Efficient drug-delivery using magnetic nanoparticles — biodistribution and therapeutic effects in tumour bearing rabbits

To treat tumours efficiently and spare normal tissues, targeted drug delivery is a promising alternative to conventional, systemic administered chemotherapy. Drug-carrying magnetic nanoparticles can be concentrated in tumours by external magnetic fields, preventing the nanomaterial from being cleared by metabolic burden before reaching the tumour. Therefore in Magnetic Drug Targeting (MDT) the favoured mode of application is believed to be intra-arterial. Here, we show that a simple yet versatile magnetic carrier-system (hydrodynamic particles diameter < 200 nm) accumulates the chemotherapeutic drug mitoxantrone efficiently in tumours. With MDT we observed the following drug accumulations relative to the recovery from all investigated tissues: tumour region: 57.2%, liver: 14.4%, kidneys: 15.2%. Systemic intra-venous application revealed different results: tumour region: 0.7%, liver: 14.4 % and kidneys: 77.8%. The therapeutic outcome was demonstrated by complete tumour remissions and a survival probability of 26.7% (P = 0.0075). These results are confirming former pilot experiments and implying a milestone towards clinical studies.From the Clinical EditorThis team of investigators studied drug carrying nanoparticles for magnetic drug targeting (MDT), demonstrating the importance of intra-arterial administration resulting in improved clinical outcomes in the studied animal model compared with intra-venous.     

Factors affecting magnetic retention of particles in the upper airways: an in vitro and ex vivo study.

This paper presents the results of experiments using an in vitro model and an ex vivo animal model (Rana catesbeiana) to study magnetic particle retention in the conducting airways, specifically the trachea and bronchi. The purpose of these experiments was to determine the significant factors for retention of magnetic particles deposited from an aerosol at the airway surface using a magnetic field. The results indicate that the apparent viscosity of the mucus layer at low shear rates is the most significant obstacle to particle retention. The results also show that particle size and aggregation play major roles in particle retention. The mucus transport rate, unlike the effect of fluid velocity in intravenous applications, did not appear to be a determining factor for particle retention. It was also found that a suitably designed magnetic system, aside from having a high intensity, needs to exert a strong radial field to promote particle aggregation. The findings suggest that one possible approach to magnetic particle retention could be delivery of a mucolytic agent along with the drug particles. This study provides the fundamentals needed for development of a targeted magnetic drug delivery system for inhaled therapeutic aerosol particles.     

Magnetically assisted intraperitoneal drug delivery for cancer chemotherapy

Intraperitoneal (IP) chemotherapy has revived hopes during the past few years for the management of peritoneal disseminations of digestive and gynecological cancers. Nevertheless, a poor drug penetration is one key drawback of IP chemotherapy since peritoneal neoplasms are notoriously resistant to drug penetration. Recent preclinical studies have focused on targeting the aberrant tumor microenvironment to improve intratumoral drug transport. However, tumor stroma targeting therapies have limited therapeutic windows and show variable outcomes across different cohort of patients. Therefore, the development of new strategies for improving the efficacy of IP chemotherapy is a certain need. In this work, we propose a new magnetically assisted strategy to elevate drug penetration into peritoneal tumor nodules and improve IP chemotherapy. A computational model was developed to assess the feasibility and predictability of the proposed active drug delivery method. The key tumor pathophysiology, including a spatially heterogeneous construct of leaky vasculature, nonfunctional lymphatics, and dense extracellular matrix (ECM), was reconstructed in silico. The transport of intraperitoneally injected magnetic nanoparticles (MNPs) inside tumors was simulated and compared with the transport of free cytotoxic agents. Our results on magnetically assisted delivery showed an order of magnitude increase in the final intratumoral concentration of drug-coated MNPs with respect to free cytotoxic agents. The intermediate MNPs with the radius range of 200–300?nm yield optimal magnetic drug targeting (MDT) performance in 5–10?mm tumors while the MDT performance remains essentially the same over a large particle radius range of 100–500?nm for a 1?mm radius small tumor. The success of MDT in larger tumors (5–10?mm in radius) was found to be markedly dependent on the choice of magnet strength and tumor-magnet distance while these two parameters were less of a concern in small tumors. We also validated in silico results against experimental results related to tumor interstitial hypertension, conventional IP chemoperfusion, and magnetically actuated movement of MNPs in excised tissue.     

