Magnetic drug targeting. II. targeted drug transport by magnetic microp articles: factors influencing therapeutic effect

The kinetic aspects of magnetically targeted drug transport are considered. The influence of the magnetic drug carrier properties, the transported drug and the target parameters on the biological effect of the drug is discussed. The mathematical model reflecting the mass-transfer processes in a blood flow system is used for the estimation of the influence of these factors on the therapeutic effect of the drug delivered to the target. The character of the effect of drug release parameters, rate of drug released inactivation and the intensity of carrier capture in the liver is shown. Mathematical modelling of magnetically targeted drug kinetics allows possibilities for prognosis of drug effects.     

Develop a novel superparamagnetic nano-carrier for drug delivery to brain glioma

Abstract

Magnetic drug carrier has been employed in drug delivery for over 30 years. Modern nanotechnology has improved its efficiency dramatically by decreasing its diameter into nano-scale. It may help chemotherapeutic agents penetrate BBB and raise local drug concentration in brain, which is the ideal model for glioma treatment. In our study, magnetic carrier was fabricated with octadecyl quaternized caroxymethyl chitosan (OQCMC), hydrophobic Fe₃O₄ ferrofluid and cholesterol, which showed a uniform diameter of 20?nm under transmission electronic microscopy and superparamagnetic character in vibration sample magnetical measurement system. To investigate the efficacy of drug delivery, paclitaxel was used as loaded drug and analyzed by the HPLC. Results showed that magnetic carrier released drugs for more than 20?d in vitro and maintain the drug concentration above 0.4?μg/g for 16?h in rat brain after magnetic targeting. Drug concentration increased by 1–3 folds when delivered by carrier without magnetic targeting, and by 3–15 folds after magnetic targeting. Cellular study revealed that the magnetic carrier was clearly localized in the targeted cortex neural cells and U251-MG cell lines. These results showed that this magnetic carrier is capable of maintaining high drug concentration in magnetically targeted area and carrying drugs or genes into cells, which is potentially promising for local chemotherapy to brain tumors.     

磁性药物载体在抗肿瘤方面的研究进展

通过外加磁场的引导作用,使负载抗癌药物的磁性载体靶向定位于靶区,提高靶组织的药物浓度,有效降低药物对正常组织或细胞的毒副作用及其他不良反应。磁性药物载体还具有靶向性、缓释、控释等优点,已成为了肿瘤靶向治疗常用的新型载体系统。本文综述了磁性药物载体磁性纳米颗粒、磁性脂质体、磁性微球在肿瘤治疗与诊断中的应用进展。     

还原响应型药物载体的研究进展

还原响应型药物载体以其高效快速释放药物、毒副作用小、可生物降解的优良特性,逐渐成为药物载体领域研究的热点,也是最具临床应用潜力的智能药物载体之一。本文综述了还原响应型药物载体研究的最新进展,包括还原响应的药物、基因与载体的偶联物及还原响应的纳米聚合物胶束、纳米囊泡、纳米中空微球、纳米脂质体等的合成和药物释放的机制以及各类载体的优缺点,为其在药剂学中的进一步应用提供理论依据。     

树状大分子作为新型药物载体的研究进展

树状大分子是一类高度枝化的单分散性大分子，其内部结构呈疏水性，外表面呈亲水性，可称为“单分子胶束”。本文在简介树状大分子的发展及结构特点的基础上，阐述了树状大分子作为药物载体的作用特点及其与药物的结合方式。目前，树状大分子在介导药物靶向传递及基因转染等方面的应用也备受关注，是一种颇有发展潜力的新型载体。     

