Effect of conformation of interfacial adsorbed chains on physical aging of polymer nanocomposites.

The dynamics of polymer nanocomposites varies depending on the physics and chemistry at the polymer-nanoparticle interface. The physical aging of the nanocomposites is accelerated or retarded based on interfacial interactions and the state of polymer adsorption at the interfaces. In this study, we investigated the aging kinetics of silica-polystyrene nanocomposites using differential scanning calorimetry, focusing on the effect of local conformations of chains adsorbed on the nanofiller surface. The results show that the temperature dependence of the aging rate follows a Vogel-Fulcher-Tammann relationship at high temperatures, whereas it exhibits an Arrhenius-like behavior below a characteristic temperature (Tc). Notably, at T < Tc, the aging rate decreases with increasing loop height of the chains adsorbed on the filler surface, but the activation energy remains unchanged. We proposed that the suppression of the aging rate at T < Tc is likely related to an increase in the length scale over which the slow interfacial dynamics can propagate due to the increased topological interactions between the chain loops of a larger size and the free chains in the matrix. The increased packing frustration occurring at the filler surface occupied by the larger loops might also contribute to the decreased aging rate.

Sequential Administration of Nanoadjuvant and Nanoantigen Matters in Host Immunity.

To explore the sequence of administrating particulate nanovaccines, we fabricate model antigen OVA and molecular adjuvant CpG into separate nanoparticles to generate nanoantigen (NP(OVA)) and nanoadjuvant (NP(CpG)). We found that administrating NP(CpG) ahead of NP(OVA) polarized immune response toward Th1. In normal mice, such administration stimulated higher frequency of antigen-specific CD8+ T cells and stronger memory T cells than both inverted sequence and coinjecting. In tumor-bearing mice, more effector T cells were observed in the NP(CpG) ahead group than that in other ways. This study demonstrates that the immunity could be modulated by the sequential inoculation.

Scalable Manufacturing of Enteric Encapsulation Systems for Site-Specific Oral Insulin Delivery.

Oral drug delivery is a more favored mode of administration because of its ease of administration, high patient compliance, and low healthcare costs. However, no oral protein formulations are commercially available currently due to hostile gastrointestinal (GI) barriers resulting in insignificant oral bioavailability of macromolecular drugs. Herein, we used insulin as a model protein drug; insulin-loaded N-(2-hydroxy)-propyl-3-trimethylammonium chloride modified chitosan (HTCC)/sodium tripolyphosphate (TPP) nanocomplex (NC) as a nanocore was further encapsulated into enteric Eudragit L100-55 material, through a two-step flash nanocomplexation (FNC) process in a reliable and scalable manner, forming our NC-in-Eudragit composite particles (NE). Particle size and surface properties of our optimized NE were tailored to protect the loaded insulin from acidic degradation in the hostile stomach environment and to achieve intestinal site-specific drug release as well as the improvement of oral delivery efficiency of insulin. In addition, the oral administration of the optimized NE to type 1 diabetic rats could induce a very significant hypoglycemic effect with a relative oral bioavailability of 13.3%. Our results demonstrated that enteric encapsulation of nanotherapeutics using a FNC apparatus could cause drug formulations to possess better size controllability, batch-mode reproducibility, and homogeneous surface coating and then significantly enhance their oral bioavailability of insulin, indicating its great potential for clinical translation of oral protein therapeutics.

Hydrogen-Bonded Tannic Acid-Based Anticancer Nanoparticle for Enhancement of Oral Chemotherapy.

Oral chemotherapy has been emerging as a hopeful therapeutic regimen for the treatment of various cancers because of its high safety and convenience, lower costs, and high patient compliance. Currently, nanoparticulate drug delivery systems (NDDS) exhibit many unique advantages in mediating oral drug delivery; however, many anticancer drugs that were susceptible in hostile gastrointestinal (GI) environment showed poor permeability across intestinal epithelium, and most materials used as drug carriers are nonactive excipients and displayed no therapeutically relevant function, which leads to low oral bioavailability and therapeutic efficacy of anticancer drugs (e.g., paclitaxel). Inspired by these, in this study, paclitaxel (PTX) was used as a model drug, depending on intermolecular hydrogen-bonded interactions, PTX-loaded tannic acid/poly( N-vinylpyrrolidone) nanoparticles (PTX-NP) were produced by a flash nanoprecipitation (FNP) process. The optimized PTX-NP showed an average diameter of 54 nm with a drug encapsulation efficiency of 80% and loading capacity of 14.5%. Molecular dynamics simulations were carried out to illuminate the assembling mechanism of hydrogen-bonded PTX-NP. In vitro and in vivo results confirmed that PTX-NP showed pH-dependent intestinal site-specific drug release, P-gp inhibitory function by tannic acid (TA), prolonged intestinal retention, and improved trans-epithelial transport properties. Oral administration of PTX-NP generated a high oral delivery efficiency and relative oral bioavailability of 25.6% in rats, and further displayed a significant tumor-inhibition effect in a xenograft breast tumor model. These findings confirmed that our PTX-NP might be a promising oral drug formulation for chemotherapy.

Uniform Core-Shell Nanoparticles with Thiolated Hyaluronic Acid Coating to Enhance Oral Delivery of Insulin.

