Newly engineered magnetic erythrocytes for sustained and targeted delivery of anti-cancer therapeutic compounds

Cytotoxic chemotherapy of cancer is limited by serious, sometimes life-threatening, side effects that arise from toxicities to sensitive normal cells because the therapies are not selective for malignant cells. So how can they be selectively improved? Alternative pharmaceutical formulations of anti-cancer agents have been investigated in order to improve conventional chemotherapy treatment. These formulations are associated with problems like severe toxic side effects on healthy organs, drug resistance and limited access of the drug to the tumor sites suggested the need to focus on site-specific controlled drug delivery systems. In response to these concerns, we have developed a new drug delivery system based on magnetic erythrocytes engineered with a viral spike fusion protein. This new erythrocyte-based drug delivery system has the potential for magnetic-controlled site-specific localization and highly efficient fusion capability with the targeted cells. Here we show that the erythro-magneto-HA virosomes drug delivery system is able to attach and fuse with the target cells and to efficiently release therapeutic compounds inside the cells. The efficacy of the anti-cancer drug employed is increased and the dose required is 10 time less than that needed with conventional therapy.     

IMD-0354 Targets Breast Cancer Stem Cells: A Novel Approach for an Adjuvant to Chemotherapy to Prevent Multidrug Resistance in a Murine Model

Although early detection of breast cancer improved in recent years, prognosis of patients with late stage breast cancer remains poor, mostly due to development of multidrug resistance (MDR) followed by tumor recurrence. Cancer stem cells (CSCs), with higher drug efflux capability and other stem cell-like properties, are concentrated in a side population (SP) of cells, which were proposed to be responsible for MDR and tumor repopulation that cause patients to succumb to breast cancer. Therefore, targeting of CSCs as an adjuvant to chemotherapy should be able to provide a more effective treatment of this disease. Here, we used IMD-0354, an inhibitor of NF-κB, identified for targeting CSCs, in a combination therapy with doxorubicin encapsulated in targeted nanoparticles. IMD-0354 did target CSCs, evidenced by a decrease in the SP, demonstrated by the inhibition of the following: dye/drug efflux, reduction in ABC transporters as well as in colony formation in soft agar and low attachment plates. Decrease of stem-like gene expression of Oct4, Nanog and Sox2, and apoptosis resistance related to the Survivin gene also was observed after treatment with this compound. In addition, IMD-0354 targeted non-CSCs as indicated by reducing viability and increasing apoptosis. Targeted drug delivery, achieved with a legumain inhibitor, proved to enhance drug delivery under hypoxia, a hallmark of the tumor microenvironment, but not under normoxia. Together, this allowed a safe, non-toxic delivery of both anticancer agents to the tumor microenvironment of mice bearing syngeneic metastatic breast cancer. Targeting both bulk tumor cells with a chemotherapeutic agent and CSCs with IMD-0354 should be able to reduce MDR. This could eventually result in decreasing tumor recurrences and/or improve the outcome of metastatic disease.     

Tumor extracellular acidity-activated nanoparticles as drug delivery systems for enhanced cancer therapy

pH-responsive nanoparticles (NPs) are currently under intense development as drug delivery systems for cancer therapy. Among various pH-responsiveness, NPs that are designed to target slightly acidic extracellular pH environment (pH_e) of solid tumors provide a new paradigm of tumor targeted drug delivery. Compared to conventional specific surface targeting approaches, the pH_e-targeting strategy is considered to be more general due to the common occurrence of acidic microenvironment in solid tumors. This review mainly focuses on the design and applications of pH_e-activated NPs, with special emphasis on pH_e-activated surface charge reversal NPs, for drug and siRNA delivery to tumors. The novel development of NPs described here offers great potential for achieving better therapeutic effects in cancer treatment.     

Paclitaxel-loaded poly(gamma-glutamic acid)-poly(lactide) nanoparticles as a targeted drug delivery system against cultured HepG2 cells

The study was to develop paclitaxel-loaded formulations using a novel type of self-assembled nanoparticles that was composed of block copolymers synthesized from poly(gamma-glutamic acid) and poly(lactide) via a simple coupling reaction. The nanoparticles (the NPs) were prepared with various feed weight ratios of paclitaxel to block copolymer (the P/BC ratio). The morphology of all prepared nanoparticles was spherical and the surfaces were smooth. Increasing the P/BC ratio significantly increased the drug loading content of the prepared nanoparticles, but remarkably reduced the drug loading efficiency. The release rate of paclitaxel from the NPs decreased significantly as the P/BC ratio increased. For the potential of targeting liver cancer cells, galactosamine was further conjugated on the prepared nanoparticles (the Gal-NPs) as a targeting moiety. It was found that the activity in inhibiting the growth of HepG2 cells (a liver cancer cell line) by the Gal-NPs was comparable to that of a clinically available paclitaxel formulation, while the NPs displayed a significantly less activity. This may be attributed to the fact that the Gal-NPs had a specific interaction with HepG2 cells via ligand-receptor recognition. Cells treated with distinct paclitaxel formulations resulted in arrest in the G2/M phase. The arrest of cells in the G2/M phase was highly suggestive of interference by paclitaxel with spindle formation and was consistent with the morphological findings presented herein. In conclusion, the active targeting nature of the Gal-NPs prepared in the study may be used as a potential drug delivery system for the targeted delivery to liver cancers.     

