Design of a multiple drug delivery system directed at periodontitis

Periodontal disease is highly prevalent, with 90% of the world population affected by either periodontitis or its preceding condition, gingivitis. These conditions are caused by bacterial biofilms on teeth, which stimulate a chronic inflammatory response that leads to loss of alveolar bone and, ultimately, the tooth. Current treatment methods for periodontitis address specific parts of the disease, with no individual treatment serving as a complete therapy. The present research sought to demonstrate development of a multiple drug delivery system for stepwise treatment of different stages of periodontal disease. More specifically, multilayered films were fabricated from an association polymer comprising cellulose acetate phthalate and Pluronic F-127 to achieve sequential release of drugs. The four types of drugs used were metronidazole, ketoprofen, doxycycline, and simvastatin to eliminate infection, inhibit inflammation, prevent tissue destruction, and aid bone regeneration, respectively. Different erosion times and adjustable sequential release profiles were achieved by modifying the number of layers or by inclusion of a slower-eroding polymer layer. Analysis of antibiotic and anti-inflammatory bioactivity showed that drugs released from the devices retained 100% bioactivity. The multilayered CAPP delivery system offers a versatile approach for releasing different drugs based on the pathogenesis of periodontitis and other conditions.     

白蛋白纳米粒的制备及内耳跨膜给药的初步研究

目的 目前在临床上国内外尚无对内耳病局部用药的缓释剂,本研究旨在探讨能否将白蛋白纳米粒载体材料作为鼓室跨膜给药缓释剂.方法 采用去溶剂化法制备空白白蛋白纳米粒并进行系统表征和细胞毒性评价.为便于观察,选取一种红色荧光染料即罗丹明B（RhB）作为模型药物,以物理吸附方式与空白白蛋白纳米粒结合形成载药白蛋白纳米粒,测定其载药量、包封率及体外药物释放曲线,同时采用小动物活体成像技术观察其注入豚鼠听泡内跨圆窗膜转运扩散情况.结果 制备的白蛋白纳米粒为实心球形,表面光滑,平均粒径大小为476 nm,Zeta电位为15.4 mV.体外药物释放结果表明,该纳米粒具有缓释效果.经戊二醛交联固定的白蛋白纳米粒具有一定的细胞毒性;而经热变性处理的白蛋白纳米粒具有较好的细胞相容性.小动物活体成像实验可以看到RhB在听泡内滞留扩散,而后经解剖观察,证明白蛋白纳米粒可在圆窗膜表面附着并穿越圆窗膜实现跨膜向耳蜗内转运.结论 制备的白蛋白纳米粒结构完整,制备方法简单、无毒性,可以很好地包载药物并具有缓释功能,为进一步制备可注射跨圆窗膜定向缓释纳米凝胶奠定了坚实的基础.     

Local drug delivery with a self-contained, programmable, microfluidic system

The development and optimization of many new drug therapies requires long-term local delivery with controlled, but variable dosage. Current methods for chronic drug delivery have limited utility because they either cannot deliver drugs locally to a specific organ or tissue, do not permit changes in delivery rate in situ, or cannot be used in clinical trials in an untethered, wearable configuration. Here, we describe a small, self-contained system for liquid-phase drug delivery. This system enables studies lasting several months and infusion rates can be programmed and modified remotely. A commercial miniature pump is integrated with microfabricated components to generate ultralow flow rates and stroke volumes. Solutions are delivered in pulses as small as 370 nL, with pulses delivered at any interval of 1 min or longer. A unique feature of the system is the ability to infuse and immediately withdraw liquid, resulting in zero net volume transfer while compounds are exchanged by mixing and diffusion with endogenous fluid. We present in vitro results demonstrating repeatability of the delivered pulse volume for nearly 3 months. Furthermore, we present in vivo results in an otology application, infusing into the cochlea of a guinea pig a glutamate receptor antagonist, which causes localized and reversible changes in auditory sensitivity. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

