Bangshang Zhu

Oxime Linkage: A Robust Tool for the Design of pH-Sensitive Polymeric Drug Carriers

Oxime bonds dispersed in the backbones of the synthetic polymers, while young in the current spectrum of the biomedical application, are rapidly extending into their own niche. In the present work, oxime linkages were confirmed to be a robust tool for the design of pH-sensitive polymeric drug delivery systems. The triblock copolymer (PEG-OPCL-PEG) consisting of hydrophilic poly(ethylene glycol) (PEG) and hydrophobic oxime-tethered polycaprolactone (OPCL) was successfully prepared by aminooxy terminals of OPCL ligating with aldehyde-terminated PEG (PEG-CHO). Owing to its amphiphilic architecture, PEG-OPCL-PEG self-assembled into the micelles in aqueous media, validated by the measurement of critical micelle concentration (CMC). The MTT assay showed that PEG-OPCL-PEG exhibited low cytotoxicity against NIH/3T3 normal cells. Doxorubicin (DOX) as a model drug was encapsulated into the PEG-OPCL-PEG micelles. Drug release study revealed that the DOX release from micelles was significantly accelerated at mildly acid pH of 5.0 compared to physiological pH of 7.4, suggesting the pH-responsive feature of the drug delivery systems with oxime linkages. Flow cytometry and confocal laser scanning microscopy (CLSM) measurements indicated that these DOX-loaded micelles were easily internalized by living cells. MTT assay against HeLa cancer cells showed DOX-loaded PEG-OPCL-PEG micelles had a high anticancer efficacy. All of these results demonstrate that these polymeric micelles self-assembled from oxime-tethered block copolymers are promising carriers for the pH-triggered intracellular delivery of hydrophobic anticancer drugs.

Supramolecular Copolymer Micelles Based on the Complementary Multiple Hydrogen Bonds of Nucleobases for Drug Delivery

Novel supramolecular copolymer micelles with stimuli-responsive abilities were successfully prepared through the complementary multiple hydrogen bonds of nucleobases and then applied for rapid intracellular release of drugs. First, both adenine-terminated poly(ε-caprolactone) (PCL-A) and uracil-terminated poly(ethylene glycol) (PEG-U) were synthesized. The supramolecular amphiphilic block copolymers (PCL-A:U-PEG) were formed based on multiple hydrogen bonding interactions between PCL-A and PEG-U. The micelles self-assembled from PCL-A:U-PEG were sufficiently stable in water but prone to fast aggregation in acidic condition due to the dynamic and sensitive nature of noncovalent interactions. The low cytotoxicity of supramolecular copolymer micelles was confirmed by MTT assay against NIH/3T3 normal cells. As a hydrophobic anticancer model drug, doxorubicin (DOX) was encapsulated into these supramolecular copolymer micelles. In vitro release studies demonstrated that the release of DOX from micelles was significantly faster at mildly acid pH of 5.0 compared to physiological pH. MTT assay against HeLa cancer cells showed DOX-loaded micelles had high anticancer efficacy. Hence, these supramolecular copolymer micelles based on the complementary multiple hydrogen bonds of nucleobases are very promising candidates for rapid controlled release of drugs.

Multifunctional pH-sensitive superparamagnetic iron-oxide nanocomposites for targeted drug delivery and MR imaging.

A multifunctional pH-sensitive superparamagnetic iron-oxide (SPIO) nanocomposite system was developed for simultaneous tumor magnetic resonance imaging (MRI) and therapy. Small-size SPIO nanoparticles were chemically bonded with antitumor drug doxorubicin (DOX) and biocompatible poly(ethylene glycol) (PEG) through pH-sensitive acylhydrazone linkages, resulting in the formation of SPIO nanocomposites with magnetic targeting and pH-sensitive properties. These DOX-conjugated SPIO nanocomposites exhibited not only good stability in aqueous solution but also high saturation magnetizations. Under an acidic environment, the DOX was quickly released from the SPIO nanocomposites due to the cleavage of pH-sensitive acylhydrazone linkages. With the help of magnetic field, the DOX-conjugated SPIO nanocomposites showed high cellular uptake, indicating their magnetic targeting property. Comparing to free DOX, the DOX-conjugated SPIO nanocomposites showed better antitumor effect under magnetic field. At the same time, the relaxivity value of these SPIO nanocomposites was higher than 146s(-1)mM(-1) Fe, leading to ~4 times enhancement compared to that of free SPIO nanoparticles. As a negative contrast agent, these SPIO nanocomposites illustrated high resolution in MRI diagnosis of tumor-bearing mice. All of these results confirm that these pH-sensitive SPIO nanocomposites are promising hybrid materials for synergistic MRI diagnosis and tumor therapy.

A supramolecular approach to the preparation of charge-tunable dendritic polycations for efficient gene delivery

A facile supramolecular approach for the preparation of charge-tunable dendritic polycations, by a combination of the multi-functionality of dendritic polymers with the dynamic-tunable ability of supramolecular polymers, has been developed. It provides a new strategy for designing and developing efficient gene vectors via noncovalent interactions.

