Dongfei Liu

Co-delivery of a hydrophobic small molecule and a hydrophilic peptide by porous silicon nanoparticles

Nanoparticulate drug delivery systems offer remarkable opportunities for clinical treatment. However, there are several challenges when they are employed to deliver multiple cargos/payloads, particularly concerning the synchronous delivery of small molecular weight drugs and relatively larger peptides. Since porous silicon (PSi) nanoparticles (NPs) can easily contain high payloads of drugs with various properties, we evaluated their carrier potential in multi-drug delivery for co-loading of the hydrophobic drug indomethacin and the hydrophilic human peptide YY3-36 (PYY3-36). Sequential loading of these two drugs into the PSi NPs enhanced the drug release rate of each drug and also their amount permeated across Caco-2 and Caco-2/HT29 cell monolayers. Regardless of the loading approach used, dual or single, the drug permeation profiles were in good correlation with their drug release behaviour. Furthermore, the permeation studies indicated the critical role of the mucus intestinal layer and the paracellular resistance in the permeation of the therapeutic compounds across the intestinal wall. Loading with PYY3-36 also greatly improved the cytocompatibility of the PSi NPs. Conformational analysis indicated that the PYY3-36 could still display biological activity after release from the PSi NPs and permeation across the intestinal cell monolayers. These results are the first demonstration of the promising potential of PSi NPs for simultaneous multi-drug delivery of both hydrophobic and hydrophilic compounds.

Microfluidic Assembly of Monodisperse Multistage pH‐Responsive Polymer/Porous Silicon Composites for Precisely Controlled Multi‐Drug Delivery

We report an advanced drug delivery platform for combination chemotherapy by concurrently incorporating two different drugs into microcompoistes with ratiometric control over the loading degree. Atorvastatin and celecoxib were selected as model drugs due to their different physicochemical properties and synergetic effect on colorectal cancer prevention and inhibition. To be effective in colorectal cancer prevention and inhibition, the produced microcomposite contained hypromellose acetate succinate, which is insoluble in acidic conditions but highly dissolving at neutral or alkaline pH conditions. Taking advantage of the large pore volume of porous silicon (PSi), atorvastatin was firstly loaded into the PSi matrix, and then encapsulated into the pH-responsive polymer microparticles containing celecoxib by microfluidics in order to obtain multi-drug loaded polymer/PSi microcomposites. The prepared microcomposites showed monodisperse size distribution, multistage pH-response, precise ratiometric controlled loading degree towards the simultaneously loaded drug molecules, and tailored release kinetics of the loaded cargos. This attractive microcomposite platform protects the payloads from being released at low pH-values, and enhances their release at higher pH-values, which can be further used for colon cancer prevention and treatment. Overall, the pH-responsive polymer/PSi-based microcomposite can be used as a universal platform for the delivery of different drug molecules for combination therapy.

Fabrication of a Multifunctional Nano‐in‐micro Drug Delivery Platform by Microfluidic Templated Encapsulation of Porous Silicon in Polymer Matrix

A multifunctional nano-in-micro drug delivery platform is developed by conjugating the porous silicon nanoparticles with mucoadhesive polymers and subsequent encapsulation into a pH-responsive polymer using microfluidics. The multistage platform shows monodisperse size distribution and pH-responsive payload release, and the released nanoparticles are mucoadhesive. Moreover, this platform is capable of simultaneously loading and releasing multidrugs with distinct properties.

Microfluidic assisted one-step fabrication of porous silicon@acetalated dextran nanocomposites for precisely controlled combination chemotherapy.

An advanced nanocomposite consisting of an encapsulated porous silicon (PSi) nanoparticle and an acid-degradable acetalated dextran (AcDX) matrix (nano-in-nano), was efficiently fabricated by a one-step microfluidic self-assembly approach. The obtained nano-in-nano PSi@AcDX composites showed improved surface smoothness, homogeneous size distribution, and considerably enhanced cytocompatibility. Furthermore, multiple drugs with different physicochemical properties have been simultaneously loaded into the nanocomposites with a ratiometric control. The release kinetics of all the payloads was predominantly controlled by the decomposition rate of the outer AcDX matrix. To facilitate the intracellular drug delivery, a nona-arginine cell-penetrating peptide (CPP) was chemically conjugated onto the surface of the nanocomposites by oxime click chemistry. Taking advantage of the significantly improved cell uptake, the proliferation of two breast cancer cell lines was markedly inhibited by the CPP-functionalized multidrug-loaded nanocomposites. Overall, this nano-in-nano PSi@polymer composite prepared by the microfluidic self-assembly approach is a universal platform for nanoparticles encapsulation and precisely controlled combination chemotherapy.