Oral delivery of protein drugs is an attractive route of administration due to its convenience for repeated dosing and good patient compliance. However, currently oral protein therapeutics show very low bioavailability mainly due to the existence of hostile gastrointestinal (GI) environments, including mucus layers and intestinal epithelial barriers. Herein, using insulin as a model protein therapeutic, the core-shell nanoparticles with thiolated hyaluronic acid (HA-SH) coating (NPHA-SH ) are produced utilizing a two-step flash nanocomplexation process to enhance oral delivery efficiency of insulin. A positively charged nanoparticle core is first generated by electrostatic complexation between insulin and N-(2-hydroxypropyl)-3-trimethyl ammonium chloride modified chitosan (HTCC), followed by surface coating with HA-SH. The optimized NPHA-SH shows an average size of 100 nm with high encapsulation efficiency (91.1%) and loading capacity (38%). In vitro and ex vivo results confirm that NPHA-SH shows high mucus-penetration ability, improved intestinal retention and transepithelial transport property due to its thiolated surface and the ability of HA-SH coating to dissociate from the nanoparticle surface when across the mucosal layer. Oral administration of NPHA-SH to Type 1 diabetic rats yields high efficacy and an average relative bioavailability of 11.3%. These results demonstrate that the HA-SH coated core-shell nanoparticles are a promising oral delivery vehicle for protein therapeutics.

Scalable production of core-shell nanoparticles by flash nanocomplexation to enhance mucosal transport for oral delivery of insulin.

Scalable manufacturing continues to present a major barrier for clinical translation of nanotherapeutics. Methods available for fabricating protein-encapsulating nanoparticles in a scalable fashion are scarce. Protein delivery often requires multiple functionalities to be incorporated into the same vehicle. Specifically for nanoparticle-mediated oral delivery of protein therapeutics, protection in GI tract, site-specific release, facilitating transmucosal permeation, and enhancing epithelial transport are a few desirable features to be engineered into a nanoparticle system. Here we devised a sequential flash nanocomplexation (FNC) technique for the scalable production of a core-shell structured nanoparticle system by combining materials choice and particle size and structure to fulfill these functions, therefore enhancing the delivery efficiency of insulin. This method is highly effective in controlling the size, generating core-shell structure with high encapsulation efficiency (97%) and payload capacity (67%) using insulin/l-penetratin complex nanoparticles as a core coated with hyaluronic acid (HA). Both the in vitro and in vivo models confirmed that the HA coating on these core-shell nanoparticles enhanced the permeation of nanoparticles through the intestinal mucus layer and improved trans-epithelial absorption of insulin nanoparticles; and the enhancement effect was most prominent using HA with the highest average molecular weight. The insulin-loaded nanoparticles were then encapsulated into enteric microcapsules (MCs) in an FNC process to provide additional protection against the acidic environment in the stomach while allowing rapid release of insulin nanoparticles when they reach small intestine. The optimized multifunctional MCs delivered an effective glucose reduction in a Type I diabetes rat model following a single oral administration, yielding a relative bioavailability of 11% in comparison with subcutaneous injection of free-form insulin. This FNC technique is highly effective in controlling particle size and structure to improve delivery properties and function. It can be easily extended to oral delivery for other protein therapeutics.

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 (Re > 1600) 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 45 nm) 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 5.1 g h-1 when a flow rate of 50 mL min-1 is used. Evaluated in a Type I diabetes rat model, the smaller nanoparticles (45 nm and 115 nm) control the blood glucose level through oral administration more effectively than the larger particles (240 nm). 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.

Probing the rheological properties of supported thin polystyrene films by investigating the growth dynamics of wetting ridges.

Despite its importance in the processing of nanomaterials, the rheological behavior of thin polymer films is poorly understood, partly due to the inherent measurement challenges. Herein, we have developed a facile method for investigating the rheological behavior of supported thin polymeric films by monitoring the growth of the "wetting ridge"-a microscopic protrusion on the film surface due to the capillary forces exerted by a drop of ionic liquid placed on the film surface. It was found that the growth dynamics of the wetting ridge and the behavior of polystyrene rheology are directly linked. Important rheological properties, such as the flow temperature (Tf), viscosity (η), and terminal relaxation time (τ0) of thin polystyrene films, can be derived by studying the development of the height of the wetting ridge with time and the sample temperature. Rheological studies using the proposed approach for supported thin polystyrene (PS) films with thickness down to 20 nm demonstrate that the PS thin film exhibits facilitated flow, with reduced viscosity and lowered viscous temperature and a shortened rubbery plateau, when SiOx-Si was used as the substrate. However, sluggish flow was observed for the PS film supported by hydrogen-passivated silicon substrates (H-Si). The differences in enthalpic interactions between PS and the substrates are the reason for this divergence in the whole-chain mobility and flow ability of thin PS films deposited on SiOx-Si and H-Si surfaces. These results indicate that this approach could be a reliable rheological probe for supported thin polymeric films with different thicknesses and various substrates.

Surface dynamics of poly(methyl methacrylate) films affected by the concentration of casting solutions.

The effect of the concentration of casting solutions on the surface dynamics of the corresponding spin-coated poly(methyl methacrylate) (PMMA) film was investigated by measuring the surface reorganization of fluorine tracer-labeled PMMA. The onset temperature of fluorinated PMMA chain end reorganization (T(onsetR)) was identified and is shown to depend on the PMMA concentration in the film-forming solution. It was found that the surface T(onsetR) and relaxation activation energy E(a) of the PMMA films prepared from 4.2 wt% PMMA cyclohexanone solution are 70 °C and 260 kJ mol(-1), respectively, which are higher than those of the PMMA films prepared from 0.8 wt% PMMA cyclohexanone solution (55 °C and 144 kJ mol(-1), respectively). The T(onsetR) and E(a) of PMMA films increased with increasing concentration of casting solutions within the range of 1.8 wt% to 4 wt%. The chain entanglement of PMMA chains is proposed to be the speculative origin for these observed depressed dynamics of poly(methyl methacrylate) chains on the films' surface prepared using casting solutions of various concentrations.