Jianbiao Ma

Magnetic and pH-sensitive nanoparticles for antitumor drug delivery

A dually responsive nanocarrier with multilayer core-shell architecture was prepared based on Fe(3)O(4)@SiO(2) nanoparticles coated with mPEG-poly(l-Asparagine). Imidazole groups (pK(a)∼6.0) were tethered to the side chains of poly(l-Asparagine) segments by aminolysis. These nanoparticles were expected to be sensitive to both magnetic field and pH environment. The obtained materials were characterized with FTIR, dynamic light scattering, ζ-potential, TEM, TGA and hysteresis loop analysis. It was found that this Fe(3)O(4)@SiO(2)-polymer complex can form nano-scale core-shell-corona trilayer particles (∼250 nm) in aqueous solution. The Fe(3)O(4)@SiO(2), poly(L-Asparagine) and mPEG segments serve as a super-paramagnetic core, a pH-sensitive shell, and a hydrophilic corona, respectively. An antitumor agent, doxorubicin (DOX), was successfully loaded into the nanocarrier via combined actions of hydrophobic interaction and hydrogen bonding. The drug release profiles displayed a pH-dependent behavior. DOX release rate increased significantly as the ambient pH dropped from the physiological pH (7.4) to acidic (5.5). This is most likely due to protonation and a change in hydrophilicity of the imidazole groups in the poly(l-Asparagine) segments. This new approach may serve as a promising platform to formulate magnetic targeted drug delivery systems.

A novel delivery system of doxorubicin with high load and pH-responsive release from the nanoparticles of poly (α,β-aspartic acid) derivative.

A poly (amino acid)-based amphiphilic copolymer was utilized to fabricate a better micellar drug delivery system (DDS) with improved compatibility and sustained release of doxorubicin (DOX). First, poly (ethylene glycol) monomethyl ether (mPEG) and DOX were conjugated onto polyasparihyazide (PAHy), prepared by hydrazinolysis of the poly (succinimide) (PSI), to afford an amphiphilic polymer [PEG-hyd-P (AHy-hyd-DOX)] with acid-liable hydrazone bonds. The DOX, chemically conjugated to the PAHy, was designed to supply hydrophobic segments. PEGs were also grafted to the polymer via hydrazone bonds to supply hydrophiphilic segments and prolong its lifetime in blood circulation. Free DOX molecules could be entrapped into the nanoparticles fabricated by such an amphiphilic polymer (PEG-hyd-P (AHy-hyd-DOX)), via hydrophobic interaction and π-π stacking between the conjugated and free DOX molecules to obtain a pH responsive drug delivery system with high DOX loaded. The drug loading capacity, drug release behavior, and morphology of the micelles were investigated. The biological activity of micelles was evaluated in vitro. The drug loading capacity was intensively augmented by adjusting the feed ratio, and the maximum loading capacity was as high as 38%. Besides, the DOX-loaded system exhibited pH-dependent drug release profiles in vitro. The cumulative release of DOX was much faster at pH 5.0 than that at pH 7.4. The DOX-loaded system kept highly antitumor activity for a long time, compared with free DOX. This easy-prepared DDS, with features of biocompatibility, biodegradability, high drug loading capacity and pH-responsiveness, was a promising controlled release delivery system for DOX.

Layer-by-Layer (LBL) Self-Assembled Biohybrid Nanomaterials for Efficient Antibacterial Applications.

Although antibiotics have been widely used in clinical applications to treat pathogenic infections at present, the problem of drug-resistance associated with abuse of antibiotics is becoming a potential threat to human beings. We report a biohybrid nanomaterial consisting of antibiotics, enzyme, polymers, hyaluronic acid (HA), and mesoporous silica nanoparticles (MSNs), which exhibits efficient in vitro and in vivo antibacterial activity with good biocompatibility and negligible hemolytic side effect. Herein, biocompatible layer-by-layer (LBL) coated MSNs are designed and crafted to release encapsulated antibiotics, e.g., amoxicillin (AMO), upon triggering with hyaluronidase, produced by various pathogenic Staphylococcus aureus (S. aureus). The LBL coating process comprises lysozyme (Lys), HA, and 1,2-ethanediamine (EDA)-modified polyglycerol methacrylate (PGMA). The Lys and cationic polymers provided multivalent interactions between MSN-Lys-HA-PGMA and bacterial membrane and accordingly immobilized the nanoparticles to facilitate the synergistic effect of these antibacterial agents. Loading process was characterized by dynamic light scattering (DLS), transmission electron microscopy (TEM), thermogravimetric analysis (TGA), and X-ray diffraction spectroscopy (XRD). The minimal inhibition concentration (MIC) of MSN-Lys-HA-PGMA treated to antibiotic resistant bacteria is much lower than that of isodose Lys and AMO. Especially, MSN-Lys-HA-PGMA exhibited good inhibition for pathogens in bacteria-infected wounds in vivo. Therefore, this type of new biohybrid nanomaterials showed great potential as novel antibacterial agents.

