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.     

可生物降解高分子微针的制作及透皮应用

透皮给药相比于传统的给药方式,具有更多的优势．但是,皮肤的角质层能够阻止外源性物质的侵犯,限制了透皮给药系统的应用．为此,基于微针的透皮给药系统的提出增大了透皮给药系统的应用范围．首先,采用MEM技术制作单晶硅微针．接下来,提出一种新颖、简单而且经济的方法快速制作聚乳酸微针．通过理论分析及有限元分析微针的力学性能,表明微针有足够的强度．体外透皮实验表明,未经微针处理的皮肤,钙黄绿素10h的累计渗透量只有0．17±0．07 μg／cm2;手动进针处理的皮肤只达到4．54±1．17 μg／cm2,比未用微针处理的皮肤增加了30倍;经过进针器处理的皮肤,各个时间点的渗透量均有显著性提高（P〈0．05）,渗透量达到45．37±5．80 μg／cm2,比未用微针处理的皮肤增加了300倍．所有的结果都表明,本实验室制备可降解的聚乳酸微针的方法新颖、快速且经济,而且对于透皮给药系统来说具有很大的潜在价值．     

Microfluidic Synthesis of pH‐Sensitive Multicompartmental Microparticles for Multimodulated Drug Release

Stimuli‐responsive carriers releasing multiple drugs have been researched for synergistic combinatorial cancer treatment with reduced side‐effects. However, previously used drug carriers have limitations in encapsulating multiple drug components in a single carrier and releasing each drug independently. In this work, pH‐sensitive, multimodulated, anisotropic drug carrier particles are synthesized using an acid‐cleavable polymer and stop‐flow lithography. The particles exhibit a faster drug release rate at the acidic pH of tumors than at physiological pH, demonstrating their potential for tumor‐selective drug release. The drug release rate of the particles can be adjusted by controlling the monomer composition. To accomplish multimodulated drug release, multicompartmental particles are synthesized. The drug release profile of each compartment is programmed by tailoring the monomer composition. These pH‐sensitive, multicompartmental particles are promising drug carriers enabling tumor‐selective and multimodulated release of multiple drugs for synergistic combination cancer therapy.     

Inhibition of 3‐D Tumor Spheroids by Timed‐Released Hydrophilic and Hydrophobic Drugs from Multilayered Polymeric Microparticles

First‐line cancer chemotherapy necessitates high parenteral dosage and repeated dosing of a combination of drugs over a prolonged period. Current commercially available chemotherapeutic agents, such as Doxil and Taxol, are only capable of delivering single drug in a bolus dose. The aim of this study is to develop dual‐drug‐loaded, multilayered microparticles and to investigate their antitumor efficacy compared with single‐drug‐loaded particles. Results show hydrophilic doxorubicin HCl (DOX) and hydrophobic paclitaxel (PTX) localized in the poly(dl ‐lactic‐co‐glycolic acid, 50:50) (PLGA) shell and in the poly(l ‐lactic acid) (PLLA) core, respectively. The introduction of poly[(1,6‐bis‐carboxyphenoxy) hexane] (PCPH) into PLGA/PLLA microparticles causes PTX to be localized in the PLLA and PCPH mid‐layers, whereas DOX is found in both the PLGA shell and core. PLGA/PLLA/PCPH microparticles with denser shells allow better control of DOX release. A delayed release of PTX is observed with the addition of PCPH. Three‐dimensional MCF‐7 spheroid studies demonstrate that controlled co‐delivery of DOX and PTX from multilayered microparticles produces a greater reduction in spheroid growth rate compared with single‐drug‐loaded particles. This study provides mechanistic insights into how distinctive structure of multilayered microparticles can be designed to modulate the release profiles of anticancer drugs, and how co‐delivery can potentially provide better antitumor response.     

聚乳酸类可生物降解材料在缓控释药物制剂中的应用

综述了用聚乳酸类可生物降解型高分子材料制备缓控释药物载体的研究现状.分别介绍了该类材料在微粒给药载体、凝胶制剂、缓释支架和埋植制剂的应用及其制备方法.阐述了目前聚乳酸类生物降解材料在缓控释药物制剂中的主要问题,展望了其发展前景.     