Development and Characterization of Chitosan Cross-Linked With Tripolyphosphate as a Sustained Release Agent in Tablets,Part I: Design of Experiments and Optimization

Certain issues with the use of particles of chitosan (Ch) cross-linked with tripolyphosphate (TPP) in sustained release formulations include inefficient drug loading, burst drug release, and incomplete drug release. Acetaminophen was added to Ch:TPP particles to test for advantages of drug addition extragranularly over drug addition made during cross-linking. The influences of Ch concentration, Ch:TPP ratio, temperature, ionic strength, and pH were assessed. Design of experiments allowed identification of factors and 2-factor interactions that have significant effects on average particle size and size distribution, yield, zeta potential, and true density of the particles, as well as drug release from the directly compressed tablets. Statistical model equations directed production of a control batch that minimized span, maximized yield, and targeted a t₅₀ of 90 min (sample A); sample B that differed by targeting a t₅₀ of 240-300 min to provide sustained release; and sample C that differed from sample B by maximizing span. Sample B maximized yield and provided its targeted t₅₀ and the smallest average particle size, with the higher zeta potential and the lower span of samples B and C. Extragranular addition of a drug to Ch:TPP particles achieved 100% drug loading, eliminated a burst drug release, and can accomplish complete drug release.     

Development of multiple-layer polymeric particles for targeted and controlled drug delivery

The purpose of this work was to develop multilayered particles consisting of a magnetic core and two encompassing shells made up of poly(N-isopropylacrylamide) (PNIPAAm) and poly(d,l-lactide-co-glycolide) (PLGA) for targeted and controlled drug delivery. Transmission electron microscopy confirmed that multilayered particles were obtained with PNIPAAm magnetic nanoparticles embedded within the PLGA shell. Factorial analysis studies also showed that the particle size was inversely proportional to the surfactant concentration and sonication power and directly proportional to the PLGA concentration. Drug-release results demonstrated that these multilayer particles produced an initial burst release and a subsequent sustained release of both bovine serum albumin (BSA) and curcumin loaded into the core and shell of the particle, respectively. BSA release was also affected by changes in temperature. In conclusion, our results indicate that the multilayered magnetic particles could be synthesized and used for targeted and controlled delivery of multiple drugs with different release mechanisms.From the Clinical EditorAuthors demonstrate the synthesis of multilayered particles consisting of a magnetic core and two encompassing shells made up of poly (N-isopropylacrylamide) (PNIPAAm) and poly(D, L-lactide-co-glycolide) (PLGA) for targeted and controlled drug delivery. The presented results indicate successful synthesis and application for targeted and controlled delivery of multiple drugs with different release mechanisms.     

Possibilities and Limiting Factors for the Use of Dissolution as a Quality Control Tool to Detect Presence of Crystallinity for Amorphous Solid Dispersions: An Experimental and Modeling Investigation

In this article, experiments on tablets containing a model compound, grazoprevir, were conducted to explore how media selection for a quality control dissolution method can influence the sensitivity for the dissolution method toward drug crystallinity detection in an amorphous solid dispersion formulation. The experiment shows that under ideal nonsink conditions with respect to crystalline solubility, dissolution can indeed be predictive of crystallinity in the formulation. However, the limit of detection for crystallinity with quality control dissolution can change based on inherent variabilities in the drug product. In addition, it is demonstrated that the method's sensitivity and accuracy might be reduced if the crystalline particles are sufficiently small with respect to the solid dispersion particles. To further demonstrate the limits of the dissolution method, a dissolution model was also explored to simulate and predict the sensitivity of the dissolution response toward crystallinity based on solubility in the media and particle size of the crystals.     

