叶酸受体介导的靶向纳米给药系统研究进展

叶酸受体在许多恶性肿瘤细胞表面过度表达,而在正常细胞中则几乎不表达或只有少量表达。利用叶酸受体表达的特性,通过将叶酸修饰于药物载体表面,可使药物靶向输送至叶酸受体过度表达的肿瘤细胞中,从而避免对正常细胞产生毒性,提高药物疗效;而纳米给药系统因粒径较小等原因可使药物在肿瘤部位浓集。本文对近年来叶酸受体介导的靶向纳米给药系统进行了综述。     

叶酸靶向的肿瘤治疗研究进展

叶酸靶向的递药系统是一种新兴的治疗多种恶性肿瘤的方法。利用叶酸分子与肿瘤细胞表面叶酸受体的高亲和力,叶酸偶联的化合物能够将分子大小不同的复合物递送给病理细胞而不对正常组织造成伤害。目前,通过这种方法成功递送到叶酸受体高表达肿瘤细胞的复合物包括:蛋白毒素、化疗药物、免疫治疗剂、基因载体、反义寡核苷酸、小分子干扰RNA和纳米载体。该文综述了多种叶酸作为靶向配体治疗恶性肿瘤的方法。     

靶向叶酸受体和线粒体的载雷公藤红素PAMAM纳米递药系统构建及体外抗炎作用

促炎巨噬细胞在类风湿性关节炎的发生和发展中发挥关键调控作用。本研究构建了一种可靶向叶酸受体和线粒体的载雷公藤红素(celastrol, Cel)聚酰胺-胺树枝状聚合物(polyamide-amine dendrimer, PAMAM)纳米递药系统,实现可靶向炎症巨噬细胞的集化疗和光热于一体的协同治疗。以PAMAM为纳米载体,通过酰胺反应偶联叶酸受体靶向基团叶酸(folic acid, FA)和线粒体靶向基团IR808 (同时作为光热剂),通过静电吸附作用负载抗炎药Cel,制备了FA-PAMAM-IR808/Cel纳米复合物。体外表征结果表明,该纳米复合物中Cel载药量为50.90%,粒径为130～160 nm,平均电位在1.0～3.5 mV,释药呈现pH敏感性,经近红外光照射10 min温度可达42.5℃;体外摄取实验表明,纳米复合物有明显的叶酸靶向性和线粒体靶向性;纳米复合物在近红外光照后可显著增强细胞毒性和诱导细胞凋亡能力,并浓度依赖性降低促炎因子肿瘤坏死因子α (TNF-α)、白细胞介素-1β (IL-1β)、白细胞介素-6 (IL-6)、一氧化氮(NO)分泌量。本研究为开发新型...     

用于肿瘤治疗和诊断的叶酸复合物

对可用于肿瘤治疗或具有潜在临床应用价值的叶酸复合物,如叶酸-基因载体,叶酸-纳米药物,叶酸-脂质体药物和可用于肿瘤诊断的叶酸-放射性核素、叶酸-核磁共振造影剂、叶酸-量子点进行了介绍,并展望了叶酸-近红外染料复合物在恶性肿瘤早期诊断方面的应用前景。叶酸受体在许多肿瘤中过度表达,而在正常组织中很少甚至几乎不表达。把化疗药物或诊断试剂开发为叶酸受体介导的叶酸复合物制剂将有可能实现对肿瘤更精准的靶向治疗和诊断。     

叶酸受体介导的靶向给药研究进展

目的：介绍叶酸受体介导的靶向给药研究进展。方法：根据近年来的文献资料，对叶酸受体介导的靶向给药研究进行综述。结果：叶酸受体可以与叶酸及其类似物特异性结合，从而提高药物在肿瘤、关节炎的组织分布，达到靶向诊断、治疗的目的。结论：叶酸受体介导的靶向给药是一种很有前景的给药方式。     

叶酸受体介导的靶向给药研究进展

叶酸受体可以与叶酸及其类似物特异性结合,通过介导细胞内化将其摄入细胞胞浆。利用叶酸受体在肿瘤和关节炎细胞的过度表达,使药物与叶酸结合,以叶酸受体为作用靶点,即可将药物主动靶向肿瘤和关节炎细胞,从而提高药物在肿瘤、关节炎的组织分布,达到靶向诊断、治疗的目的。本文就叶酸受体及其组织分布,叶酸受体介导的内吞作用,叶酸受体介导的肿瘤和关节炎的靶向诊断、治疗的研究进展进行了综述。     

