Yongming Chen

Scalable fabrication of size-controlled chitosan nanoparticles for oral delivery of insulin

Controlled delivery of protein would find diverse therapeutic applications. Formulation of protein nanoparticles by polyelectrolyte complexation between the protein and a natural polymer such as chitosan (CS) is a popular approach. However, the current method of batch-mode mixing faces significant challenges in scaling up while maintaining size control, high uniformity, and high encapsulation efficiency. Here we report a new method, termed flash nanocomplexation (FNC), to fabricate insulin nanoparticles by infusing aqueous solutions of CS, tripolyphosphate (TPP), and insulin under rapid mixing condition (Rexa0>xa01600) in a multi-inlet vortex mixer. In comparison with the bulk-mixing method, the optimized FNC process produces CS/TPP/insulin nanoparticles with a smaller size (down to 45xa0nm) and narrower size distribution, higher encapsulation efficiency (up to 90%), and pH-dependent nanoparticle dissolution and insulin release. The CS/TPP/insulin nanoparticles can be lyophilized and reconstituted without loss of activity, and produced at a throughput of 5.1xa0gxa0h-1 when a flow rate of 50xa0mLxa0min-1 is used. Evaluated in a Type I diabetes rat model, the smaller nanoparticles (45xa0nm and 115xa0nm) control the blood glucose level through oral administration more effectively than the larger particles (240xa0nm). This efficient, reproducible and continuous FNC technique is amenable to scale-up in order to address the critical barrier of manufacturing for the translation of protein nanoparticles.

Synthesis of novel biobased polyimides derived from isomannide with good optical transparency, solubility and thermal stability

Novel biobased polyimides (PIs) with good optical transparency and comprehensive properties were synthesized from isomannide-derived diamine and dianhydride monomers. Three kinds of diamines including 2,5-diamino-2,5-dideoxy-1,4:3,6-dianhydroiditol (M1), 1,4:3,6-dianhydro-2,5-di-O-(4-aminophenyl)-D-mannitol (M2), and 1,4:3,6-dianhydro-2,5-di-O-(2-trifluoromethyl-4-aminophenyl)-D-mannitol (M3), as well as 1,4:3,6-dianhydro-2,5-di-O-(3,4-dicarboxyphenyl)-D-mannitol dianhydride (M4), were prepared based on isomannide. These diamines M1–M3 were reacted with M4 and a commercial dianhydride, 4,4′-oxydiphthalic anhydride (ODPA), via a two-step polymerization method, respectively, to yield a series of biobased PI films, PI-1 to PI-6. The resultant PIs had a high content of biomass up to 48 wt%, and they can be readily soluble in various non-proton polar solvents at room temperature. Most of the biobased PIs showed good optical transparency (transmittances at 450 nm over than 80%), along with a cut-off wavelength of 343–364 nm. Furthermore, due to the existence of rigid alicyclic isomannide among the polymeric backbone, biobased PIs maintained fairly high thermal stability with a glass transition temperature of 227–264 °C, and temperature at 5% weight loss over 400 °C in nitrogen. Meanwhile, these PIs exhibited outstanding mechanical properties with tensile strengths greater than 90 MPa and elongation at break higher than 6.0%. It was also found that the biobased PI series with alicyclic M1 possessed higher thermal stability than PIs with semi-aromatic diamines M2 and M3. Thereof, the introduction of biomass building blocks into PIs can offer a great opportunity to develop new sustainable materials with high performance for microelectronic and optoelectronic applications.

Onion-like microspheres with tricomponent from gelable triblock copolymers.

Onion-like functional microspheres with three alternate layers were obtained by aerosol-assisted self-assembly of a functional block copolymer, poly(3-(triethoxysilyl)propyl methacrylate)-block-polystyrene-block-poly(2-vinylpyridine) (PTEPM-b-PS-b-P2VP). Through self-gelation reaction occurred in the PTEPM layers, organic/inorganic hybrid functional spheres with highly ordered concentric curved lamellar structure were prepared. Using these hybrid onion-like microspheres as templates, gold ions were entrapped into the P2VP layers and then gold nanoparticles located in each P2VP layers were formed by a reduction. By dispersing in acidic water, the onion-like polymeric spheres were broken and, as a result, sandwich-like nanoplates with curved morphology were obtained.