A Versatile and Robust Microfluidic Platform Toward High Throughput Synthesis of Homogeneous Nanoparticles with Tunable Properties

A versatile and robust microfluidic nanoprecipitation platform for high throughput synthesis of nanoparticles is fabricated. The versatility of this platform is proven through the successful preparation of different types of nanoparticles. This platform presents great robustness, with homogeneous nanoparticles always being obtained, regardless of the formulation parameters. The diameter and surface charge of the prepared nanoparticles can also be easily tuned.

Microfluidic Templated Mesoporous Silicon–Solid Lipid Microcomposites for Sustained Drug Delivery

A major challenge for a drug-delivery system is to engineer stable drug carriers with excellent biocompatibility, monodisperse size, and controllable release profiles. In this study, we used a microfluidic technique to encapsulate thermally hydrocarbonized porous silicon (THCPSi) microparticles within solid lipid microparticles (SLMs) to overcome the drawbacks accompanied by THCPSi microparticles. Formulation and process factors, such as lipid matrixes, organic solvents, emulsifiers, and methods to evaporate the organic solvents, were all evaluated and optimized to prepare monodisperse stable SLMs. FTIR analysis together with confocal images showed the clear deposition of THCPSi microparticles inside the monodisperse SLM matrix. The formation of monodisperse THCPSi-solid lipid microcomposites (THCPSi-SLMCs) not only altered the surface hydrophobicity and morphology of THCPSi microparticles but also remarkably enhanced their cytocompatibility with intestinal (Caco-2 and HT-29) cancer cells. Regardless of the solubility of the loaded therapeutics (aqueous insoluble, fenofibrate and furosemide; aqueous soluble, methotrexate and ranitidine) and the pH values of the release media (1.2, 5.0, and 7.4), the time for the release of 50% of the payloads from THCPSi-SLMC was at least 1.3 times longer than that from the THCPSi microparticles. The sustained release of both water-soluble and -insoluble drugs together with a reduced burst-release effect from monodisperse THCPSi-SLMC was achieved, indicating the successful encapsulation of THCPSi microparticles into the SLM matrix. The fabricated THCPSi-SLMCs exhibited monodisperse spherical morphology, enhanced cytocompatibility, and prolonged both water-soluble and -insoluble drug release, which makes it an attractive controllable drug-delivery platform.

Simple Microfluidic Approach to Fabricate Monodisperse Hollow Microparticles for Multidrug Delivery

Herein, we report the production of monodisperse hollow microparticles from three different polymers, namely, pH-responsive acetylated dextran and hypromellose acetate succinate and biodegradable poly(lactic-co-glycolic acid), at varying polymer concentrations using a poly(dimethylsiloxane)-based microfluidic device. Hollow microparticles formed during solvent diffusion into the continuous phase when the polymer close to the interface solidified, forming the shell. In the inner part of the particle, phase separation induced solvent droplet formation, which dissolved the shell, forming a hole and a hollow-core particle. Computational simulations showed that, despite the presence of convective recirculation around the droplet, the mass-transfer rate of the solvent dissolution from the droplet to the surrounding phase was dominated by diffusion. To illustrate the potential use of hollow microparticles, we simultaneously encapsulated two anticancer drugs and investigated their loading and release profiles. In addition, by utilizing different polymer shells and polymer concentrations, the release profiles of the model drugs could be tailored according to specific demands and applications. The high encapsulation efficiency, controlled drug release, unique hollow microparticle structure, small particle size (<7 μm), and flexibility of the polymer choice could make these microparticles advanced platforms for pulmonary drug delivery.