Nanostructured lipid carriers system: Recent advances in drug delivery

Nanostructured lipid carrier (NLC) is second generation smarter drug carrier system having solid matrix at room temperature. This carrier system is made up of physiological, biodegradable and biocompatible lipid materials and surfactants and is accepted by regulatory authorities for application in different drug delivery systems. The availability of many products in the market in short span of time reveals the success story of this delivery system. Since the introduction of the first product, around 30 NLC preparations are commercially available. NLC exhibit superior advantages over other colloidal carriers viz., nanoemulsions, polymeric nanoparticles, liposomes, SLN etc. and thus, have been explored to more extent in pharmaceutical technology. The whole set of unique advantages such as enhanced drug loading capacity, prevention of drug expulsion, leads to more flexibility for modulation of drug release and makes NLC versatile delivery system for various routes of administration. The present review gives insights on the definitions and characterization of NLC as colloidal carriers including the production techniques and suitable formulations. This review paper also highlights the importance of NLC in pharmaceutical applications for the various routes of drug delivery viz., topical, oral, pulmonary, ocular and parenteral administration and its future perspective as a pharmaceutical carrier.     

The influence of drug loading on formulation structure and aerosol performance in carrier based dry powder inhalers

Previous studies have reported that carrier:drug ratio and carrier size influence the aerosol performance of dry powder inhalation systems. These previous studies were complicated by the heterogeneous nature of the carriers used, making it difficult to define an explicit relationship between parameters and performance. Here, the authors studied the influence of drug loading and carrier size on drug aerosol performance using homogeneous spherical model carriers. Different formulations containing drug (salbutamol sulphate) and carriers (polystyrene beads with median diameters of 82.8 μm, 277.5 μm and 582.9 μm, respectively) were prepared by varying the ratio of carrier to drug (from ∼5:1 to ∼85:1). The surface morphology of the carrier particles and force of adhesion were investigated using atomic force microscopy, while the aerosol performance was evaluated using a multi-stage liquid impinger. The carrier surface morphology for all carrier sizes was homogenous with root-mean square roughness values ≤112 nm. No significant difference in the force of adhesion between salbutamol sulphate and the three carrier sizes was observed. Significant differences in aerosol performance of salbutamol sulphate (measured as fine particle dose (FPD) and fraction (FPF) ≤ 5 μm) from the carriers were observed. Specifically, as carrier size increased FPF decreased. In comparison, as drug loading increased there was no change in FPF until a critical threshold was exceeded. Such observations suggest that: (A) aerosolisation performance is governed by carrier collisions and (B) when homogeneous carriers are used, the aerosol performance remains constant with respect to drug concentration, until the formulation transitions from an ordered mix to an agglomerated and/or segregated powder bed.     

Capture of magnetic carriers within large arteries using external magnetic fields

Our overall research goal is to advance the safety and effectiveness of acute ischemic stroke therapy by improving the benefit/risk ratio of thrombolysis and hence, the long-term outcome of acute ischemic stroke victims. Our approach is the development of a novel tissue plasminogen activator (t-PA) delivery system based on t-PA-loaded magnetic nano- and microcarriers guided directly to the site of vascular occlusion by external magnetic fields. Such a t-PA delivery system would conveniently combine the advantages of both intravenous (systemic) and intraarterial (catheter-facilitated) thrombolysis: non-invasiveness—the magnetic t-PA carriers can be injected intravenously and targeted, as drug delivery is magnetically guided to and t-PA focally released at and within the vascular clot to induce lysis. The focus of our discussion are the two necessary, fundamental and interrelated bioengineering steps: the research and development of well-characterized, biocompatible, functionally active and t-PA-loaded (encapsulated) magnetic nano- and microcarriers able to induce effective thrombolysis, and the design of magnetic guidance systems for targeted tPA-delivery allowing also the triggered release of the thrombolytic agent at the clot site. In this paper, we theoretically demonstrated magnetic trapping of blood borne magnetic nano- and microcarriers from human large vessels, especially arteries. Then, some preliminary experiments using primate models (monkeys) were done to identify successful in vivo sequestration of magnetic carriers in large and smaller arterial branches after arterial upstream and systemic venous injection. Histology (hematoxylin–eosin stain) verified intraarterial carrier concentration (identified as black carrier agglomerates on H and E staining) at the arterial region above the surface magnet. The results revealed the feasibility of magnetic drug-targeting at arteries and solidified the proposed t-PA delivery system.     

