Mesoporous NaYbF4@NaGdF4 core-shell up-conversion nanoparticles for targeted drug delivery and multimodal imaging

We developed a facile strategy to obtain a new kind of mesoporous core-shell structured up-conversion nanoparticles (mUCNPs), composed of a NaYbF₄:2%Er core and a mesoporous NaGdF₄ shell. This mesoporous shell not only enhanced the up-conversion luminescence but also endowed many other functionalities of the nanoparticles such as drug delivery and bio-imaging capabilities. Moreover, after being conjugated with polyethylenimine (PEI) and folic acid (FA), core-shell mUCNPs exhibited good water dispersibility, enhanced drug delivery efficiency, and remarkable targeting ability to cancer cells. To certify the folate receptors (FR)-mediated targeted drug delivery, cell viability assay, cell up-conversion luminescence imaging and flow cytometry analysis were carried out. Furthermore, apart from the application for targeted drug delivery, the as-prepared core-shell mUCNPs could also be employed as the contrast agents for X-ray computed tomography (CT) and magnetic resonance (MR) imaging, because of the strong X-ray attenuation ability of Yb and high longitudinal molar relaxivity (r₁) of Gd in the nanoparticles, providing the potential for simultaneously bio-imaging and cancer-targeting therapy.     

Preparation of gelatin nanospheres incorporating quantum dots and iron oxide nanoparticles for multimodal cell imaging

The objective of this study is to prepare a multimodal probe which can simultaneously visualize cells by optical and magnetic resonance (MR) imaging modalities. Gelatin nanospheres incorporating quantum dots (QD) and iron oxide nanoparticles (IONP) were prepared by the conventional emulsion method. The percentage of QD and IONP incorporated in gelatin nanospheres was changed by the concentrations of gelatin and glutaraldehyde used. However, the apparent size and surface zeta potential were hardly changed. Gelatin nanospheres incorporating QD and IONP were treated with octa-arginine (R8) of a cell-penetrating peptide. When incubated with normal human articular chondrocytes, gelatin nanospheres incorporating QD and IONP were efficiently internalized into the cells although their cytotoxicity was observed at the R8 concentration of 320 μM. The cells internalizing gelatin nanospheres incorporating QD and IONP could be visualized by both the optical and MR imaging modalities. It is concluded that gelatin nanospheres incorporating QD and IONP are promising for the probe of multimodal cell imaging.     

PEGylated fullerene/iron oxide nanocomposites for photodynamic therapy,targeted drug delivery and MR imaging

Recently, fullerene and fullerene derivatives owning to their highly enriched physical and chemical properties have been widely explored for applications in many different fields including biomedicine. In this study, iron oxide nanoparticles (IONPs) were decorated onto the surface of fullerene (C60), and then PEGylation was performed to improve the solubility and biocompatibility of C60-IONP, obtaining a multi-functional C60-IONP-PEG nanocomposite with strong superparamagnetism and powerful photodynamic therapy capacity. Hematoporphyrin monomethyl ether (HMME), a new photodynamic anti-cancer drug, was conjugated to C60-IONP-PEG, forming a C60-IONP-PEG/HMME drug delivery system, which demonstrated an excellent magnetic targeting ability in cancer therapy. Compared with free HMME, remarkably enhanced photodynamic cancer cell killing effect using C60-IONP-PEG/HMME was realized not only in a cultured B16-F10 cells in vitro but also in an in vivo murine tumor model due to 23-fold higher HMME uptake of tumor and strong photodynamic activity of C60-IONP-PEG. Moreover, C60-IONP-PEG could be further used as a T₂-contrast agent for in vivo magnetic resonance imaging. Our work showed C60-IONP-PEG/HMME had a great potential for cancer theranostic applications.     

靶向给药体系在骨转移瘤中的研究进展

骨骼是除肝脏和肺脏外恶性肿瘤最常见的转移部位.骨转移(bone metastasis)被认为是临床严重的并发症之一.有文献显示超过70％的各类癌症晚期患者会发生骨转移,骨转移会诱发骨痛、病理性骨折、脊髓压迫和高钙血症等,因其导致的死亡率和致残率分别为20％和45％.在保证治疗原发肿瘤的基础上,怎样最大限度的治疗骨转移瘤和诱发最小的副作用是目前医学界研究的热点.靶向给药体系(targeted drug delivery system)包括双磷酸盐类、四环素类、单克隆抗体、聚乙烯亚胺等,它能有效的抑制骨转移,旨在为治疗骨转移提供更有效的策略.     

