumor more deeply and affect the cells far from the vasculature.

Covalently Combining Carbon Nanotubes with Anticancer Agent: Preparation and Antitumor Activity

A multiwalled carbon nanotube (MWNT)-based drug delivery system was developed by covalently combining carbon nanotubes with the antitumor agent 10-hydroxycamptothecin (HCPT) using hydrophilic diaminotriethylene glycol as the spacer between nanotube and drug moieties. The surface functionalizations of the nanotube were carried out by enrichment of carboxylic groups with optimized oxidization treatment, followed by covalently linking hydrophilic diaminotriethylene glycol via amidation reaction, and then HCPT was chemically attached to carbon nanotubes through a cleavable ester linkage. It is demonstrated that the obtained MWNT-HCPT conjugates are superior in antitumor activity both in vitro and in vivo to clinical HCPT formulation. In vivo single photon emission computed tomography (SPECT) imaging and ex vivo gamma scintillation counting analyses reveal that MWNT-HCPT conjugates have relatively long blood circulation and high drug accumulation in the tumor site. These properties together with the enhanced cell uptake and multivalent presentation of HCPT on a single nanotube benefit substantially the antitumor effects and would boost significantly the applications of carbon nanotubes in the biomedicine field.

Multifunctional Nanocarriers for Cell Imaging, Drug Delivery, and Near-IR Photothermal Therapy

Multifunctional nanocarriers based on chitosan/gold nanorod (CS-AuNR) hybrid nanospheres have been successfully fabricated by a simple nonsolvent-aided counterion complexation method. Anticancer drug cisplatin was subsequently loaded into the obtained hybrid nanospheres, utilizing the loading space provided by the chitosan spherical matrix. In vitro cell experiments demonstrated that the CS-AuNR hybrid nanospheres can not only be utilized as contrast agents for real-time cell imaging but also serve as a near-infrared (NIR) thermotherapy nanodevice to achieve irradiation-induced cancer cell death owing to the unique optical properties endowed by the encapsulated gold nanorods. In addition, an effective attack on the cancer cells by the loaded anticancer drug cisplatin has also been observed, rendering the obtained nanocarriers an all-in-one system possessing drug delivery, cell imaging, and photothermal therapy functionalities.

Doxorubicin delivery to 3D multicellular spheroids and tumors based on boronic acid-rich chitosan nanoparticles

Boronic acid-rich chitosan-poly(N-3-acrylamidophenylboronic acid) nanoparticles (CS-PAPBA NPs) with the tunable size were successfully prepared by polymerizing N-3-acrylamidophenylboronic acid in the presence of chitosan in an aqueous solution. The CS-PAPBA NPs were then functionalized by a tumor-penetrating peptide iRGD and loading doxorubicin (DOX). The interaction between boronic acid groups of hydrophobic PAPBA and the amino groups of hydrophilic chitosan inside the nanoparticles was examined by solid-state NMR measurement. The size and morphology of nanoparticles were characterized by dynamic light scattering and electron microscopy. The cellular uptake, tumor penetration, biodistribution and antitumor activity of the nanoparticles were evaluated by using three-dimensional (3-D) multicellular spheroids (MCs) as the in vitro model and H22 tumor-bearing mice as the in vivo model. It was found that the iRGD-conjugated nanoparticles significantly improved the efficiency of DOX penetration in MCs, compared with free DOX and non-conjugated nanoparticles, resulting in the efficient cell killing in the MCs. In vivo antitumor activity examination indicated that iRGD-conjugated CS-PAPBA nanoparticles promoted the accumulation of nanoparticles in tumor tissue and enhanced their penetration in tumor areas, both of which improved the efficiency of DOX-loaded nanoparticles in restraining tumor growth and prolonging the life time of H22 tumor-bearing mice.