Nanoparticles as drug delivery systems

Controlled drug delivery systems (DDS) have several advantages compared to the traditional forms of drugs. A drug is transported to the place of action, hence, its influence on vital tissues and undesirable side effects can be minimized. Accumulation of therapeutic compounds in the target site increases and, consequently, the required doses of drugs are lower. This modern form of therapy is especially important when there is a discrepancy between the dose or the concentration of a drug and its therapeutic results or toxic effects. Cell-specific targeting can be accomplished by attaching drugs to specially designed carriers. Various nanostructures, including liposomes, polymers, dendrimers, silicon or carbon materials, and magnetic nanoparticles, have been tested as carriers in drug delivery systems. In this review, the aforementioned nanocarriers and their connections with drugs are analyzed. Special attention is paid to the functionalization of magnetic nanoparticles as carriers in DDS. Then, the advantages and disadvantages of using magnetic nanoparticles as DDS are discussed.     

Polymeric micelles with stimuli-triggering systems for advanced cancer drug targeting

Abstract

Since the 1990s, nanoscale drug carriers have played a pivotal role in cancer chemotherapy, acting through passive drug delivery mechanisms and subsequent pharmaceutical action at tumor tissues with reduction of adverse effects. Polymeric micelles, as supramolecular assemblies of amphiphilic polymers, have been considerably developed as promising drug carrier candidates, and a number of clinical studies of anticancer drug-loaded polymeric micelle carriers for cancer chemotherapy applications are now in progress. However, these systems still face several issues; at present, the simultaneous control of target-selective delivery and release of incorporated drugs remains difficult. To resolve these points, the introduction of stimuli-responsive mechanisms to drug carrier systems is believed to be a promising approach to provide better solutions for future tumor drug targeting strategies. As possible trigger signals, biological acidic pH, light, heating/cooling and ultrasound actively play significant roles in signal-triggering drug release and carrier interaction with target cells. This review article summarizes several molecular designs for stimuli-responsive polymeric micelles in response to variation of pH, light and temperature and discusses their potentials as next-generation tumor drug targeting systems.     

纳米多孔二氧化硅作为药物载体的研究进展

目的介绍几种纳米多孔二氧化硅作为药物载体的应用及最新发展动态。方法以国内外有代表性的文献资料31篇为依据,对介孔二氧化硅、二氧化硅气凝胶、微粉硅胶等几种多孔二氧化硅药物载体的结构特性、应用及发展动态进行分析、整理和归纳。结果纳米多孔二氧化硅作为药物载体,借助于其纳米孔道结构、形貌或孔道的控制及表面功能化修饰,可以实现药物的速释、缓释及pH或温度敏感释放。结论纳米多孔二氧化硅作为药物载体具有广阔的应用前景。     

Driving forces for drug loading in drug carriers

Abstract

The loading capacity of a drug carrier is determined essentially by intermolecular interactions between drugs and carrier materials. In this review, the process of drug loading is described in detail based on the differences in the driving force for drug incorporation, including hydrophobic interaction, electrostatic interaction, hydrogen bonding, Pi–Pi stacking and van der Waals force. Modifying drug-loading sites of carrier materials with interacting groups aiming at tailoring drug–carrier interactions is reviewed by highlighting its importance for improving in vitro properties such as the loading capacity, release behaviour and stability. Other factors affecting drug loading, methods employed to predict the encapsulation capacity and the techniques to verify intermolecular interactions are also discussed to inform the readers of all-sided information on drug-loading processes and theories. The drug carriers can be designed more reasonably with the better understanding of the nature and interacting mechanism of intermolecular interactions.     