Graphene and graphene oxide as new nanocarriers for drug delivery applications

The biomedical applications of graphene-based materials, including drug delivery, have grown rapidly in the past few years. Graphene and graphene oxide have been extensively explored as some of the most promising biomaterials for biomedical applications due to their unique properties: two-dimensional planar structure, large surface area, chemical and mechanical stability, superb conductivity and good biocompatibility. These properties result in promising applications for the design of advanced drug delivery systems and delivery of a broad range of therapeutics. In this review we present an overview of recent advances in this field of research. We briefly describe current methods for the surface modification of graphene-based nanocarriers, their biocompatibility and toxicity, followed by a summary of the most appealing examples demonstrated for the delivery of anti-cancer drugs and genes. Additionally, new drug delivery concepts based on controlling mechanisms, including targeting and stimulation with pH, chemical interactions, thermal, photo- and magnetic induction, are discussed. Finally the review is summarized, with a brief conclusion of future prospects and challenges in this field.     

Polyelectrolyte/silver nanocomposite multilayer films as multifunctional thin film platforms for remote activated protein and drug delivery

We demonstrate a nanoparticle loading protocol to develop a transparent, multifunctional polyelectrolyte multilayer film for externally activated drug and protein delivery. The composite film was designed by alternate adsorption of poly(allylamine hydrochloride) (PAH) and dextran sulfate (DS) on a glass substrate followed by nanoparticle synthesis through a polyol reduction method. The films showed a uniform distribution of spherical silver nanoparticles with an average diameter of 50 ± 20 nm, which increased to 80 ± 20 nm when the AgNO₃ concentration was increased from 25 to 50 mM. The porous and supramolecular structure of the polyelectrolyte multilayer film was used to immobilize ciprofloxacin hydrochloride (CH) and bovine serum albumin (BSA) within the polymeric network of the film. When exposed to external triggers such as ultrasonication and laser light the loaded films were ruptured and released the loaded BSA and CH. The release of CH is faster than that of BSA due to a higher diffusion rate. Circular dichroism measurements confirmed that there was no significant change in the conformation of released BSA in comparison with native BSA. The fabricated films showed significant antibacterial activity against the bacterial pathogen Staphylococcus aureus. Applications envisioned for such drug-loaded films include drug and vaccine delivery through the transdermal route, antimicrobial or anti-inflammatory coatings on implants and drug-releasing coatings for stents.     

The degradation and biocompatibility of pH-sensitive biodegradable polyurethanes for intracellular multifunctional antitumor drug delivery

To obtain controllable stepwise biodegradable polymer for multifunctional antitumor drug carriers, pH-sensitive biodegradable polyurethanes were firstly synthesized using poly(ε-caprolactone) (PCL) and pH-sensitive poly(ε-caprolactone)-hydrazone-poly(ethylene glycol)-hydrazone-poly(ε-caprolactone) macrodiol (PCLH) as soft segment; l-lysine ethyl ester diisocyanate (LDI), l-lysine derivative tripeptide and 1,4-butandiol (BDO) as hard segment; and hydrazone-linked methoxyl-poly(ethylene glycol)(m-PEG-Hyd) as end-capper. Then, an extensive degradation process of the prepared pH-sensitive polyurethanes was investigated in vitro with proton nuclear magnetic resonance spectra (¹H NMR), gel permeation chromatograph (GPC), scanning electron microscopy (SEM), and weight loss. It was found that the degradation of these polyurethanes occurred via the random hydrolytic ester cleavage along the PCL segments close to PEG segments in enzymatic solutions while the hydrazone bond in the polymer chain was more easily cleaved in acidic media, which was accelerated with decreasing pH value. Furthermore, the biocompatibility in vivo was evaluated in an intramuscular implantation model on Sprague-Dawley rats, using SEM and light microscopy. The result showed that the prepared polyurethanes can be easily degraded and the degradation products do not induce any adverse response from surrounding muscle tissues. Our work suggests that the prepared pH-sensitive polyurethanes could be promising materials as controllable biodegradable and non-cyctotoxic multifunctional carriers for active intracellular drug delivery.     