脑肿瘤靶向纳米递药系统的研究进展

脑肿瘤中恶性肿瘤较为常见,脑瘤发展快、治疗难导致了较高的死亡率。采用化学药物治疗时,药物进入脑肿瘤组织必须通过血脑屏障和血- 脑瘤屏障。一些有潜力的抗肿瘤药物由于自身物理化学性质的限制,不能有效到达肿瘤。针对脑肿瘤形成和发展不同阶段的特点,目前脑肿瘤靶向递药有3 种策略：跨血脑屏障（BBB）转运递药、跨血- 脑瘤屏障（BBTB）转运递药和利用实体瘤的高通透性和滞留效应（EPR 效应）递药,已被广泛研究的纳米递药载体有脂质体、固体脂质纳米粒、聚合物胶束、树枝状聚合物、碳纳米管、聚合物纳米粒、磁性纳米粒等。控制载药纳米微粒粒径大小以及对其表面进行修饰可改善药物在体内的分布与滞留,提高化疗药物的疗效,降低毒副作用。多级靶向纳米递药系统有潜力成为治疗脑肿瘤的重要辅助方式。     

甲氨蝶呤叶酸受体-磁双重靶向纳米粒的制备及评价

目的：以甲氨蝶呤为药物模型,制备用于肿瘤靶向治疗的叶酸受体-磁双重靶向纳米药物。方法：未采用 预成型的磁性纳米粒,一步合成磁性纳米粒核二氧化硅壳超顺磁性的纳米粒,并借助透射、扫描电镜观察微球形态,用 硅烷偶联剂进行表面修饰,在表面化学偶联上叶酸,修饰甲氨蝶呤后利用紫外可见分光光度计测量载药量及包封率。结 果：磁性纳米粒在电镜下呈现核壳样球型微粒,平均粒径为20 nm,纳米粒载药量为26.71%,包封率为64.76%。结论： 叶酸受体-磁双重载药纳米粒为肿瘤的靶向治疗提供了一种可能的新剂型,有较好的临床应用前景。     

生物素在肿瘤靶向递药中的研究进展

运用靶向递药系统给药是目前治疗癌症的有效方法,靶向配体的选择是靶向递药的关键。生物素受体在多数肿瘤细胞表面过表达,但在正常细胞中低表达或不表达,因此,生物素可作为配体与药物载体相连,用于肿瘤靶向递药。简述生物素及生物素受体,综述生物素修饰的脂质体、胶束、纳米粒等载药系统在肿瘤靶向诊断和治疗中的研究进展,以期为相关研究开发与临床应用提供参考。     

甲氨蝶呤叶酸受体-磁双重靶向纳米粒的制备及评价

目的：以甲氨蝶呤为药物模型，制备用于肿瘤靶向治疗的叶酸受体-磁双重靶向纳米药物。方法：未采用 预成型的磁性纳米粒，一步合成磁性纳米粒核二氧化硅壳超顺磁性的纳米粒，并借助透射、扫描电镜观察微球形态，用 硅烷偶联剂进行表面修饰，在表面化学偶联上叶酸，修饰甲氨蝶呤后利用紫外可见分光光度计测量载药量及包封率。结 果：磁性纳米粒在电镜下呈现核壳样球型微粒，平均粒径为20 nm，纳米粒载药量为26.71%，包封率为64.76%。结论： 叶酸受体-磁双重载药纳米粒为肿瘤的靶向治疗提供了一种可能的新剂型，有较好的临床应用前景。     

叶酸修饰壳聚糖在肿瘤靶向制剂中的研究进展

壳聚糖及其衍生物具有无毒、生物可降解性和良好的生物相容性等特点,在药物递送系统中有良好的应用前景。叶酸受体在肿瘤细胞过表达,利用叶酸与其受体的特异性结合,可实现靶向肿瘤效应。该文综述叶酸修饰壳聚糖及其在肿瘤靶向制剂方面的研究。     

Tumor selectivity of stealth multi-functionalized superparamagnetic iron oxide nanoparticles

Superparamagnetic iron oxide nanoparticles (SPIO-NPs) have traditionally been used as MRI contrast agent for disease imaging via passive targeting. However, there has been an increasing interest in the development of SPIO-NPs to cellular-specific targeting for imaging and drug delivery currently. The objective of our study was to develop a novel active tumor-targeting SPIO-NPs system by surface-modifying superparamagnetic iron oxide nanoparticles (SPIO-NPs) with o-carboxymethyl chitosans (OCMCS) and folic acid (FA) to improve their biocompatibility and ability to target specific tumor cells as well as to evade reticuloendothelial system (RES). The results in vitro indicated the covalent surface-modification of SPIO-NPs with OCMCS significantly reduced not only the nano-cytotoxicity but also the capture of SPIO-NPs by macrophage cells. On the other hand, the folic acid modification promoted the uptake of nanoparticles by FR-positive tumor cell lines, but had little impact on other cells without folate receptor (FR). MRI image and tumor histological analysis demonstrated the FA-OCMCS-SPIO-NPs had the ability to target tumor cells with FR in vivo. OCMCS and folic acid modification of SPIO-NPs could significantly improve both the SPIO-NPs biocompatibility and the FR target for MRI imaging, potential carrier for drug targeting and hyperthermia.     