Theoretical analysis of the release of drug from completely dissolving carriers containing drug particles

The approach of "controlled supply of slow-release particles" is evaluated for a dissolving carrier system containing drug particles. Drug dissolution from this system is calculated after solving a convolution integral. The effects of geometry and relative dissolution time between drug particles and carrier device on drug dissolution kinetics are considered. Minima in the deviation of the dissolution profiles from linearity as a function of relative dissolution time are found. The impacts of geometry on the minima are discussed. Incorporation of a second system of isometric drug particles in an isometric carrier shows less deviation from constant-release kinetics when suitable values of the parameters affecting drug release are used in the calculations. A substantially constant rate of release of drug can be realized for a system of two carriers, each containing "slow-release" drug particles. The initial deviation from linearity in the sigmoidally shaped profile of drug dissolved in time from one of the two carriers is eliminated by the release of dissolved drug from the second carrier. About 80% of the drug content is dissolved at a constant rate by the combination of the two carriers.     

透明质酸及其衍生物用作药物载体的研究进展

鉴于透明质酸具有良好的生物相容性、生物可降解性、无免疫原性,以及对肿瘤细胞的高亲和性,透明质酸及其衍生物作为新型药物载体的研究备受瞩目。综述近年来透明质酸及其衍生物作为药物载体的应用研究进展,主要包括纳米粒、凝胶、阳离子聚合物基因载体等方面。     

Studies on dissolution enhancement and mathematical modeling of drug release of a poorly water-soluble drug using water-soluble carriers.

Role of various water-soluble carriers was studied for dissolution enhancement of a poorly soluble model drug, rofecoxib, using solid dispersion approach. Diverse carriers viz. polyethylene glycols (PEG 4000 and 6000), polyglycolized fatty acid ester (Gelucire 44/14), polyvinylpyrollidone K25 (PVP), poloxamers (Lutrol F127 and F68), polyols (mannitol, sorbitol), organic acid (citric acid) and hydrotropes (urea, nicotinamide) were investigated for the purpose. Phase-solubility studies revealed AL type of curves for each carrier, indicating linear increase in drug solubility with carrier concentration. The sign and magnitude of the thermodynamic parameter, Gibbs free energy of transfer, indicated spontaneity of solubilization process. All the solid dispersions showed dissolution improvement vis-à-vis pure drug to varying degrees, with citric acid, PVP and poloxamers as the most promising carriers. Mathematical modeling of in vitro dissolution data indicated the best fitting with Korsemeyer-Peppas model and the drug release kinetics primarily as Fickian diffusion. Solid state characterization of the drug-poloxamer binary system using XRD, FTIR, DSC and SEM techniques revealed distinct loss of drug crystallinity in the formulation, ostensibly accounting for enhancement in dissolution rate.     

Engineering Targeted In Vivo Drug Delivery. I. The Physiological and Physicochemical Principles Governing Opportunities and Limitations

A physiologically based model is presented to aid prediction of the pharmacological benefits to be derived from the administration of a drug as a targeted drug–carrier combination. An improvement in the therapeutic index and an increase in the therapeutic availability are the primary benefits sought. A measure of the former is obtained from the value of the drug targeting index, a newly derived parameter. Both the drug targeting index and the therapeutic availability are directly calculable. The minimum information needed for approximating both parameters is the candidate drug's total-body clearance and some knowledge of the target site's anatomy and blood flow. Drugs with high total-body clearance values that are known to act at target tissues having effective blood flows that are small relative to the blood flow to the normal eliminating organs will benefit most from combination with an efficient, targeted carrier. Direct elimination of the drug at the target site or at the tissue where toxicity originates dramatically improves the drug targeting index value. The fraction of drug actually released from the carrier at both target and nontarget sites can radically affect index values. In some cases a 1% change in the fraction of the dose delivered to the target can result in a 50% change in the drug targeting index value. It is argued that most drugs already developed have a low potential to benefit from combination with a drug carrier. The approach allows one to distinguish clearly those drugs that can benefit from combination with targeted in vivo drug carriers from those drugs that cannot.To whom correspondence should be addressed.     