Functional sandwich-like organic/inorganic nanoplates from gelable triblock terpolymers

A functional gelable triblock terpolymer, poly(3-(triethoxysilyl)propyl methacrylate)-block-polystyrene-block-poly(2-vinylpyridine) (PTEPM-b-PS-b-P2VP), was prepared by reversible addition-fragmentation chain transfer (RAFT) mediated radical polymerization. This sample can microphase-separate to form a three-phase four-layer lamellar morphology in the bulk. After in-situ self-gelation only in PTEPM microdomains, we obtained an organic/inorganic hybrid bulk material with the basic lamellar microstructure unit composed of an inner crosslinked PTEPM layer sandwiched first by PS and then by P2VP layers. By dispersing in acidic water and tetrahydrofuran, novel sandwich-like hybrid nanoplates were prepared as characterized by electron microscopy and atomic force microscopy. The properties of pH sensitivity, gold nanoparticle stabilization and surface activity were explored. Further modification of P2VP hairs with 1-bromohexane and 1-capric acid, respectively, was carried out which supplied versatile ways to tune elaborate structure of the planar polymer nanoobjects.

Simple, clean preparation method for cross-linked α-cyclodextrin nanoparticles via inclusion complexation.

A simple, clean method was presented in this letter to prepare cross-linked α-cyclodextrin (α-CD) nanoparticles with a low dispersion. The nanoparticles were synthesized in water by cross-linking the inclusion complex of α-CDs and poly(ethylene glycol) (PEG). The structure of the nanoparticles was characterized by (1)H NMR, nuclear overhauser enhancement spectroscopy (NOESY), and wide-angle X-ray diffraction (XRD). Spherical morphology was observed by scanning electron microscopy (SEM) for these nanoparticles. Their average hydrodynamic radius was determined to be 67 nm by dynamic light scattering (DLS). Small guest molecules could be included in the cross-linked α-CD nanoparticles, and anticancer drug cisplatin was used to evaluate the drug release behavior.

Bamboo leaf-like micro-nano sheets self-assembled by block copolymers as wafers for cells.

Bamboo leaf shaped poly(ethylene oxide)-b-poly(ϵ-caprolactone) (PEO-b-PCL) sheets were prepared via crystallization-driven self-assembly. By selecting an appropriate mixed solvent, the polymer sheets, with a PCL single-crystal layer sandwiched by two PEO layers, were obtained efficiently. The morphology and structure of the sheets were characterized by microscopes and diffraction techniques. As a non-spherical model particle, endocytosis of the sheets was investigated on RAW 264.7, U937, HUVECs, HeLa, and 293 T cells. The polymer sheets, just like wafers for cells, displayed a selective internalization to different cells, which showed a potential application in accurate cell targeting drug delivery and imaging.

Encapsulation properties of reverse-amphiphilic core/shell polymeric nanoobjects with different shapes

Reverse-amphiphilic core/shell polymeric nanoobjects (PNOs) with lamellar, cylindrical and spherical morphologies derived from poly(glycidyl methacrylate)-block-poly(n-butyl methacrylate) (PGMA-b-PnBMA) diblock copolymers were used as nanocapsules to encapsulate anionic hydrophilic dyes. Through the bulk self-assembly of PGMA-b-PnBMA with different compositions, bulk materials with different microphase-separated morphologies were obtained. Ammonium hydroxide was used to crosslink the epoxy groups in the PGMA domains and amine groups were simultaneously introduced into the PGMA domains. Then the bulk materials were dispersed in toluene to generate shaped PNOs. After quaternizing amine groups in the cores, shaped PNOs with electropositive hydrophilic cores and hydrophobic PnBMA hairs were obtained. These PNOs dispersed in toluene were used as nanocapsules to transfer calmagite, an anionic hydrophilic dye, from water into the cores. The encapsulation capacities of these shaped PNOs were evaluated by comparing the number loading ratios (mole number of dyes encapsulated per mole of PGMA-b-PnBMA diblock copolymer chains (nd/np)). Spherical nanocapsules had the highest nd/np owing to the large specific area of the interface between the cores and shells of the spherical PNOs. The nd/np of the cylindrical nanocapsules was approximately half that of the spherical ones and a little higher than nd/np of the lamellar ones. As well as having the ability to encapsulate hydrophilic dyes in organic solution, the spherical nanocapsules could also be used to effectively separate dyes with different charges and uniformly color PnBMA bulk materials.