Toward improved selectivity of targeted delivery: The potential of magnetic nanoparticles

Magnetic nanoparticles, mostly iron oxide-based nanoparticles, have long been used as contrasting agents in magnetic resonance imaging (MRI) applications, heat mediators in hyperthermia treatments and carriers for targeted drug delivery. Magnetic nanoparticles offer some attractive characteristics for targeted drug delivery such as drug carrying ability, nano-scale dimensions and magnetism-driven selective targeting. In this issue, Escribano et al. demonstrated that iron oxide-based magnetic nanoparticles with an implanted magnet can improve selective targeting to the site of inflammation. This result opens a promising avenue for magnetic drug targeting to inflammatory diseases.     

Nano- and micro-based inhaled drug delivery systems for targeting alveolar macrophages

Introduction: Macrophages are the most versatile cells in the hematopoietic system and are strategically distributed in tissues to fight pathogens or other foreign particles. In the lung, however, for intracellular infections such as tuberculosis, pneumonia and aspergillosis, bacteria and fungi utilize the alveolar macrophage as a breeding ground. This has become a challenge for the treatment of these infections, as most drugs do not effectively reach the macrophages at therapeutic levels. Alveolar macrophages also play an important role to initiative adaptive immunity toward combating inflammation and cancer in the lung.

Areas covered: This review focuses on the development of micro- and nanotechnology-based drug delivery systems to target alveolar macrophages in association with intracellular infections, cancer and lung inflammation. Aspects of nanoparticle and micron-sized particle engineering through exploitation of particles’ physicochemical characteristics such as particle size, surface charge and geometry of particles are discussed. In addition, the application of nanocarriers such as liposomes, polymeric nanoparticles and dendrimers are covered with respect to macrophage targeting.

Expert opinion: Drug delivery targeted to alveolar macrophages in the lung is becoming a reality thanks to micro- and nanotechnology breakthrough. The literature review shows that regulation of physicochemical parameters of particles could be a recipe to enhance macrophage targeting and uptake. However, there is still a need to identify more target-specific receptors in order to facilitate drug targeting. Besides that, the toxicity of nanocarriers arising from prolonged residence in the lung should be taken into consideration during formulation.     

Application of Plant Viruses as Nano Drug Delivery Systems

Nano-sized drug delivery systems based on virus-derived platforms have promising delivery and targeting efficiencies. To date, much of our understanding of these systems is obtained from studies of animal viruses. Application of plant viruses for drug delivery is in the nascent stage, but it is becoming apparent that plant viral particles can be engineered to possess novel properties to meet the unique requirements of targeted drug delivery. Chemical functionalization of a plant viral particle surface can impart stealth properties to prolong in vivo circulation half-life and/or targeting capability to direct drug delivery to diseased tissues. The amino acid sequence of the viral coat protein can be genetically manipulated to yield protein cages of specific chemistry and morphology, while the conformation of the protein cage can be directed, via the external environment, to disassemble, then reassemble in vitro to exchange native viral genomic material with exogenous cargo. The purpose of this commentary is to evaluate current literature to assess the potential of nano-scale plant-virus-based drug delivery systems for the targeted delivery of chemotherapeutic agents.     

Association of chemotherapeutic drugs with dendrimer nanocarriers: an assessment of the merits of covalent conjugation compared to noncovalent encapsulation