外泌体新型药物运载系统的研究进展

外泌体是来源于细胞内膜系统的囊泡样纳米结构,直径在40~100 nm之间,可由各种类型的细胞分泌释放。外泌体携带源于母细胞的分子物质,如蛋白质、mRNA、miRNA和脂类,参与机体的生理和病理过程。由于具有毒性低、无免疫原性和渗透性好等优势,外泌体作为新型的药物运载系统已成为众多研究者关注的焦点。本文基于外泌体特有的纳米结构和生理功能,就近年来外泌体载药系统研究的发展历程、载药优势及外泌体的工程化改造的现状和可能遇到的问题进行概述。     

Model-based optimized steering and focusing of local magnetic particle concentrations for targeted drug delivery

Magnetic drug targeting (MDT) is an application in the field of targeted drug delivery in which magnetic (nano)particles act as drug carriers. The particles can be steered toward specific regions in the human body by adapting the currents of external (electro)magnets. Accurate models of particle movement and control algorithms for the electromagnet currents are two of the many requirements to ensure effective drug targeting. In this work, a control approach for the currents is presented, based on an underlying physical model that describes the dynamics of particles in a liquid in terms of their concentration in each point in space. Using this model, the control algorithm determines the currents generating the magnetic fields that maximize the particle concentration in spots of interest over a period of time. Such an approach is computationally only feasible thanks to our innovative combination of model order reduction with the method of direct multiple shooting. Simulation results of an in-vitro targeting setup demonstrated that a particle collection can be successfully guided toward the targeted spot with limited dispersion through a surrounding liquid. As now present and future particle behavior can be taken into account, and non-stationary surrounding liquids can be dealt with, a more precise and flexible targeting is achieved compared to existing MDT methods. This proves that the presented methodology can bring MDT closer to its clinical application. Moreover, the developed model is compatible with state-of-the-art imaging methods, paving the way for theranostic platforms that combine both therapy as well as diagnostics.     

Enhanced tumor targeting effects of a novel paclitaxel-loaded polymer: PEG–PCCL-modified magnetic iron oxide nanoparticles

Background: Multifunctional magnetic nanoparticles (MNP) have been newly developed for tumor-targeted drug carriers. To address challenges including biocompatibility, stability, nontoxicity, and targeting efficiency, here we report the novel drug deliverer poly(ethylene glycol) carboxyl–poly(?-caprolactone) modified MNP (PEG–PCCL-MNP) suitable for magnetic targeting based on our previous studies.

Methods: Their in vitro characterization and cytotoxicity assessments, in vivo cytotoxicity assessments, and antitumor efficacy study were elaborately investigated.

Results: The size of PEG–PCCL-MNP was 79.6?±?0.945?nm. PEG–PCCL-MNP showed little in vitro or in vivo cytotoxicity and good biocompatibility, as well as effective tumor-specific cell targeting for drug delivery with the presence of external magnetic field.

Discussion: PEG–PCCL-MNP is a potential candidate of biocompatible and tumor-specific targeting drug vehicle for hydrophobic drugs.     

树枝状聚合物聚酰胺-胺作为药物载体应用研究进展

树枝状聚合物聚酰胺-胺(PAMAM)是一种三维的、高度枝化的树枝状高分子,具有单一分散性、无免疫原性、细胞毒性较低、生物可降解等特性,目前作为药物载体在药学领域引起了高度关注。文中分别综述了其载药机制及其在静脉、口服、经皮、眼部等不同给药途径的应用研究进展。研究发现其载药机制主要为物理包埋载药与静电、共价结合载药。PAMAM作为药物载体能够增加药物的溶解度,不同途径给药后能延缓药物的释放,增加药物皮肤渗透系数,延长角膜滞留时间,从而增加药物的生物利用度,是一种颇具发展潜力的新型药物载体。