AS1411 aptamer tagged PLGA-lecithin-PEG nanoparticles for tumor cell targeting and drug delivery

Liposomes and polymers are widely used drug carriers for controlled release since they offer many advantages like increased treatment effectiveness, reduced toxicity and are of biodegradable nature. In this work, anticancer drug‐loaded PLGA‐lecithin‐PEG nanoparticles (NPs) were synthesized and were functionalized with AS1411 anti‐nucleolin aptamers for site‐specific targeting against tumor cells which over expresses nucleolin receptors. The particles were characterized by transmission electron microscope (TEM) and X‐ray photoelectron spectroscopy (XPS). The drug‐loading efficiency, encapsulation efficiency and in vitro drug release studies were conducted using UV spectroscopy. Cytotoxicity studies were carried out in two different cancer cell lines, MCF‐7 and GI‐1 cells and two different normal cells, L929 cells and HMEC cells. Confocal microscopy and flowcytometry confirmed the cellular uptake of particles and targeted drug delivery. The morphology analysis of the NPs proved that the particles were smooth and spherical in shape with a size ranging from 60 to 110 nm. Drug‐loading studies indicated that under the same drug loading, the aptamer‐targeted NPs show enhanced cancer killing effect compared to the corresponding non‐targeted NPs. In addition, the PLGA‐lecithin‐PEG NPs exhibited high encapsulation efficiency and superior sustained drug release than the drug loaded in plain PLGA NPs. The results confirmed that AS1411 aptamer‐PLGA‐lecithin‐PEG NPs are potential carrier candidates for differential targeted drug delivery. Biotechnol. Bioeng. 2012; 109: 2920–2931. © 2012 Wiley Periodicals, Inc.     

ssDNA Aptamer Specifically Targets and Selectively Delivers Cytotoxic Drug Doxorubicin to HepG2 Cells

Hepatocellular carcinoma (HCC) is the third leading cause of death due to cancer worldwide with over 500,000 people affected annually. Although chemotherapy has been widely used to treat patients with HCC, alternate modalities to specifically deliver therapeutic cargos to cancer cells have been sought in recent years due to the severe side effects of chemotherapy. In this respect, aptamer-based tumor targeted drug delivery has emerged as a promising approach to increase the efficacy of chemotherapy and reduce or eliminate drug toxicity. In this study, we developed a new HepG2-specific aptamer (HCA#3) by a procedure known as systematic evolution of ligands by exponential enrichment (SELEX) and exploited its role as a targeting ligand to deliver doxorubicin (Dox) to HepG2 cells in vitro. The selected 76-base nucleotide aptamer preferentially bound to HepG2 hepatocellular carcinoma cells but not to control cells. The aptamer HCA#3 was modified with paired CG repeats at the 5′-end to carry and deliver a high payload of intercalated Dox molecules at the CG sites. Four Dox molecules (mol/mol) were fully intercalated in each conjugate aptamer-Dox (ApDC) molecule. Biostability analysis showed that the ApDC molecules are stable in serum. Functional analysis showed that ApDC specifically targeted and released Dox within HepG2 cells but not in control cells, and treatment with HCA#3 ApDC induced HepG2 cell apoptosis but had minimal effect on control cells. Our study demonstrated that HCA#3 ApDC is a promising aptamer-targeted therapeutic that can specifically deliver and release a high doxorubicin payload in HCC cells.     

Carbon nanotubes in cancer diagnosis and therapy

During the past years, great progress has been made in the field of nanomaterials given their great potential in biomedical applications. Carbon nanotubes (CNTs), due to their unique physicochemical properties, have become a popular tool in cancer diagnosis and therapy. They are considered one of the most promising nanomaterials with the capability of both detecting the cancerous cells and delivering drugs or small therapeutic molecules to these cells. Over the last several years, CNTs have been explored in almost every single cancer treatment modality, including drug delivery, lymphatic targeted chemotherapy, thermal therapy, photodynamic therapy, and gene therapy. In this review, we will show how they have been introduced into the diagnosis and treatment of cancer. Novel SWNT-based tumor-targeted drug delivery systems (DDS) will be highlighted. Furthermore, the in vitro and in vivo toxicity of CNTs reported in recent years will be summarized.     