Cancer is a leading cause of death within developed nations, and part of this morbidity is due to difficulties associated with its treatment. Currently, anticancer therapy relies heavily upon the administration of small molecule cytotoxic drugs that attack both cancerous and noncancerous cells due to limited selectivity of the drugs and widespread distribution of the cytotoxic molecules throughout the body. The antitumor efficacy and systemic toxicity of existing chemotherapeutic drugs can, however, be improved by employing formulation and particle engineering approaches. Thus, drug delivery systems can be developed that more specifically target tumor tissue using both passive (such as the enhanced permeation and retention effect) and active (through the use of cancer targeting ligands) modalities. Dendrimers are one such system that can be developed with high structural monodispersity, long plasma circulation times and precise control over surface structure and biodistribution properties. Chemotherapeutic drugs can be associated with dendrimers via covalent conjugation to the surface, or via encapsulation of drugs within the structure. Each of these approaches has demonstrated therapeutic benefit relative to the administration of free drug. Thus far, however, there has not been a systematic review toward which drug association approach will provide the best outcomes in terms of antitumor efficacy and systemic toxicity. Hence, the current literature is reviewed here and recommendations are proposed as to the suggested approach to develop dendrimers as tumor targeted drug-delivery vectors.     

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.     

Liposomes as targetable drug carriers

The general problem of targeted drug transport is critically reviewed and three principle components of targeted systems are discussed: the target, the vector molecule, and the carrier. Different systems of drug targeting are briefly described: local drug application, chemical modification of the drug molecule, physical targeting under the action of pH, temperature, or magnetic field. The idea of a vector molecule is discussed and different methods of vector molecule coupling with the drug are reviewed (direct coupling, coupling via spacer group or polymer molecule, etc.). It is shown that the most promising approach seems to be the use of a drug-containing microcontainer with the vector molecule immobilized on its outer surface. Different types of microcontainers are briefly described: microcapsules, cell hosts, and liposomes. The advantages of liposomes as drug containers are shown and the main problems of their use for drug targeting in vitro and in vivo conditions are discussed. One of the most important problems is the problem of vector molecule immobilization on liposome surfaces. The principle four different immobilization methods: adsorbtion, incorporation, covalent binding, and hydrophobic binding. Targeted liposome transport is described in model systems, cell cultures, and experimental animals. It is shown that targeted liposomes may release a drug via diffusion, lysis, or endocytosis by appropriate cells. The problems of targeted liposome technology and clinical application are analyzed.     

Efficacy Interactions of PEG–DOX–N-acetyl Glucosamine Prodrug Conjugate for Anticancer Therapy

Present investigation is exploring structure–biocompatibility interaction of tumour targeted polyethylene glycol (PEG) based drug conjugate of doxorubicin using N-acetyl glucosamine as targeting ligand. The synthesized polymer drug conjugate was evaluated for particle size, zeta potential, molecular weight, haemolysis activity, cytotoxicity, protein binding and in vitro receptor (lectin) binding study. The particle size of synthesized conjugate was observed to be around 30 nm with polydispersability index of 0.213 indicating mono-disperse particles. Fluorescence quenching assay addressed relatively lower binding interactions of polymer drug conjugate to bovine serum albumin in comparison with free doxorubicin which may be governed to the hydrophilicity of polyethylene glycol and N-acetyl glucosamine. The cell compatibility and haemolysis study showed that PEG drug conjugate was nontoxic and biocompatible, which recommends the suitability of polymer drug conjugates for delivering biological active agents systemically. In vitro ligand–lectin receptor binding assays of synthesized targeted polymer conjugate suggest the possibility of promising interaction of N-acetyl glucosamine in vivo. Thus, the study indicated the suitability of N-acetyl glucosamine anchored targeted polymer drug conjugate in delivering bio-therapeutics for specifically targeting to tumour tissues.     

Stochastic models for prodrug targeting. 1. Diffusion of the efflux drug

In modeling prodrug targeting using the stochastic approach, we first modeled diffusion of the efflux drug. Drug efflux is one of the major reasons for the failure of prodrug strategy: the active agent is pumped out the membrane ("efflux"), causing an insufficient amount to be delivered to the targeted sites and thus diminishing the efficacy of chemotherapy. Because the biological body is a nonlinear nonequilibrium complex system, the molecular transport taking place in vivo often showed stochasticity. The model described here for diffusion of the efflux drug is basically a diffusion process with reflecting/absorbing boundary conditions, divided into two distinctive regions with one allowing the particles to jump to the origin as a result of efflux pumping. We study discrete time birth-death Markov chain and compute the time-dependent spatial probability density function (PDF) of particles. The results showed that the jumping probability, although small, has a significant impact on the evolution of PDF of the efflux drug. The implications of this model were discussed.     