Conjugates of TAT and folate with DOX-loaded chitosan micelles offer effective intracellular delivery ability

The key for better antitumor efficacy is to improve the specificity of antitumor drugs for tumor cells and diminish their cytotoxicity to normal tissues. Targeted nanoparticles as antitumor drug delivery system can resolve this problem. In this study, we prepared folate and TAT (arginine-rich cell-penetrating peptide) modified N-PEG-N′-octyl-chitosan to form the folate/TAT-PEG-OC micelles. Then, the molecular structure, morphology, size distribution and bio-safety of the micelles were characterized. In order to investigate the drug-loading capacity of folate/TAT-PEG-OC micelles, doxorubicin (DOX) was used as model drug to prepare DOX-loaded chitosan micelles. Here, the confocal microscopy was used to evaluate the cellular uptake of DOX/folate/TAT-PEG-OC micelles, while the self-built NIR imaging system was used to evaluate the dynamic behavior of ICG-Der-01/folate/TAT-PEG-OC micelles in vivo. Our results demonstrate that the dual-modified PEG-OC micelles not only have good morphology, uniform size distribution and excellent drug loading capacity, but also show a strong capability for the efficient intracellular uptake and enhanced targeting behaviors in a folate receptor positive tumor model (Bel-7402 human hepatocellular cells). All these results suggest the potential application of folate/TAT-PEG-OC micelles in the targeted diagnosis and therapy to different kinds of folate receptor positive tumors.     

Folate-modified poly(2-ethyl-2-oxazoline) as hydrophilic corona in polymeric micelles for enhanced intracellular doxorubicin delivery

The transmembrane transport of drug loaded micelles to intracellular compartment is quite crucial for efficient drug delivery. In the current study, we investigated the cellular internalization and anticancer activity of doxorubicin loaded micelles with folate modified stealthy PEOz corona. Folate-decorated micelles incorporating doxorubicin were characterized for particle size, degree of folate decoration, drug loading content and encapsulation efficiency, morphology, and surface charge. The targeting capability and cell viability were assessed using HeLa, KB, A549 and MCF-7/ADR cell lines. In vitro study clearly illustrated the folate receptor (FR) mediated targeting of FA modified micelles to FR-positive human HeLa, KB and MCF-7/ADR cells, while specific delivery to FR-negative A549 cells was not apparently increased at the same experimental conditions. Cytotoxicity assay showed 60% and 58% decrease in IC₅₀ values for HeLa and KB cells, while only a slight decrease for A549 cells, following treatment with folate modified formulations. The enhanced intracellular delivery of FA modified micelles in MCF-7/ADR cells was also observed. In vivo antitumor tests revealed DOX entrapped FA-PEOz-PCL micelles effectively inhibited the tumor growth and reduced the toxicity to mice compared with free DOX. The current study showed that the targeted nano-vector improved cytotoxicity of DOX and suggested that this novel PEOz endowed stealthy micelle system held great promise in tumor targeted therapy.     

Superparamagnetic iron oxide nanoparticle 'theranostics' for multimodality tumor imaging, gene delivery, targeted drug and prodrug delivery

The superparamagnetic iron oxide nanoparticle (SPIO) 'theranostics', which contain imaging probes for tumor diagnosis and therapeutic compounds for therapy in a single nanoparticle, might provide significant benefits compared with exiting tumor imaging and therapeutic strategies. In this review, we summarize the progress of SPIO 'theranostics' that integrate tumor targeting, multimodality imaging, and gene delivery or targeted drug and prodrug delivery. This review describes various methods of SPIO synthesis, surface coating and characterization. Different tumor-targeting strategies, such as antibody fragments, nucleotides and receptor ligands, are discussed to improve SPIO delivery for multimodality imaging. We also examine the utility of SPIOs for gene delivery, siRNA delivery and imaging. Several methods for drug encapsulation and conjugation onto SPIOs are compared for targeted drug delivery, site-specific release and imaging-guided drug delivery. Finally, we also review the pharmacokinetics (including biodistribution) of SPIOs based on their characteristics.     