Microfluidic Production of Biodegradable Microcapsules for Sustained Release of Hydrophilic Actives

Biodegradable microcapsules with a large aqueous lumen and ultrathin membrane are microfluidically designed for sustained release of hydrophilic bioactives using water‐in‐oil‐in‐water double‐emulsion drops as a template. As a shell phase, an organic solution of poly(lactic‐co‐glycolic acid) is used, which is consolidated to form a biodegradable membrane. The encapsulants stored in the lumen are released over a long period of time as the membranes degrade. The period can be controlled in a range of —three to five months at neutral pH condition by adjusting membrane thickness, providing highly sustained release and potentially enabling the programed release of multiple drugs. At acidic or basic condition, the degradation is accelerated, leading to the release in the period of approximately two months. As the membrane is semipermeable, the microcapsules respond to the osmotic pressure difference across the membrane. The microcapsules are inflated in hypotonic condition and deflated in hypertonic condition. Both conditions cause cracks on the membrane, resulting in the fast release of encapsulants in a day. The microcapsules implanted in mice also show sustained release, despite the period is decreased to a month. It is believed that the microcapsules are promising for the in vivo sustained release of drugs for high and long‐term efficacy.     

Multifunctional Hybrid Nanoparticles for Traceable Drug Delivery and Intracellular Microenvironment‐Controlled Multistage Drug‐Release in Neurons

Innovative nanoparticles hold promising potential for disease therapy as drug delivery systems. For brain‐disease therapy, a drug delivery system that can sustainably control drug‐release and monitor fluorescence of the drug cargos is highly desirable. In this study, a light‐traceable and intracellular microenvironment‐responsive drug delivery system was developed based on the combination of glutathione‐responsive autoflurescent nanogel, dendrimer‐like mesoporous silica nanoparticles, and gold nanoparticles. The resulting hybrid nanoparticles represent a new class of delivery system that can efficiently load, transport, and control multistage‐release of sulfydryl‐containing drugs into neurons, with light‐traceable monitoring for future brain‐disease therapy.     

One‐Step Fabrication of Triple‐Layered Polymeric Microparticles with Layer Localization of Drugs as a Novel Drug‐Delivery System

Particulate systems have tremendous potential to achieve controlled release and targeted delivery of drugs. However, conventional single‐layered particles have several inherent limitations, including initial burst release, the inability to provide zero‐order release, and a lack of time‐delayed or pulsatile release of therapeutic agents. Multilayered particles have the potential to overcome these disadvantages. Herein, it is shown how triple‐layered polymeric microparticles can be fabricated through a simple, economical, reliable, and versatile one‐step solvent evaporation technique. Particle morphologies and layer configurations are determined by scanning electron microscopy, polymer dissolution tests, and Raman mapping. Key fabrication parameters that affect the formation of triple‐layered polymeric microparticles comprising poly(DL ‐lactide‐co‐glycolide) (50:50), poly(L ‐lactide), and poly(ethylene‐co‐vinyl acetate) (40 wt% vinyl acetate) are discussed, along with their formation mechanisms. Layer thickness and the configurations of these microparticles are altered by changing the polymer mass ratios. Finally, it is shown that drugs can be localized in specific layers of the microparticles. This fabrication process can therefore be used to tailor microparticle designs, thus allowing such “designer” particulate drug‐delivery systems to function across a wide range of applications.     

Rapid Quantification of Live Cell Receptors Using Bioluminescence in a Flow‐Based Microfluidic Device

The number of receptors expressed by cells plays an important role in controlling cell signaling events, thus determining its behaviour, state and fate. Current methods of quantifying receptors on cells are either laborious or do not maintain the cells in their native form. Here, a method integrating highly sensitive bioluminescence, high precision microfluidics and small footprint of lensfree optics is developed to quantify cell surface receptors. This method is safe to use, less laborious, and faster than the conventional radiolabelling and near field scanning methods. It is also more sensitive than fluorescence based assays and is ideal for high throughput screening. In quantifying β₁ adrenergic receptors expressed on the surface of H9c2 cardiomyocytes, this method yields receptor numbers from 3.12 × 10⁵ to 9.36 × 10⁵ receptors/cell which are comparable with current methods. This can serve as a very good platform for rapid quantification of receptor numbers in ligand/drug binding and receptor characterization studies, which is an important part of pharmaceutical and biological research.     