金属有机骨架在肿瘤治疗中的应用进展

金属有机骨架(metal-organic frameworks,MOFs)是一类由金属结点和有机配体配位组装而成的晶体材料.金属有机骨架具有孔隙度大、孔径和尺寸可调、生物相容性好、成分可调、表面可修饰等优越性能,在肿瘤治疗领域具有重要的应用潜力.本文首先介绍了金属有机骨架用于小分子药物、生物大分子药物等药物递送体系的构建方法.随后,我们总结了近年来MOFs药物递送体系在肿瘤的化学治疗、光动力学治疗、放射性治疗、免疫治疗、光热治疗等方面的应用进展.最后,本文总结了MOFs在肿瘤治疗方面的进展和特点,并展望了MOFs在肿瘤治疗领域的研究挑战和应用前景.     

Targeted nitric oxide delivery preferentially induces glioma cell chemosensitivity via altered p53 and O6‐Methylguanine‐DNA Methyltransferase activity

Glioblastoma multiforme is the most common malignant central nervous system tumor, and also among the most difficult to treat due to a lack of response to chemotherapeutics. New methods of countering the mechanisms that confer chemoresistance to malignant gliomas could lead to significant advances in the quest to identify novel drug combinations or targeted drug delivery systems for cancer therapy. In this study, we investigate the use of a targeted nitric oxide (NO) donor as a pretreatment to sensitize glioma cells to chemotherapy. The protein chlorotoxin (CTX) has been shown to preferentially target glioma cells, and we have developed CTX–NO, a glioma‐specific, NO‐donating CTX derivative. Pretreatment of cells with CTX–NO followed by 48‐h exposure to either carmustine (BCNU) or temozolomide (TMZ), both common chemotherapeutics used in glioma treatment, resulted in increased efficacy of both therapeutics. After CTX–NO exposure, both T98G and U‐87MG human malignant glioma cells show increased sensitivity to BCNU and TMZ. Further investigation revealed that the consequences of this combination therapy was a reduction in active levels of the cytoprotective enzyme MGMT and altered p53 activity, both of which are essential in DNA repair and tumor cell resistance to chemotherapy. The combination of CTX–NO and chemotherapeutics also led to decreased cell invasion. These studies indicate that this targeted NO donor could be an invaluable tool in the development of novel approaches to treat cancer. Biotechnol. Bioeng. 2013; 110: 1211–1220. © 2012 Wiley Periodicals, Inc.     

放射性药物在肿瘤靶向治疗中的应用

放射性药物指供临床诊断或治疗用的放射性核素制剂或其标记化合物。放射性核素靶向治疗是利用对肿瘤细胞具有特异高亲和力的分子载体将核素定向导入特定的肿瘤组织,对肿瘤进行治疗。与传统的放疗和化疗相比,其具有选择性杀伤肿瘤细胞的特点。随着核医学的发展,SPECT/CT、PET/CT的普及,新靶点的发现和新型放射性药物的研发,利用放射性药物进行靶向治疗在肿瘤临床治疗中占据的地位越来越重要。本文简述了放射性药物的分类、组成及特点;综述了针对肿瘤相关抗原的放射免疫药物在非霍奇金淋巴瘤、结直肠癌和前列腺癌中的应用;受体介导的放射性核素药物在治疗神经内分泌肿瘤、前列腺癌和乳腺癌中的临床应用以及基于基因修饰的放射性药物在肿瘤靶向治疗中的实验研究进展。最后总结了放射性药物在肿瘤靶向治疗中的应用前景与面临的挑战,以期为靶向治疗肿瘤的放射性药物的开发和临床应用提供一些参考。     

Tumor-targeted pH-low insertion peptide delivery of theranostic gadolinium nanoparticles for image-guided nanoparticle-enhanced radiation therapy

Tumor targeting studies using metallic nanoparticles (NPs) have shown that the enhanced permeability and retention effect may not be sufficient to deliver the amount of intratumoral and intracellular NPs needed for effective in vivo radiosensitization. This work describes a pH-Low Insertion Peptide (pHLIP) targeted theranostic agent to enable image-guided NP-enhanced radiotherapy using a clinically feasible amount of injected NPs. Conventional gadolinium (Gd) NPs were conjugated to pHLIPs and evaluated in vitro for radiosensitivity and in vivo for mouse MRI. Cultured A549 human lung cancer cells were incubated with 0.5 mM of pHLIP-GdNP or conventional GdNP. Mass spectrometry showed 78-fold more cellular Gd uptake with pHLIP-GdNPs, and clonogenic survival assays showed 44% more enhanced radiosensitivity by 5 Gy irradiation with pHLIP-GdNPs at pH 6.2. In contrast to conventional GdNPs, MR imaging of tumor-bearing mice showed pHLIP-GdNPs had a long retention time in the tumor (>9 h), suitable for radiotherapy, and penetrated into the poorly-vascularized tumor core. The Gd-enhanced tumor corresponded with low-pH areas also independently measured by an in vivo molecular MRI technique. pHLIPs actively target cell surface acidity from tumor cell metabolism and deliver GdNPs into cells in solid tumors. Intracellular delivery enhances the effect of short-range radiosensitizing photoelectrons and Auger electrons. Because acidity is a general hallmark of tumor cells, the delivery is more general than antibody targeting. Imaging the in vivo NP biodistribution and more acidic (often more aggressive) tumors has the potential for quantitative radiotherapy treatment planning and pre-selecting patients who will likely benefit more from NP radiation enhancement.     