Targeted drug delivery via the folate receptor

The folate receptor is a highly selective tumor marker overexpressed in greater than 90% of ovarian carcinomas. Two general strategies have been developed for the targeted delivery of drugs to folate receptor-positive tumor cells: by coupling to a monoclonal antibody against the receptor and by coupling to a high affinity ligand, folic acid. First, antibodies against the folate receptor, including their fragments and derivatives, have been evaluated for tumor imaging and immunotherapy clinically and have shown significant targeting efficacy in ovarian cancer patients. Folic acid, a high affinity ligand of the folate receptor, retains its receptor binding properties when derivatized via its gamma-carboxyl. Folate conjugation, therefore, presents an alternative method of targeting the folate receptor. This second strategy has been successfully applied in vitro for the receptor-specific delivery of protein toxins, anti-T-cell receptor antibodies, interleukin-2, chemotherapy agents, gamma-emitting radiopharmaceuticals, magnetic resonance imaging contrast agents, liposomal drug carriers, and gene transfer vectors. Low molecular weight radiopharmaceuticals based on folate conjugates showed much more favorable pharmacokinetic properties than radiolabeled antibodies and greater tumor selectivity in folate receptor-positive animal tumor models. The small size, convenient availability, simple conjugation chemistry, and presumed lack of immunogenicity of folic acid make it an ideal ligand for targeted delivery to tumors.     

Superparamagnetic iron oxide nanoparticle ‘theranostics’ for multimodality tumor imaging,gene delivery,targeted drug and prodrug delivery

The superparamagnetic iron oxide nanoparticle (SPIO) ‘theranostics’, which contain imaging probes for tumor diagnosis and therapeutic compounds for therapy in a single nanoparticle, might provide significant benefits compared with exiting tumor imaging and therapeutic strategies. In this review, we summarize the progress of SPIO ‘theranostics’ that integrate tumor targeting, multimodality imaging, and gene delivery or targeted drug and prodrug delivery. This review describes various methods of SPIO synthesis, surface coating and characterization. Different tumor-targeting strategies, such as antibody fragments, nucleotides and receptor ligands, are discussed to improve SPIO delivery for multimodality imaging. We also examine the utility of SPIOs for gene delivery, siRNA delivery and imaging. Several methods for drug encapsulation and conjugation onto SPIOs are compared for targeted drug delivery, site-specific release and imaging-guided drug delivery. Finally, we also review the pharmacokinetics (including biodistribution) of SPIOs based on their characteristics.     

Magnetic micelles as a potential platform for dual targeted drug delivery in cancer therapy

The magnetic nanomicelles as a potential platform for dual targeted (folate-mediated and magnetic-guided) drug delivery were developed to enhance the efficiency and veracity of drug delivering to tumor site. The magnetic nanocarriers were synthesized based on superparamagnetic iron oxide nanoparticles (SPIONs), biocompatible Pluronic F127 and poly(dl-lactic acid) (F127-PLA) copolymer chemically conjugated with tumor-targeting ligand-folic acid (FA) via a facile chemical conjugation method. Doxorubicin hydrochloride (DOX·HCl) was selected as a model anticancer drug to investigate the in vitro drug release and antiproliferative effect of tumor cells in vitro and in vivo in the presence or absence of an external magnetic filed (MF) with strength of 0.1T. The Alamar blue assay exhibited that these magnetic nanomicelles possessed remarkable cell-specific targeting in vitro. Additionally this smart system enabling folate receptor-mediated uptake into tumor cells, showed strong responsiveness to MF. The primary in vivo tumor model study, which was carried out in VX2 tumor-bearing male New Zealand white rabbits, demonstrated that the nanomicelles could be guided into tumor site more efficiently by application of MF, and further represented significant therapeutic efficiency to solid tumor.     

Design and function of a dendrimer-based therapeutic nanodevice targeted to tumor cells through the folate receptor

Purpose. We sought to develop nanoscale drug delivery materials that would allow targeted intracellular delivery while having an imaging capability for tracking uptake of the material. A complex nanodevice was designed and synthesized that targets tumor cells through the folate receptor. Methods. The device is based on an ethylenediamine core polyamidoamine dendrimer of generation 5. Folic acid, fluorescein, and methotrexate were covalently attached to the surface to provide targeting, imaging, and intracellular drug delivery capabilities. Molecular modeling determined the optimal dendrimer surface modification for the function of the device and suggested a surface modification that improved targeting. Results. Three nanodevices were synthesized. Experimental targeting data in KB cells confirmed the modeling predictions of specific and highly selective binding. Targeted delivery improved the cytotoxic response of the cells to methotrexate 100-fold over free drug. Conclusions. These results demonstrate the ability to design and produce polymer-based nanodevices for the intracellular targeting of drugs, imaging agents, and other materials.