Mesoporous Silica Nanoparticles for Intracellular Controlled Drug Delivery

The application of nanotechnology in the field of drug delivery has attracted much attention in the latest decades. Recent breakthroughs on the morphology control and surface functionalization of inorganic‐based delivery vehicles, such as mesoporous silica nanoparticles (MSNs), have brought new possibilities to this burgeoning area of research. The ability to functionalize the surface of mesoporous‐silica‐based nanocarriers with stimuli‐responsive groups, nanoparticles, polymers, and proteins that work as caps and gatekeepers for controlled release of various cargos is just one of the exciting results reported in the literature that highlights MSNs as a promising platform for various biotechnological and biomedical applications. This review focuses on the most recent progresses in the application of MSNs for intracellular drug delivery. The latest research on the pathways of entry into live mammalian and plant cells together with intracellular trafficking are described. One of the main areas of interest in this field is the development of site‐specific drug delivery vehicles; the contribution of MSNs toward this topic is also summarized. In addition, the current research progress on the biocompatibility of this material in vitro and in vivo is discussed. Finally, the latest breakthroughs for intracellular controlled drug release using stimuli‐responsive mesoporous‐silica‐based systems are described.     

Engineering Biomimetic Platesomes for pH‐Responsive Drug Delivery and Enhanced Antitumor Activity

Biomimetic camouflage, i.e., using natural cell membranes for drug delivery, has demonstrated advantages over synthetic materials in both pharmacokinetics and biocompatibility, and so represents a promising solution for the development of safe nanomedicine. However, only limited efforts have been dedicated to engineering such camouflage to endow it with optimized or additional properties, in particular properties critical to a “smart” drug delivery system, such as stimuli‐responsive drug release. A pH‐responsive biomimetic “platesome” for specific drug delivery to tumors and tumor‐triggered drug release is described. This platesome nanovehicle is constructed by merging platelet membranes with functionalized synthetic liposomes and exhibits enhanced tumor affinity, due to its platelet membrane–based camouflage, and selectively releases its cargo in response to the acidic microenvironment of lysosomal compartments. In mouse cancer models, it shows significantly better antitumor efficacy than nanoformulations based on a platesome without pH responsiveness or those based on traditional pH‐sensitive liposomes. A convenient way to incorporate stimuli‐responsive features into biomimetic nanoparticles is described, demonstrating the potential of engineered cell membranes as biomimetic camouflages for a new generation of biocompatible and efficient nanocarriers.     

Cellulose‐Based Microparticles for Magnetically Controlled Optical Modulation and Sensing

Responsive materials with birefringent optical properties have been exploited for the manipulation of light in several modern electronic devices. While electrical fields are often utilized to achieve optical modulation, magnetic stimuli may offer an enticing complementary approach for controlling and manipulating light remotely. Here, the synthesis and characterization of magnetically responsive birefringent microparticles with unusual magneto‐optical properties are reported. These functional microparticles are prepared via a microfluidic emulsification process, in which water‐based droplets are generated in a flow‐focusing device and stretched into anisotropic shapes before conversion into particles via photopolymerization. Birefringence properties are achieved by aligning cellulose nanocrystals within the microparticles during droplet stretching, whereas magnetic responsiveness results from the addition of superparamagnetic nanoparticles to the initial droplet template. When suspended in a fluid, the microparticles can be controllably manipulated via an external magnetic field to result in unique magneto‐optical coupling effects. Using a remotely actuated magnetic field coupled to a polarized optical microscope, these microparticles can be employed to convert magnetic into optical signals or to estimate the viscosity of the suspending fluid through magnetically driven microrheology.