Paclitaxel-loaded poly(N-vinylpyrrolidone)-b-poly(ε-caprolactone) nanoparticles: Preparation and antitumor activity in vivo

Paclitaxel (PTX)-loaded poly(N-vinylpyrrolidone)-b-poly(epsilon-caprolactone) (PVP-b-PCL) nanoparticles with high drug payload were successfully prepared by a modified nano-precipitation method and characterized by transmission electron microscopy (TEM), atomic force microscopy (AFM), dynamic light scattering (DLS) and zeta potential. The satisfactory drug loading content (>25%) and high encapsulation efficiency (>85%) were achieved. The in vivo real-time biodistribution of PTX-loaded nanoparticles was investigated using near-infrared fluorescence (NIRF) imaging. The antitumor effect of PTX-loaded nanoparticles was evaluated, both, in vitro on three different cancer cell lines and in vivo on hepatic H22 tumor bearing mice model via intravenous administration (i.v.). It is found that PTX-loaded nanoparticles exhibit significant superior in vivo antitumor effect than the commercially available Taxol formulation by combining the tumor volumes and survival rates measurement, intravital positron emission tomography and computed tomography (PET/CT) imaging.

Hypoxia-specific ultrasensitive detection of tumours and cancer cells in vivo

Highly sensitive and specific non-invasive molecular imaging methods are particularly desirable for the early detection of cancers. Here we report a near-infrared optical imaging probe highly specific to the hypoxic tumour microenvironment to detect tumour and cancer cells with the sensitivity to a few thousands cancer cells. This oxygen-sensitive, near-infrared emitting and water-soluble phosphorescent macromolecular probe can not only report the hypoxic tumour environment of various cancer models, including metastatic tumours in vivo, but can also detect a small amount of cancer cells before the formation of the tumour based on the increased oxygen consumption during cancer cell proliferation. Thus, the reported hypoxia-sensitive probe may offer an imaging tool for characterizing the tumour microenvironment in vivo, detecting cancer cells at a very early stage of tumour development and lymph node metastasis.

Near-IR-triggered photothermal/photodynamic dual-modality therapy system via chitosan hybrid nanospheres.

Gold nanorods (AuNR)- and indocyanine green (ICG)-encapsulated chitosan hybrid nanospheres (CS-AuNR-ICG NSs) were successfully prepared and used for photothermal and photodynamic combined therapy with a single irradiation. These nanospheres were characterized by transmission electron microscopy, dynamic light scattering and UV-Vis absorption spectra. The in vivo anticancer effects of the hybrid nanospheres were examined by photodynamic therapy (PDT), photothermal therapy (PTT), and PTT/PDT combined therapy. It was found that the hybrid nanospheres had spherical size of 180 nm and a broad adsorption from 650 nm to 900 nm. The spherical chitosan matrix could effectively load ICG and protect it from the rapid hydrolysis. In vivo near-infrared fluorescence imaging and biodistribution demonstrated that ICG and AuNR could be selectively delivered to the tumor site with high accumulation. With the irradiation by 808 nm laser, chitosan hybrid nanospheres were capable to simultaneously produce sufficient hyperthermia and reactive oxygen species to kill cancer cells at irradiation sites, resulting in the complete tumor disappearance in the most of tumor-bearing mice. Compared with photothermal therapy or photodynamic therapy alone, the combined therapy had a significantly synergistic effect and improved the therapeutic efficacy.

The antitumor effect of novel docetaxel-loaded thermosensitive micelles.

To further evaluate the novel docetaxel-loaded micelle based on the biodegradable thermosensitive copolymer poly(N-isopropylacrylamide-co-acrylamide)-b-poly(dl-lactide) that we had synthesized before, in this paper, we studied its in vitro cytotoxicity in three different tumor cell lines by standard MTT assays using different tumor cell lines, followed by studies of acute toxicity and the tumor distribution studies which were conducted in Kunming mice. Meanwhile, the in vivo antitumor efficacy as well as toxicity of the micelle was evaluated in C57BL/6 mice. According to our findings, the in vitro cytotoxicity of docetaxel-loaded micelles was lower than that of the conventional docetaxel formulation at 37 degrees C, while hyperthermia greatly enhanced the efficacy of drug-loaded micelles. The acute toxicity study showed reduced toxicity of docetaxel-loaded micelle compared to that of conventional docetaxel formulation. Moreover, docetaxel-loaded micelle enabled a prominent higher docetaxel concentration in tumor than conventional docetaxel formulation. Furthermore, a significantly higher antitumor efficacy was observed in mice treated with docetaxel-loaded micelles accompanied by hyperthermia; docetaxel-loaded micelles also caused less body weight loss of mice. This study demonstrates an increased antitumor efficacy and reduced toxicity of the novel docetaxel-loaded micelle and indicates its prospect of clinical applications.