PEG-g-chitosan thermosensitive hydrogel for implant drug delivery: cytotoxicity,in vivo degradation and drug release

Thermosensitive hydrogels based on chitosan are of great interests for injectable implant drug delivery. The poly(ethylene glycol)-grafted-chitosan (PEG-g-CS) hydrogel was reported as a potential thermosensitive system. The objective of the present study is to evaluate the cytotoxicity, in vivo degradation and drug release of PEG-g-CS hydrogel. Cytotoxicity was evaluated using L929 murine fibrosarcoma cell line. Degradation and drug release in vivo were investigated by subcutaneous injection of the hydrogel into Sprague-Dawley rats. PEG-g-CS polymer exhibits no significant cytotoxicity when its concentration is less than 3 mg mL^?1. After being implanted, PEG-g-CS hydrogel maintains its integrity for two weeks and collapses, merging into the tissue, in the third week. It causes moderate inflammatory response but no fibrous encapsulation around the hydrogel is found. The hydrogel presents a three-week sustained release of cyclosporine A with no significant burst release in vitro and produces the effective drug concentration in blood for more than five weeks in vivo, performing almost the same bioavailability to chitosan/glycerophosphate hydrogel. Further modifications of PEG-g-CS hydrogel might be necessary to modulate the degradation and to mitigate the fluctuations in blood drug concentration.     

Biocompatibility and in vivo degradation of chitosan based hydrogels as potential drug carrier

Carboxymethyl chitosan-graft-polylactide (CMCS-PLA) and carboxymethyl chitosan (CMCS) hydrogels were prepared by using 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride/N-hydroxysuccinimide (EDC/NHS) as crosslinking agent and catalyst at room temperature. The biocompatibility of the hydrogels was evaluated with the aim of assessing their potential as drug carrier. Various aspects of biocompatibility were considered, including MTT assay, agar diffusion test, release of lactate dehydrogenase (LDH), hemolytic test, plasma recalcification time (PRT), and dynamic clotting time. MTT assay showed that the cytotoxicity level of both hydrogels to L-929 cells was 0 or 1. The LDH release of CMCS and CMCS-PLA was 26 and 29%, respectively, which is slightly higher than that of the negative control (21%) and much lower than that of the negative control (87%). The hemolysis ratio of CMCS and CMCS-PLA was 1.4 and 1.7%, respectively, suggesting outstanding anti-hemolysis properties of both materials. The PRT value of CMCS and CMCS-PLA was higher by 77 and 99% than the value of the positive control. All the results revealed that the hydrogels present good cytocompatibility and hemocompatibility in vitro. In vivo degradation and tissue compatibility were evaluated by subcutaneous injection in the dorsal area of rats. CMCS and CMCS-PLA hydrogels were completely degraded and the inflammatory response also completely disappeared around hydrogels after 19 days in vivo. It is thus concluded that hydrogels formed of CMCS and CMCS-PLA with outstanding biocompatibility are promising as potential drug carrier.     

Hypoxia-induced angiogenesis is increased by the controlled release of deferoxiamine from gelatin hydrogels

The objective of this study is to design biodegradable hydrogels for the controlled release of deferoxiamine (DFO) and evaluate their biological activity. When the DFO was added to human umbilical vein endothelial cells cultured in 5.0% O₂, the level of hypoxia-inducible factor-1α and vascular endothelial growth factor significantly increased compared with that without DFO. The expression of angiogenesis-related genes was accordingly increased by the DFO addition. An aqueous solution of mixed gelatin and DFO was freeze-dried, and dehydrothermally treated at 140 °C for 24 h to prepare a gelatin hydrogel incorporating DFO. In the release test with phosphate-buffered saline solution (PBS) at 37 °C, an initial DFO release of 60% was observed, followed by no release. When placed in PBS containing collagenase, the hydrogel was enzymatically degraded with time, and consequently released DFO in a degradation-dependent manner. After the hydrogel incorporating DFO was injected intramuscularly into a mouse model of hind limb ischemia, the number of new blood vessels formed was significantly higher than that with free DFO and DFO-free hydrogel. It is concluded that the DFO-containing hydrogel shows promising for inducing angiogenesis locally.     