Hierarchical targeted hepatocyte mitochondrial multifunctional chitosan nanoparticles for anticancer drug delivery

The overwhelming majority of drugs exert their pharmacological effects after reaching their target sites of action, however, these target sites are mainly located in the cytosol or intracellular organelles. Consequently, delivering drugs to the specific organelle is the key to achieve maximum therapeutic effects and minimum side-effects. In the work reported here, we designed, synthesized, and evaluated a novel mitochondrial-targeted multifunctional nanoparticles (MNPs) based on chitosan derivatives according to the physiological environment of the tumor and the requirement of mitochondrial targeting drug delivery. The intelligent chitosan nanoparticles possess various functions such as stealth, hepatocyte targeting, multistage pH-response, lysosomal escape and mitochondrial targeting, which lead to targeted drug release after the progressively shedding of functional groups, thus realize the efficient intracellular delivery and mitochondrial localization, inhibit the growth of tumor, elevate the antitumor efficacy, and reduce the toxicity of anticancer drugs. It provides a safe and efficient nanocarrier platform for mitochondria targeting anticancer drug delivery.     

Multifunctional quantum dots and liposome complexes in drug delivery

Incorporating both diagnostic and therapeutic functions into a single nanoscale system is an effective modern drug delivery strategy. Combining liposomes with semiconductor quantum dots (QDs) has great potential to achieve such dual functions, referred to in this review as a liposomal QD hybrid system (L-QD). Here we review the recent literature dealing with the design and application of L-QD for advances in bio-imaging and drug delivery. After a summary of L-QD synthesis processes and evaluation of their properties, we will focus on their multifunctional applications, ranging from in vitro cell imaging to theranostic drug delivery approaches     

Surface-modified nanocrystalline ceramics for drug delivery applications

Drug delivery systems comprised of various types of carriers have long been the object of pharmacological investigation. The search has been stimulated by the belief that carriers will lead to reduced drug toxicity, dosage requirements, enhanced cellular targeting and improved shelf-life. Among the carriers investigated are complex polymeric carbohydrates, synthetic proteins and liposomal structures. For the past four years, we have been experimenting with a radically new class of carriers comprised of surface-modified nanocrystalline ceramics. While the ceramics provide the structural stability of a largely immutable solid, the surface modification creates a glassy molecular stabilization film to which pharmacological agents may be bound non-covalently from an aqueous phase with minimal structural denaturation. As a consequence of maintained structural integrity and owing to concentration effects afforded by the surfaces of the nanocrystalline materials, drug activity following surface immobilization is preserved. We have used successfully surface-modified nanocrystalline ceramics to deliver viral antigens for the purpose of evoking an immune response, oxygenated haemoglobin for cell respiration and insulin for carbohydrate metabolism. The theoretical principles, technical details and experimental results are reviewed. Surface-modified nanocrystalline materials offer an exciting new approach to the well-recognized challenges of drug delivery. Biomaterials (1994) 15, 1201–1207     

Magnetic nanovectors for drug delivery

Nanotechnology holds the promise of novel and more effective treatments for vexing human health issues. Among these are the use of nanoparticle platforms for site-specific delivery of therapeutics to tumors, both by passive and active mechanisms; the latter includes magnetic vectoring of magnetically responsive nanoparticles (MNP) that are functionalized to carry a drug payload that is released at the tumor. The conceptual basis, which actually dates back a number of decades, resides in physical (magnetic) enhancement, with magnetic field gradients aligned non-parallel to the direction of flow in the tumor vasculature, of existing passive mechanisms for extravasation and accumulation of MNP in the tumor interstitial fluid, followed by MNP internalization. In this review, we will assess the most recent developments and current status of this approach, considering MNP that are composed of one or more of the three elements that are ferromagnetic at physiological temperature: nickel, cobalt and iron. The effects on cellular functions in vitro, the ability to successfully vector the platform in vivo, the anti-tumor effects of such localized nano-vectors, and any associated toxicities for these MNP will be presented. The merits and shortcomings of nanomaterials made of each of the three elements will be highlighted, and a roadmap for moving this long-established approach forward to clinical evaluation will be put forth.     