Polyelectrolyte complex nanoparticles of amino poly(glycerol methacrylate)s and insulin.

Amino poly(glycerol methacrylate)s (PGOHMAs) were synthesized from linear or star-shaped poly(glycidyl methacrylate)s (PGMA)s via ring opening reactions with 1,2-ethanediamine, 1,4-butanediamine and diethylenetriamine, respectively. The resulting cationic polymers were employed to form polyelectrolyte complexes (PECs) with insulin. Parameters influencing complex formation were investigated by dynamic light scattering (DLS). PECs in the size range of 100-200 nm were obtained under optimal conditions, i.e., the pH value of PECs was 5.58-6.27, the concentration of NaCl was 0.02 mol/L, and insulin-polymer weight ratio was 0.8. The insulin association efficiency (AE) of current system increased with zeta potentials of PECs. Circular dichroism (CD) analysis corroborated that the structure of insulin in the PEC nanoparticles was preserved after lyophilization. Fourier transform infrared (FT-IR) and X-ray diffraction (XRD) experiments demonstrated that weak physical interactions between insulin and amino PGOHMAs play an important role in the formation of PECs. The release of insulin depends on both structure and architecture of amino PGOHMAs. These PECs would be potentially useful for mucosal administration.

An injectable and biodegradable hydrogel based on poly(α,β-aspartic acid) derivatives for localized drug delivery

An injectable hydrogel via hydrazone cross-linking was prepared under mild conditions without addition of cross-linker or catalyst. Hydrazine and aldehyde modified poly(aspartic acid)s were used as two gel precursors. Both of them are water-soluble and biodegradable polymers with a protein-like structure, and obtained by aminolysis reaction of polysuccinimide. The latter can be prepared by thermal polycondensation of aspartic acid. Hydrogels were prepared in PBS solution and characterized by different methods including gel content and swelling, Fourier transformed-infrared spectroscopy, and in vitro degradation experiment. A scanning electron microscope viewed the interior morphology of the obtained hydrogels, which showed porous three-dimensional structures. Different porous sizes were present, which could be well controlled by the degree of aldehyde substitution in precursor poly(aspartic acid) derivatives. The doxorubicin-loaded hydrogels were prepared and showed a pH-sensitive release profile. The release rate can be accelerated by decreasing the environmental pH from a physiological to a weak acidic condition. Moreover, the cell adhesion and growth behaviors on the hydrogel were studied and the polymeric hydrogel showed good biocompatibility.

Amino poly(glycerol methacrylate)s for oligonucleic acid delivery with enhanced transfection efficiency and low cytotoxicity

To improve the transfection activity and reduce cell cytotoxicity of polycations with antisense oligonucleotide (AON), poly(glycidyl methacrylate)s (PGMAs) were modified with different amines, i.e., methylethylamine (MEA), 2-amino-1-butanol (2-ABO) and 4-amino-1-butanol (4-ABO). The structures of resulting polymers were well characterized and their thermal properties were studied by differential scanning calorimetry (DSC). The amino PGMA could self-assemble with AON in a Tris buffer solution, resulting in narrowly distributed polymer/AON complexes with a size of 0.1–0.3 μm at an amine-group-of-polymer/phosphate-group-of-nucleotide ratio (N/P ratio) of 0.5–3. Spherical nanoparticles of the complexes were visualized using atomic force microscopy (AFM), and the gel electrophoresis and zeta potential assay evidenced the formation of complexes at relatively low N/P ratios. Stability of the complexes towards dissociation was tested using ethidium bromide displacement assay. Protection of the incorporated AON against DNase I degradation was also evaluated. An increased charge ratio and a synergistic effect of hydrogen bonding in this system contributed to the increased stability of the complex, which prevents the incorporated AON from nuclease degradation. In vitro cytotoxicity experiments on COS-7 cells showed that all amino PGMAs displayed lower toxicity compared to the control PEI25k, except for the polymers with a relatively high molecular weight (30 kDa). In addition, the MEA modified linear and star-shaped PGMA (Mn in the range of 15–20 kDa) as well as 4-ABO modified linear PGMA complexes exhibited higher transfection efficiencies in vitro, compared to PEI25k. These results demonstrated that amino PGMAs with suitable amine groups and molecular weight can be used as safe and efficient AON delivery polymers.