Magnetic drug-targeting carrier encapsulated with thermosensitive smart polymer: core-shell nanoparticle carrier and drug release response

A novel magnetic drug-targeting carrier consisting of magnetic nanoparticles encapsulated with a smart polymer with characteristics of controlled drug release is described. The carrier is characterized by functionalized magnetite (Fe₃O₄) and conjugated therapeutic agent doxorubicin, which is encapsulated with the thermosensitive polymer, dextran-g-poly(N-isopropylacrylamide-co-N,N-dimethylacrylamide) [dextran-g-poly(NIPAAm-co-DMAAm)]. The surface of magnetite nanoparticles was functionalized by chemical bonding with 3-mercaptopropionic acid hydrazide (HSCH₂CH₂CONHNH₂) via Fe–S covalent bonds. The anticancer therapeutic drug, doxorubicin, was attached to the surface of the functionalized magnetic nanoparticles through an acid-labile hydrazone-bond, formed by the reaction of hydrazide group of HSCH₂CH₂CONHNH₂ with the carbonyl group of doxorubicin. The dextran-g-poly(NIPAAm-co-DMAAm) smart polymer exhibits a lower critical solution temperature (LCST) of 38 °C, which is representative of a phase transition behavior. This behavior allows for an on–off trigger mechanism. At an experimental temperature lower than LCST, the drug release was very low. However, at a temperature greater than LCST, there was an initially rapid drug release followed by a controlled released in the second stage, especially, in the mild acidic buffer solution of pH 5.3. The release of drug is envisaged to occur by the collapse of the encapsulated thermosensitive polymer and cleavage of the acid-labile hydrazone linkage. The proposed carrier is appropriately suitable for magnetic targeting drug delivery system with longer circulation time, reduced side effects and controlled drug release in response to the change in external temperature.     

Fabrication of multi-layered biodegradable drug delivery device based on micro-structuring of PLGA polymers

A programmable and biodegradable drug delivery device is desirable when a drug needs to be administered locally. While most local drug delivery devices made of biodegradable polymers relied on the degradation of the polymers, the degradation-based release control is often limited by the property of the polymers. Thus, we propose micro-geometry as an alternative measure of controlling drug release. The proposed devices consist of three functional layers: diffusion control layer via micro-orifices, diffusion layer, and drug reservoir layers. A micro-fabrication technology was used to shape an array of micro-orifices and micro-cavities in 85/15PLGA layers. A thin layer of fast degrading 50/50PLGA was placed as the diffusion layer between the 85/15PLGA layers to prevent any burst-type release. To modulate the release of the devices, the dimension and location of the micro-orifices were varied and the responding in vitro release response of tetracycline was monitored over 2 weeks. The release response to the different micro-geometry was prominent and further analyzed by FEM simulation. Comparison of the experiments to the simulated results identified that the variation of micro-geometry influenced also the volume-dependent degradation rate and induced the osmotic pressure.     

1994 whitaker lecture: Polymers for drug delivery and tissue engineering

This paper reviews three areas of the author's research. The first area concerns the development of technologies to release macromolecules continuously from solid polymers. By embedding solid protein (or other macromolecule) powders at the correct concentration in hydrophobic polymers, prolonged release for over 100 days can be achieved. The second area involves the synthesis of new biodegradable polymers specifically designed for drug delivery. A novel family of polymers, polyanhydrides, now being explored in a number of medical applications is examined. The use of these polymers to deliver chemotherapeutic agents locally may provide a new approach to treat brain cancer. The final research topic is in the area of tissue engineering. By placing mammalian cells on biodegradable polymer scaffolds, a variety of tissues have been created in animal models. Cartilage is discussed as a model tissue.     