Core/Shell Nanocomposites Produced by Superfast Sequential Microfluidic Nanoprecipitation

Although a number of techniques exist for generating structured organic nanocomposites, it is still challenging to fabricate them in a controllable, yet universal and scalable manner. In this work, a microfluidic platform, exploiting superfast (milliseconds) time intervals between sequential nanoprecipitation processes, has been developed for high-throughput production of structured core/shell nanocomposites. The extremely short time interval between the sequential nanoprecipitation processes, facilitated by the multiplexed microfluidic design, allows us to solve the instability issues of nanocomposite cores without using any stabilizers. Beyond high throughput production rate (∼700 g/day on a single device), the generated core/shell nanocomposites harness the inherent ultrahigh drug loading degree and enhanced payload dissolution kinetics of drug nanocrystals and the controlled drug release from polymer-based nanoparticles.

Smart Porous Silicon Nanoparticles with Polymeric Coatings for Sequential Combination Therapy

In spite of the advances in drug delivery, the preparation of smart nanocomposites capable of precisely controlled release of multiple drugs for sequential combination therapy is still challenging. Here, a novel drug delivery nanocomposite was prepared by coating porous silicon (PSi) nanoparticles with poly(beta-amino ester) (PAE) and Pluronic F-127, respectively. Two anticancer drugs, doxorubicin (DOX) and paclitaxel (PTX), were separately loaded into the core of PSi and the shell of F127. The nanocomposite displayed enhanced colloidal stability and good cytocompatibility. Moreover, a spatiotemporal drug release was achieved for sequential combination therapy by precisely controlling the release kinetics of the two tested drugs. The release of PTX and DOX occurred in a time-staggered manner; PTX was released much faster and earlier than DOX at pH 7.0. The grafted PAE on the external surface of PSi acted as a pH-responsive nanovalve for the site-specific release of DOX. In vitro cytotoxicity tests demonstrated that the DOX and PTX coloaded nanoparticles exhibited a better synergistic effect than the free drugs in inducing cellular apoptosis. Therefore, the present study demonstrates a promising strategy to enhance the efficiency of combination cancer therapies by precisely controlling the release kinetics of different drugs.

Microfluidic assembly of a nano-in-micro dual drug delivery platform composed of halloysite nanotubes and a pH-responsive polymer for colon cancer therapy

Harsh conditions of the gastrointestinal tract hinder the oral delivery of many drugs. Developing oral drug delivery systems based on commercially available materials is becoming more challenging due to the demand for simultaneously delivering physicochemically different drugs for treating complex diseases. A novel architecture, namely nanotube-in-microsphere, was developed as a drug delivery platform by encapsulating halloysite nanotubes (HNTs) in a pH-responsive hydroxypropyl methylcellulose acetate succinate polymer using microfluidics. HNTs were selected as orally acceptable clay mineral and their lumen was enlarged by selective acid etching. Model drugs (atorvastatin and celecoxib) with different physicochemical properties and synergistic effect on colon cancer prevention and inhibition were simultaneously incorporated into the microspheres at a precise ratio, with atorvastatin and celecoxib being loaded in the HNTs and polymer matrix, respectively. The microspheres showed spherical shape, narrow particle size distribution and pH-responsive dissolution behavior. This nanotube/pH-responsive polymer composite protected the loaded drugs from premature release at pH⩽6.5, but allowed their fast release and enhanced the drug permeability, and the inhibition of colon cancer cell proliferation at pH 7.4. Overall, the nano-in-micro drug delivery composite fabricated by microfluidics is a promising and flexible platform for the delivery of multiple drugs for combination therapy. STATEMENT OF SIGNIFICANCE Halloysite nanotubes (HNTs) are attracting increasing attention for drug delivery applications. However, conventional HNTs-based oral drug delivery systems are lack of the capability to precisely control the drug release at a desired site in the gastrointestinal tract. In this study, a nanotube-in-microsphere drug delivery platform is developed by encapsulating HNTs in a pH-responsive polymer using microfluidics. Drugs with different physicochemical properties and synergistic effect on colon cancer therapy were simultaneously incorporated in the microspheres. The prepared microspheres prevented the premature release of the loaded drugs after exposure to the harsh conditions of the gastrointestinal tract, but allowed their simultaneously fast release, and enhanced the drug permeability and the inhibition of colon cancer cell proliferation in response to the colon pH.