壳聚糖微/纳米粒在定向给药系统中的应用研究

目的：介绍壳聚糖微/纳米粒在新型定向给药系统中的应用,为发展安全高效的壳聚糖微/纳米粒定向给药系统提供参考。方法：综合近年来出版的有关文献,对壳聚糖基本性质,定位给药于各组织部位进行了探讨。结果：壳聚糖微/纳米粒可应用于脑、眼、鼻、口、肺、胃、小肠、结肠等器官靶向给药。结论：壳聚糖微/纳米粒作为一种新型药用辅料,在定位给药系统中已经得到了开发和应用。     

In vitro anticancer activity of doxorubicin-loaded gelatin-coated magnetic iron oxide nanoparticles

Magnetic drug targeting allows accumulation of drug at a defined target site with the help of an external magnetic field. Current research explored uptake and anticancer activity of doxorubicin-loaded gelatin-coated magnetic iron oxide particles (DXR-GIOPs) in order to investigate potential of gelatin-coated iron oxide particles (GIOPs) as a drug carrier in the field of magnetic drug targeting. The in vitro test was done using HeLa cells as a model cell and DXR as a model drug. The cytotoxicity and uptake of GIOPs were also studied and results were compared with that of DXR-GIOPs. The results indicated that GIOPs were not toxic to HeLa cells even at higher concentration of 1.2?mg/mL; however, DXR-GIOPs showed toxicity in time as well as dose-dependent manner. Furthermore, quantitative and qualitative uptake studies showed higher uptake of DXR-GIOPs compared to GIOPs in the identical condition by the cells.     

In vitro anticancer activity of doxorubicin-loaded gelatin-coated magnetic iron oxide nanoparticles

Magnetic drug targeting allows accumulation of drug at a defined target site with the help of an external magnetic field. Current research explored uptake and anticancer activity of doxorubicin-loaded gelatin-coated magnetic iron oxide particles (DXR-GIOPs) in order to investigate potential of gelatin-coated iron oxide particles (GIOPs) as a drug carrier in the field of magnetic drug targeting. The in vitro test was done using HeLa cells as a model cell and DXR as a model drug. The cytotoxicity and uptake of GIOPs were also studied and results were compared with that of DXR-GIOPs. The results indicated that GIOPs were not toxic to HeLa cells even at higher concentration of 1.2?mg/mL; however, DXR-GIOPs showed toxicity in time as well as dose-dependent manner. Furthermore, quantitative and qualitative uptake studies showed higher uptake of DXR-GIOPs compared to GIOPs in the identical condition by the cells.     

Synthetic nano-low density lipoprotein as targeted drug delivery vehicle for glioblastoma multiforme

The low density lipoprotein (LDL) receptor has been shown to be upregulated in GBM tumor cells and is therefore a potential molecular target for the delivery of therapeutic agents. A synthetic nano-LDL (nLDL) particle was developed and tested to determine its utility as a drug delivery vehicle targeted to GBM tumors. nLDL particles were constructed by combining a synthetic peptide containing a lipid binding motif and the LDL receptor (LDLR) binding domain of apolipoprotein B-100 with a lipid emulsion consisting of phosphatidyl choline, triolein, and cholesteryl oleate. Composition analysis, fast protein liquid chromatography, and electron microscopy revealed that nLDL was highly reproducible and intermediate in size between high density lipoprotein and LDL particles (10.5+/-2.8 nm diameter). The binding and uptake of fluorescently labeled nLDL particles was assessed using fluorescence microscopy. Uptake of nLDL was time dependent, exhibiting saturation at approximately 3 h, and concentration dependent, exhibiting saturation at concentrations greater than 5 microM peptide. Using Lysotracker as a cellular marker, nLDL co-localized with lysosomes. nLDL binding was eliminated by blocking LDLRs with suramin and nLDL inhibited binding of plasma LDL to LDLRs. Collectively these data strongly suggest that the synthetic nano-LDLs described here are taken up by LDLR and can serve as a drug delivery vehicle for targeting GBM tumors via the LDLR.     