Mathematical modeling of drug release from nanostructured porous Si: Combining carrier erosion and hindered drug diffusion for predicting release kinetics

A novel, empirical, macroscopic model is developed to describe the release of a model anticancer drug, Mitoxantrone, from native and chemically modified porous Si (PSi) thin films. Drug release from these carriers results from a combination of two mechanisms, i.e. out-diffusion of the drug molecules and erosion of the Si scaffold. Thus, the proposed mathematical model adapts the Crank model to lump the effects of temporal changes in molecular interactions and carrier scaffold erosion into a comprehensive model of hindered drug diffusion from nanoscale porous systems. Careful characterization of pore size, porosity, surface area, drug loading, as well as Si scaffold degradation profiles, measured over the same time-scale as drug release, are incorporated into the model parameter estimation. A comparison of the experimental and model results shows accurate representation of the data, emphasizing the reliability of the model. The proposed model shows that drug diffusivity values significantly vary with time for the two studied carriers, which are ascribed to the distinctive role of the prevailing physical mechanisms in each system. Finally, secondary validation of the proposed model is demonstrated by showing adequate fit to published data of the release of dexamethasone from similar mesoporous Si carriers.     

A stimulus-responsive magnetic nanoparticle drug carrier: magnetite encapsulated by chitosan-grafted-copolymer

We describe a magnetic nanoparticle drug carrier for controlled drug release that responds to the change in external temperature or pH, with characteristics of longer circulation time and reduced side effects. The novel nanocarrier is characterized by a functionalized magnetite (Fe(3)O(4)) core that is conjugated with drug via acid-labile hydrazone-bond and encapsulated by the thermosensitive smart polymer, chitosan-g-poly(N-isopropylacrylamide-co-N,N-dimethylacrylamide) [chitosan-g-poly(NIPAAm-co-DMAAm)]. The chitosan-g-poly(NIPAAm-co-DMAAm) smart polymer exhibits a lower critical solution temperature (LCST) of approximately 38 degrees C, signifying phase transition behavior of the smart polymer and enabling its use for triggering on-off mechanisms. The drug release response was appreciably low at a temperature less than the LCST as compared with a temperature above the LCST. In each case, there was an initial rapid drug release, followed by a controlled released in the second stage, especially in a mild acidic buffer solution of pH 5.3. We believe that the drug release occurs via a collapse of the encapsulated thermosensitive polymer and cleavage of the acid-labile hydrazone linkage.     

The binary complex of poly(PEGMA-co-MAA) hydrogel and PLGA nanoparticles as a novel oral drug delivery system for ibuprofen delivery

To improve the bioavailability of ibuprofen (IBU), we developed a novel binary complex of poly(PEGMA-co-MAA) hydrogel and IBU-loaded PLGA nanoparticles (IBU-PLGA NPs@hydrogels) as an oral intestinal targeting drug delivery system (OIDDS). The IBU-loaded PLGA NPs and pH-sensitive hydrogels were obtained via the solvent evaporation method and radical polymerization, respectively. The final OIDDS was obtained by immersing the hydrogel chips in the IBU-loaded PLGA NPs solutions (pH 7.4) for 3 d. The size distribution and morphology of cargo-free NPs were studied by laser granularity analyzer and transmission electron microscope (TEM). The inner structures of the pH-sensitive hydrogel chips were observed with an S-4800 scanning electron microscope (SEM). The distribution states of IBU in the OIDDS were also studied with X-ray diffraction (XRD) and differential scanning calorimetry (DSC). TEM photographs illustrated that the PLGA NPs had a round shape with an average diameter about 100 nm. Fourier transform infrared spectrum (FTIR) confirmed the synthesis of poly(PEGMA-co-MAA) hydrogel. The SEM picture showed that the final hydrogel had 3D net-work structures. Moreover, the poly(PEGMA-co-MAA) hydrogel showed an excellent pH-sensitivity. The XRD and DSC curves suggested that IBU distributed in the OIDDS with an amorphous state. The cumulated release profiles indicated that the final OIDDS could release IBU in alkaline environment (e.g. intestinal tract) at a sustained manner. Therefore, the novel OIDDS could improve the oral bioavailability of IBU, and had a potential application in drug delivery.     