Carboxylated poly(glycerol methacrylate)s for doxorubicin delivery

Poly(glycerol methacrylate)s (PGOHMAs) were successfully synthesized via the hydrolysis of the epoxy groups on linear and/or star-shaped poly(glycidyl methacrylate)s (PGMAs). Further modification of the hydroxyl groups on PGOHMAs with succinic anhydride (SA) or 1,2-cyclohexanedicarboxylic anhydride (CDA) resulted in a new type of polyacid polymer, namely, PGOHMACOOH for short, which was then employed to prepare pH-sensitive assemblies using dialysis method. The carboxylated polymers were quite effective in the encapsulation of doxorubicin hydrochloride (DOX) by electrostatic interaction. Compared with poly(acrylic acid) (PAA), the star-shaped PGOHMA modified with CDA exhibited higher encapsulation efficiency and loading capacity, as well as better pH-responsive release profile. Scanning electron microscope images showed that the polymeric nanoparticles before and after encapsulation of DOX were spherical in shape. The encapsulation efficiency, loading capacity and release properties of these polymers were found to rely on their backbone architectures and the type of carboxylated functionalities. By fine-tuning these factors to achieve optimal properties, such type of polymeric materials holds promise as an attractive and effective drug delivery vehicle.

Novel vanillic acid-based poly(ether–ester)s: from synthesis to properties

Two series of bio-based poly(ether–ester)s from vanillic acid and linear α,ω-diols HO-(CH2)m-OH (m = 2, 3, 4, 10) have been successfully synthesized by the direct esterification method. These poly(ether–ester)s were characterized using FTIR, 1H-NMR, and size exclusion chromatography (SEC). Thermogravimetric analysis (TGA), differential scanning calorimetry (DSC) and dynamic mechanical analysis (DMA) were used to study their thermo-mechanical properties. The poly(ether–ester)s had weight-average molecular weights (Mw) in the range of 16 600 to 78 700 g mol−1 and polydispersities between 1.39 and 2.00. All of the bio-based poly(ether–ester)s exhibited amorphous features with their glass transition temperatures (Tgs) ranging from 5 to 67 °C. The stress–strain parameters showed that the mechanical properties of these poly(ether–ester)s were excellent. The Youngs modulus and elongation at break of the poly(ether–ester)s in this series were found to be in the range of 95–228 MPa and 14.9–311%, respectively.

pH-Responsive Self-Assembly and conformational transition of partially propyl-esterified poly(α,β-l-aspartic acid) as amphiphilic biodegradable polyanion

Poly(alpha,beta-L-aspartate) (PAsp) was partially esterified to afford an amphiphilic biodegradable polyanion, poly(sodium aspartate-co-propyl aspartate) (PAsp-Na/PAsp-P). The synthesized polyanion could be assembled into the nano-scaled aggregates in aqueous medium. The aggregate morphologies were studied by scanning electron microscopy (SEM) and transmission electron microscopy (TEM) as a function of pH. It was demonstrated that micellization of this random copolymer occurred with stimulus of pH changes to form various morphological micelles. The copolymer existed as precipitate at low pH (pH<2). When pH increased to 4, the polymers were associated into spherical micelles with the core of poly(propyl aspartate) (PAsp-P) hydrophobic units and shell of some negatively charged poly(sodium aspartate) (PAsp-Na) units. At higher pH (pH>5), toroidal nanostructures of the micelles were formed because rigid polyamide chains directly assemble into the large hollow spheres. The CD study showed that the conformation underwent a transition between alpha-helix and random coil at pH 3-7. The cooperative transitions were regulated by the degree of ionization of carboxylic side chains. When they were protonated (neutralized), the molecular backbone was in favor of the regular helical structure; when deprotonated (ionized), the electrostatic repulsions among side chains destabilized the intramolecular hydrogen bonds, thus randomizing the regular conformation.

Aggregation-Induced-Emissive Molecule Incorporated into Polymeric Nanoparticulate as FRET Donor for Observing Doxorubicin Delivery.

Tetraphenylethene (TPE) derivatives characterized with distinct aggregation-induced-emission, attempted to aggregate with doxorubicin (Dox) to formulate the interior compartment of polymeric nanoparticulate, served as fluorescence resonance energy transfer (FRET) donor to promote emission of acceptor Dox. Accordingly, this FRET formulation allowed identification of Dox in complexed form by detecting FRET. Important insight into the Dox releasing can be subsequently explored by extracting complexed Dox (FRET) from the overall Dox via direct single-photon excitation of Dox. Of note, functional catiomers were used to complex with FRET partners for a template formulation, which was verified to induce pH-responsive release in the targeted subcellular compartment. Hence, this well-defined multifunctional system entitles in situ observation of the drug releasing profile and insight on drug delivery journey from the tip of injection vein to the subcellular organelle of the targeted cells.