The application of high-content analysis in the study of targeted particulate delivery systems for intracellular drug delivery to alveolar macrophages

With an ever increasing number of particulate drug delivery systems being developed for the intracellular delivery of therapeutics a robust high-throughput method for studying particle-cell interactions is urgently required. Current methods used for analyzing particle-cell interaction include spectrofluorimetry, flow cytometry, and fluorescence/confocal microscopy, but these methods are not high throughput and provide only limited data on the specific number of particles delivered intracellularly to the target cell. The work herein presents an automated high-throughput method to analyze microparticulate drug delivery system (DDS) uptake byalveolar macrophages. Poly(lactic-co-glycolic acid) (PLGA) microparticles were prepared in a range of sizes using a solvent evaporation method. A human monocyte cell line (THP-1) was differentiated into macrophage like cells using phorbol 12-myristate 13-acetate (PMA), and cells were treated with microparticles for 1 h and studied using confocal laser scanning microscopy (CLSM), spectrofluorimetry and a high-content analysis (HCA). PLGA microparticles within the size range of 0.8-2.1 μm were found to be optimal for macrophage targeting (p < 0.05). Uptake studies carried out at 37 °C and 4 °C indicated that microparticles were internalized in an energy dependent manner. To improve particle uptake, a range of opsonic coatings were assessed. Coating PLGA particles with gelatin and ovalbumin was found to significantly increase particle uptake from 2.75 ± 0.98 particles per cell for particles coated with gelatin. Opsonic coating also significantly increased particle internalization into primary human alveolar macrophages (p < 0.01) with a 1.7-fold increase in uptake from 4.19 ± 0.48 for uncoated to 7.53 ± 0.88 particles per cell for coated particles. In comparison to techniques such as spectrofluorimetry and CLSM, HCA provides both qualitative and quantitative data on the influence of carrier design on cell targeting that can be gathered in a high-throughput format and therefore has great potential in the screening of intracellularly targeted DDS.     

磁感应加热诱导汉防己甲素释放及对肿瘤相关双孔钾离子通道TASK-3的作用研究

目的：构建体外K_2P 9.1（TASK-3）通道过度表达的非洲爪蟾卵母细胞模型;建立外部和磁感应加热2种加热方法,研究其对载汉防己甲素磁性纳米粒中药物释放行为的影响,进一步研究药物及载药磁性纳米粒对TASK-3通道电流的影响。方法：制备载汉防己甲素的聚乳酸-羟基乙酸共聚物（PLGA）磁性纳米粒,采用RP-HPLC考察外部和磁感应加热2种方法对药物释放的影响。采用双电极电压钳技术研究了汉防己甲素、Fe₃O₄-PLGA纳米粒和Tet-Fe₃O₄-PLGA纳米粒及运用磁感应加热诱导药物释放对卵母细胞表面TASK-3通道电流的影响。结果：药物释放量与速率呈现温度依赖性,汉防己甲素对Xenopus oocytes表面TASK-3通道电流有明显抑制作用并呈现剂量依赖性,未载药的PLGA磁性纳米粒对TASK3通道电流不产生影响,而Tet-Fe₃O₄-PLGA NPs在2种加热体系下均显示出对TASK-3通道明显的抑制作用。结论：Tet-Fe₃O₄-PLGA NPs在磁感应作用下能可控性增加汉防己甲素对TASK3通道电流的阻滞作用,这种应激响应性药物递送系统有望成为基于双孔钾通道K_2P9.1靶向治疗的新方法,并有可能用于其他各种癌症治疗。