纳米粒子作为药物输送和药物控释体系的应用前景

纳米粒子作为药物和基因的载体显现出极大的潜力并被广泛研究。纳米粒子的超微小体积可使药物输送智能化,例如靶向定位地将药物投递到病灶局部或专一性地作用于靶细胞。纳米粒子的载体材料可屏蔽药物不良气味、维持药物长期缓慢释放、延长药物半衰期和减小毒副作用等。本文将从纳米药物输送、控释制剂的制备和应用前景等方面进行综述。     

On the suitability of nanocrystalline ferrites as a magnetic carrier for drug delivery: functionalization, conjugation and drug release kinetics

Superparamagnetic nickel ferrite nanoparticles functionalized with polyvinyl alcohol, polyethylene oxide and polymethacrylic acid (PMAA) polymers and subsequently conjugated with doxorubicin anti-cancer drug are studied for their use as a magnetic carrier for drug delivery. Fourier transform infrared spectroscopy enabled examination of the ability of the nanoparticles to be functionalized with polymers and conjugated with doxorubicin drug. The functionalized polymer-coated nanocrystalline nickel ferrites retain the magnetic characteristics of non-functionalized nanocrystalline nickel ferrites (superparamagnetism, absence of hysteresis, remanence and coercivity at room temperature), encouraging their application as a magnetic carrier for drug delivery. The PMAA-coated nanoferrites are demonstrated as being a potentially superior magnetically targeted drug carrier based on FTIR results and drug release kinetics in the absence and presence of an external magnetic field.     

透皮给药研究的新进展

透皮给药安全可控，是无创给药的新途径，有着广阔的市场前景。现有的透皮药物限于小分子和低浓度，角质层屏障使大多数药物难以通过或难以达到有效浓度和有效速率。透皮给药的关键在于促进药物渗透，使药物透皮吸收进毛细血管。促渗手段有：使用化学促渗剂；对药物进行化学修饰制成前体药物；使用物理方法；将药物载入载体。这些方法的原理大致分为三种：改变角质层结构；外力驱动药物；将药物进行修饰或包裹。简要地介绍了增强药物透皮的物理方法和载体方法研究的新进展。     

Iron-oxide embedded solid lipid nanoparticles for magnetically controlled heating and drug delivery

This paper presents the development of magnetic lipid nanoparticles that could serve as controlled delivery vehicles for releasing encapsulated drugs in a desired manner. The nanoparticles are composed of multiple drugs in lipid matrices, which are solid at body temperature and melt around 45°C to 55°C. In addition, super-paramagnetic γ-Fe₂O₃ particles with sizes ranging from 5 to 25 nm are surface modified and dispersed uniformly in the lipid nanoparticles. In the prototype demonstration, lipid nanoparticles with average sizes between 100 and 180 nm were fabricated by high-pressure homogenization at elevated temperatures. When exposed to an alternating magnetic field of 60 kA/m at 25 kHz, a solution containing 2 g/L encapsulated γ-Fe₂O₃ particles showed a temperature increase from 37°C to 50°C in 20 min. Meanwhile, the dissipated heat melted the surrounding lipid matrices and resulted in an accelerated release of the encapsulated drugs. Within 20 min, approximately 35% of the encapsulated drug molecules were released from the lipid nanoparticles through diffusion. As such, the presented lipid nanoparticles enable a new scheme that combines magnetic control of heating and drug delivery, which could greatly enhance the performance of encapsulated drugs. A portion of this paper was presented in the 11th International Conference on Miniaturized Systems for Chemistry and Life Sciences, Paris, France, October 2007.     