静磁场靶向药物递送系统在肿瘤诊疗中的研究进展

化疗是治疗肿瘤的传统手段之一,但其具有组织非特异性,在抑制肿瘤细胞生长的同时也会对正常细胞产生毒副作用.磁靶向药物递送系统可通过具有生物相容性的、稳定的磁性纳米颗粒载体将抗癌药物在外磁场的引导下,靶向运输和浓聚在肿瘤组织.该技术不仅提高了药物运输的效率和药物的抗癌活性,还能降低药物用量和减轻毒副作用.载药磁性纳米颗粒和所应用的外磁场的性质是影响磁性纳米颗粒靶向肿瘤组织的重要影响因素.载药磁性纳米颗粒的靶向递送是否有效,主要依赖靶向目标位置处所应用的磁场和磁场强度是否足够吸引束缚载药磁性纳米颗粒在肿瘤组织中停留以及释放.对静磁场在引导磁性纳米颗粒靶向肿瘤组织研究的新进展进行综述,为静磁场在靶向肿瘤治疗方面提供一定的科研基础支持.     

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。     

Magnetic alginate microspheres: system for the position controlled delivery of nerve growth factor

The use of polymeric carriers containing dispersed magnetic nanocrystalline particles for targeted delivery of drugs in clinical practice has attracted the interest of the scientific community. In this paper a system comprised of alginate microparticles with a core of magnetite and carrying nerve growth factor (NGF) is described. The magnetic properties of these microspheres, typical of superparamagnetic materials, allow precise and controlled delivery to the intended tissue environment. Experiments carried out on PC12 cells with magnetic alginate microspheres loaded with NGF have confirmed the induction of cell differentiation which is strongly dependent on the distance from the microsphere cluster. In addition, finite element modelling (FEM) of the release profile from the microspheres in culture, indicated the possibility of creating defined and predictable NGF gradients from the loaded microspheres. These observations on the carriage and release of growth factors by the proposed microparticles open new therapeutic options for both neuronal regeneration and of the development of effective neuronal interfaces.     

脑靶向纳米药物递释系统研究进展

血脑屏障(blood-brain barrier, BBB)是中枢神经系统内的一种特殊结构,其优良的屏障特性能够保护大脑免于血液循环中有害大分子及病原体的侵害。然而,这一屏障同时也限制了药物递送的效果,并成为治疗神经退行性疾病、脑胶质瘤等脑部疾病的新药开发过程中最严峻的挑战之一。近年来,纳米技术的突破使得各类纳米颗粒(nanoparticles, NPs)逐渐得到了广泛的运用,在靶向递药领域被用做药物载体,经各种途径辅助药物实现BBB的跨越。本文主要通过阐述BBB的复杂成分和特殊特性,以理解跨越BBB的难点及可能途径;同时还介绍了目前用于药物递送系统的NPs的3种主要类型:聚合物型(polymeric-based)、仿生型(biomimetic-based)及无机型(inorganic-based)NPs;在靶向递药策略方面,本文主要介绍了吸附介导(adsorptive-mediated)、载体介导(carrier-mediated)及受体介导(receptor-mediated)的胞吞作用,并在文末对脑靶向纳米递药系统的未来发展进行了展望。     

Oligomeric nanoparticles functionalized with NIR-emitting CdTe/CdS QDs and folate for tumor-targeted imaging

We report herein the facile surface-functionalization of one type of biocompatible, oligomeric nanoparticles 1-NPs with NIR-emitting CdTe/CdS QDs and folate for tumor-targeted imaging in vivo. The –NH₂ and –SH groups of cysteine residues on the 1-NPs were utilized to covalently conjugate CdTe/CdS QDs and Mal-FA to prepare the hybrid nanoparticles 1-NPs-QDs-FA. As-prepared 1-NPs-QDs-FA showed NIR-fluorescence emission at 734 nm, selective uptake by FR-overexpressing tumor cells in vitro, and selective FR-overexpressing tumor-targeted imaging in vivo. This first example of oligomeric/inorganic hybrid nanoparticles provides people with new type of biomaterials for tumor-targeted imaging with high selectivity.     