Microphase Separation within Disk Shaped Aggregates of Triblock Bottlebrushes.

Well-defined AbBA triblock bottlebrush with poly(N,N-dimethyl acrylamide) (PAm) as A block and polyacrylate, densely grafted with poly(tert-butyl acrylate)-block-polystyrene (PBA-b-PS), as brush bB block is prepared by controlled radical polymerization and click chemistry. The triblock copolymer with a composition of PAm200 -b-b(PBA14 -b-PS47 )167 -b-PAm200 is obtained and is further transformed into PAm200 -b-b(PAA14 -b-PS47 )167 -b-PAm200 by hydrolysis of the PBA segment into poly(acrylic acid) (PAA). In a mixture of N,N-dimethylformamide (DMF) and methanol, a poor solvent of bB block, PAm200 -b-b(PAA14 -b-PS47 )167 -b-PAm200 self-assembled into disk-like platelets, which have an internal lamellar structure by further microphase-separation of PAA-b-PS branches in 2D. Moreover, Ag nanoparticles are aligned by PAA segments along the disk to form a pattern.

Different dimensional silica materials prepared using shaped block copolymer nanoobjects as catalytic templates

A general approach to fabricate a series of silica nanoobjects with sheet-like, tubular and hollow spherical shapes was reported. These silica nanoobjects were prepared by using water-dispersed diblock copolymer nanoobjects with glassy polystyrene cores and densely grafted poly(2-(dimethylamino)ethylmethacrylate) (PDMAEMA) shells as templates as well as catalysts. A sol-gel reaction of tetramethoxysilane (TMOS) was subsequently induced by PDMAEMA shells of shaped nanoobjects in water dispersions at near-neutral pH and under ambient conditions, and thus the shaped polymer@silica hybrids with a high silica content (around 70 wt% silica in hybrids) were obtained. Then silica nanoobjects of three different dimensions were further prepared by calcination at 650 °C to remove the organic components. The spherical and cylindrical silicas have a hollow structure. Formation of diblock copolymers, polymer nanoobjects, polymer@silica hybrids, and silica nanoobjects was characterized by 1H NMR spectroscopy, size exclusion chromatography (SEC), small-angle X-ray scattering (SAXS), transmission electron microscopy (TEM), scanning electron microscopy (SEM), thermogravimetric analysis (TGA), solid state 29Si CPMAS NMR analysis, N2 adsorption-desorption measurements, and Fourier-transform infrared spectroscopy (FT-IR). This methodology could be a general approach to fabricate various inorganic nanoparticles with different geometric shapes.

Synthesis and cellular internalization of spindle hematite/polymer hybrid nanoparticles.

Nonspherical spindle-shaped hematite/polymer hybrid nanoparticles (SPNPs) were synthesized via surface-initiated atom transfer radical polymerization (SI-ATRP). The long axis of the SPNPs was 370 ± 65 nm, and the short axis was 80 ± 15 nm with an aspect ratio of 4.6-4.7. The SPNPs were characterized by transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FT-IR), and X-ray photoelectron spectroscopy (XPS). Thermogravimetric analysis (TGA) was used to estimate the content of grafted polymer. Light-scattering measurement was used to detect the particle size distribution of SPNPs in water and in cell culture medium. HeLa cells internalized the SPNPs within 1 h, and the uptake reached equilibrium in 8 h. These observations contribute to better understanding of the interactions between nonspherical nanoparticles and cells, which may have implication for designing drug delivery vehicles.