碳纳米管在药物递送载体及肿瘤热疗应用方面的研究进展

目前,大多数抗癌药物在临床应用中存在着溶解性差、靶向性低、对正常组织器官毒性大等局限性,而药物载体的应用可在一定程度上缓解这些现象.近年来,一些材料如聚合物、脂质类、碳纳米管(CNTs)等被用作抗癌药物的载体,并通过对载体进行靶向修饰,使其在体内缓慢释放以维持一定的血药浓度,从而提高药物的靶向性,减少不良反应.其中,CNTs作为一种新兴的纳米材料,在纳米医学中的应用备受关注.CNTs具有纳米级管径,中空结构和较大的长径比使其具有较大的药物容量,且CNTs可选择性吸收近红外光并转化为热能,因此采用功能化的CNTs携载药物并结合热疗对肿瘤进行靶向治疗有望成为一种新的治疗手段.就CNTs的基本结构、作为药物载体的应用及其结合热疗在肿瘤治疗方面的研究现状作一综述.     

Building a polysaccharide hydrogel capsule delivery system for control release of ibuprofen

Development of a delivery system which can effectively carry hydrophobic drugs and have pH response is becoming necessary. Here we demonstrate that through preparation of β-cyclodextrin polymer (β-CDP), a hydrophobic drug molecule of ibuprofen (IBU) was incorporated into our prepared β-CDP inner cavities, aiming to improve the poor water solubility of IBU. A core-shell capsule structure has been designed for achieving the drug pH targeted and sustained release. This delivery system was built with polysaccharide polymer of Sodium alginate (SA), sodium carboxymethylcellulose (CMC) and hydroxyethyl cellulose (HEC) by physical cross-linking. The drug pH-response control release is this hydrogel system’s chief merit, which has potential value for synthesizing enteric capsule. Besides, due to our simple preparing strategy, optimal conditions can be readily determined and the synthesis process can be accurately controlled, leading to consistent and reproducible hydrogel capsules. In addition, phase-solubility method was used to investigate the solubilization effect of IBU by β-CDP. SEM was used to prove the forming of core and shell structure. FT-IR and ¹H-NMR were also used to perform structural characteristics. By the technique of UV determination, the pH targeted and sustained release study were also performed. The results have proved that our prepared polysaccharide hydrogel capsule delivery system has potential applications as oral drugs delivery in the field of biomedical materials.     

透皮给药研究的新进展

透皮给药安全可控,是无创给药的新途径,有着广阔的市场前景。现有的透皮药物限于小分子和低浓度,角质层屏障使大多数药物难以通过或难以达到有效浓度和有效速率。透皮给药的关键在于促进药物渗透,使药物透皮吸收进毛细血管。促渗手段有:使用化学促渗剂;对药物进行化学修饰制成前体药物;使用物理方法;将药物载入载体。这些方法的原理大致分为三种:改变角质层结构;外力驱动药物;将药物进行修饰或包裹。简要地介绍了增强药物透皮的物理方法和载体方法研究的新进展。     

Chitosan nanoparticle/PCL nanofiber composite for wound dressing and drug delivery

Many investigations of wound dressings equipped with drug delivery systems have recently been conducted. Chitosan is widely used not only as a material for wound dressing by the efficacy of its own, but also as a nanoparticle for drug delivery. In this study, an electrospun polycaprolactone nanofiber composite with chitosan nanoparticles (ChiNP–PCLNF) was fabricated and then evaluated for its drug release and biocompatibility to skin fibroblasts. ChiNP–PCLNF complexes showed no cytotoxicity and nanoparticles adsorbed by van der Waals force were released into aquatic environments and then penetrated into rat primary fibroblasts. Our studies demonstrate the potential for application of ChiNP–PCLNF as a wound dressing system with drug delivery for skin wound healing without side effects.