Engineered multifunctional nanomaterials for multimodal imaging of retinoblastoma cells in vitro

Multifunctional nanoparticles are next generation materials that can be simultaneously used for imaging, diagnosis, and delivery of drugs. However, materials intended for cancer diagnosis need to be investigated for its cell uptake, toxicity, and effectiveness. In the current work, we have synthesized fluorescent iron oxide nanoparticles and evaluated its efficacy against retinoblastoma cell imaging. The iron oxide nanoparticles were synthesized and stabilized using oleic acid. Sulforhodamine B was adsorbed onto albumin over the oleic acid-capped iron oxide nanoparticles. Our results demonstrated good cell uptake in a time-dependent manner and nanoparticles were found to localize in the cytosol. Further, the nanoparticles exhibited excellent negative contrast in magnetic resonance imaging (MRI) experiments and with no cytoxicity (5–100?μg/mL iron oxide nanoparticles) to both normal as well as cancer cells demonstrating its biocompatibility. Thus, this novel material integrates the ability to image tissues with high sensitivity by MRI and specifically visualize Y79 retinoblastoma cells by fluorescence imaging with no toxicity.     

Carbon nanotube lipid drug approach for targeted delivery of a chemotherapy drug in a human breast cancer xenograft animal model

Carbon nanotube (CNT) possesses excellent properties as a drug carrier. To overcome the challenge of drug functionalization with CNT, we have developed a lipid-drug approach for efficient drug loading onto CNT, in which a long chain lipid molecule is conjugated to the drug molecule so that the lipid-drug can be loaded directly onto CNT through binding of the lipid ‘tail’ in the drug molecule to CNT surfaces via hydrophobic interactions. In a proof-of-concept study, drug paclitaxel (PTX) was conjugated with a non-toxic lipid molecule docosanol for functionalization with CNT. Folic acid was also conjugated to CNT for targeted drug delivery. High level of drug loading onto SWNT could be achieved by lipid-drug approach. Conjugation of FA to SWNT-lipid-PTX led to an increase in cell penetration capacity, and the targeted SWNT-lipid-PTX showed much improved drug efficacy in vitro in comparison to free drug Taxol and non-targeted SWNT-lipid-PTX at 48 h (78.5% vs. 31.6% and 59.1% in cytotoxicity respectively, p < 0.01). In vivo analysis using a human breast cancer xenograft mice model also confirmed the improved drug efficacy. The targeted SWNT-lipid-PTX was found non-toxic as evaluated by biochemical analysis using blood samples, and by histological analysis of major organs.     

Responsive fluorescent Bi(2)O(3)@PVA hybrid nanogels for temperature-sensing, dual-modal imaging, and drug delivery

The polymer-inorganic hybrid nanogels with temperature-responsive characteristic are of considerable current interest to many fields ranging from fundamental biomaterials science to bionanomedicine. This paper reports the preparation of temperature-responsive hybrid nanogels by immobilization of Bi₂O₃ quantum dots (QDs) in the interior of a nanogel of poly(vinyl alcohol) (PVA). Unlike conventional temperature-responsive hybrid nanogels with the responsive features deriving from the temperature-responsive polymers (e.g. PNIPAMs or non-linear PEGs), we demonstrate that QDs can work cooperatively with the gel networks of PVA, an unconventional responsive polymer, to enable the temperature-induced volume phase transition of the designed Bi₂O₃@PVA hybrid nanogels. Building on the rationales, Bi₂O₃@PVA hybrid nanogels can adapt to a surrounding fluids of different temperatures over the physiologically important range of 37-40 °C, convert the disruptions in homeostasis of environmental temperature into high-sensitive fluorescent signals, enter into the mouse melanoma B16F10 cells for dark-field and fluorescence dual-modal imaging, and regulate the release of a model anticancer drug temozolomide. The unconventional strategy that can broaden the design scheme of temperature-responsive hybrid nanogels for theranostic action should enhance our ability to address the complexity of biological systems.