Hyperbranched polymers for bioimaging

Hyperbranched polymers (HBPs) are highly branched macromolecules with a three-dimensional dendritic architecture. Benefiting from their highly branched topological structures, convenient synthetic procedures and unique physical/chemical properties, HBPs have been used to construct bioimaging probes and contrast agents, which exhibit enhanced stability, reduced toxicity, prolonged plasma half-life, and improved targeting specificity. Recently, the combination of these HBP-based probes or contrast agents with various imaging modalities showed great potential in biological imaging, including optical imaging, magnetic resonance imaging, nuclear imaging, and ultrasound imaging. This review summarizes the current advances in HBPs for bioimaging as well as their potential applications in clinical diagnosis.

Supramolecular amphiphilic multiarm hyperbranched copolymer: synthesis, self-assembly and drug delivery applications

Novel supramolecular amphiphilic multiarm hyperbranched copolymers were successfully constructed through the molecular recognition of nucleobases. First, adenine-terminated H40-star-poly(e-caprolactone)-adenine (H40-star-PCL-A) and uracil-terminated poly(ethylene glycol) (PEG-U) were successfully prepared. Due to the molecular recognition between A and U moieties, supramolecular multiarm hyperbranched copolymers were obtained by simply mixing the hydrophobic H40-star-PCL-A core and hydrophilic PEG-U shell. They not only had similar properties to conventional covalent-linked multiarm hyperbranched copolymers, but also possessed a dynamic and tunable nature. These supramolecular hyperbranched copolymers were found to self-assemble into pH-responsive micelles with low critical micelle concentration (CMC) because of non-covalent connection and hyperbranched architecture. The size of the self-assembled micelles could be easily tailored by changing the ratio of hydrophobic H40-star-PCL-A core and hydrophilic PEG-U arm. Moreover, encapsulation and controlled drug release were demonstrated with the chemotherapeutic drug doxorubicin (DOX). These supramolecular hyperbranched copolymer systems represent an evolution over conventional stimuli-responsive covalent-bonded hyperbranched copolymer systems and display a significant reduction in the viability of HeLa cells upon triggered release of DOX from the supramolecular micelles.

Construction and application of a pH-sensitive nanoreactor via a double-hydrophilic multiarm hyperbranched polymer.

A double-hydrophilic multiarm hyperbranched polymer with a hyperbranched poly(amidoamine) (HPAMAM) core and many poly(ethylene glycol) monomethyl ether (MPEG) arms connected by pH-sensitive acylhydrazone bonds (HPAMAM-g-MPEG) was successfully prepared. Benefiting from the cationic dendritic core and PEGylation shell, the double-hydrophilic multiarm hyperbranched polymer was used as a nanoreactor for CdS quantum dots (CdS QDs) synthesis in aqueous solution. The obtained HPAMAM-g-MPEG and CdS/HPAMAM-g-MPEG nanocomposites were carefully characterized by (1)H NMR, (13)C NMR, Fourier transform infrared spectroscopy (FTIR), ultraviolet-visible absorption spectroscopy (UV-vis), fluorescence spectroscopy (FL), dynamic light scattering (DLS), transmission electron microscopy (TEM), selected area electron diffraction (SAED), and electronic dispersive X-ray spectroscopy (EDS) analysis. Both (1)H NMR and fluorescence spectroscopy investigations confirmed that the acylhydrazone linkage between the dendritic core and linear arms was readily broken under acidic condition (pH <5.5). When MPEG arms departed from the HPAMAM core, the fluorescence intensity of CdS/HPAMAM-g-MPEG nanocomposites greatly increased. Such pH-responsive behavior of CdS/HPAMAM-g-MPEG nanocomposites was utilized as an exploration of a novel fluorescence probe in an acidic lysosome exemplified by COS-7 cells.

Reversible photoisomerization of azobenzene-containing polymeric systems driven by visible light

A novel class of azobenzene-containing polymeric systems with reversible trans–cis photoisomerization behavior driven by visible light (ca. 450 nm) has been successfully prepared and this opens up a pathway for azobenzene-based systems in biomedical applications.

Self-assembled encapsulation systems with pH tunable release property based on reversible covalent bond

Dynamic diblock polymer PS-r-PEG formed via reversible acylhydrazone connection can be used to construct a pH-responsive self-assembled encapsulation system with high stability and sustained-release property, which shows potential in drug delivery.

Amorphous carbon dots with high two-photon fluorescence for cellular imaging passivated by hyperbranched poly(amino amine)

Amorphous carbon dots (C-Dots) with high two-photon fluorescence were prepared by using citric acid (CA) as the carbon source and hyperbranched poly(amino amine) (HPAA) as the surface passivation agent through a facile hydrothermal approach. The C-Dots with an average diameter about 10 nm were readily dispersed in water. They exhibited excellent fluorescence properties and excitation-dependent fluorescence behavior with the corresponding quantum yield (QY) of 17.1% in aqueous solution. Interestingly, the C-Dots emitted bright fluorescence even in the solid state with a QY of 16.3%, which is the highest value obtained for carbon-based nanomaterials. Using the MTT assay, the C-Dots showed low cytotoxicity against L929 normal cells. Furthermore, they were easily internalized by HeLa cells and presented high quality one- and two-photon cellular imaging, suggesting significant potential for application in biological imaging.