以EGFR为靶点的肿瘤分子靶向药物研究进展

随着分子生物学研究的进展,分子靶向治疗已成为除手术、放疗、化疗之外的第4种治疗方法,越来越多的用于临床治疗恶性肿瘤。分子靶向药物进入体内能够特异地选择致癌位点,杀伤肿瘤细胞,而不会波及周围正常的组织细胞,因此分子靶向治疗又被称为"生物导弹"。与传统化疗药物相比,分子靶向药物具有特异性强、疗效明显、副作用少等优点。按照分子靶向药物的性质主要归为两大类:一类是单克隆抗体,如西妥昔单抗等;另一类是单靶点或多靶点的小分子抑制剂,如吉非替尼等。表皮生长因子受体(EGFR)对肿瘤的生长、发展以及肿瘤干细胞的维持都有着非常重要的作用,并且在多种实体瘤中存在过表达或异常表达,因此在肿瘤治疗中,EGFR成为一个非常重要的用药靶点。现主要对目前国内已上市的针对EGFR的分子靶向药物最新的临床研究进展作一简要综述。     

Novel Epigenetic Target Therapy for Prostate Cancer: A Preclinical Study

Epigenetic events are critical contributors to the pathogenesis of cancer, and targeting epigenetic mechanisms represents a novel strategy in anticancer therapy. Classic demethylating agents, such as 5-Aza-2′-deoxycytidine (Decitabine), hold the potential for reprograming somatic cancer cells demonstrating high therapeutic efficacy in haematological malignancies. On the other hand, epigenetic treatment of solid tumours often gives rise to undesired cytotoxic side effects. Appropriate delivery systems able to enrich Decitabine at the site of action and improve its bioavailability would reduce the incidence of toxicity on healthy tissues. In this work we provide preclinical evidences of a safe, versatile and efficient targeted epigenetic therapy to treat hormone sensitive (LNCap) and hormone refractory (DU145) prostate cancers. A novel Decitabine formulation, based on the use of engineered erythrocyte (Erythro-Magneto-Hemagglutinin Virosomes, EMHVs) drug delivery system (DDS) carrying this drug, has been refined. Inside the EMHVs, the drug was shielded from the environment and phosphorylated in its active form. The novel magnetic EMHV DDS, endowed with fusogenic protein, improved the stability of the carried drug and exhibited a high efficiency in confining its delivery at the site of action in vivo by applying an external static magnetic field. Here we show that Decitabine loaded into EMHVs induces a significant tumour mass reduction in prostate cancer xenograft models at a concentration, which is seven hundred times lower than the therapeutic dose, suggesting an improved pharmacokinetics/pharmacodynamics of drug. These results are relevant for and discussed in light of developing personalised autologous therapies and innovative clinical approach for the treatment of solid tumours.     

Cellular Uptake and Antitumor Activity of DOX-hyd-PEG-FA Nanoparticles

A PEG-based, folate mediated, active tumor targeting drug delivery system using DOX-hyd-PEG-FA nanoparticles (NPs) were prepared. DOX-hyd-PEG-FA NPs showed a significantly faster DOX release in pH 5.0 medium than in pH 7.4 medium. Compared with DOX-hyd-PEG NPs, DOX-hyd-PEG-FA NPs increased the intracellular accumulation of DOX and showed a DOX translocation from lysosomes to nucleus. The cytotoxicity of DOX-hyd-PEG-FA NPs on KB cells was much higher than that of free DOX, DOX-ami-PEG-FA NPs and DOX-hyd-PEG NPs. The cytotoxicity of DOX-hyd-PEG-FA NPs on KB cells was attenuated in the presence of exogenous folic acid. The IC₅₀ of DOX-hyd-PEG-FA NPs and DOX-hyd-PEG NPs on A549 cells showed no significant difference. After DOX-hyd-PEG-FA NPs were intravenously administered, the amount of DOX distributed in tumor tissue was significantly increased, while the amount of DOX distributed in heart was greatly decreased as compared with free DOX. Compared with free DOX, NPs yielded improved survival rate, prolonged life span, delayed tumor growth and reduced the cardiotoxicity in tumor bearing mice model. These results indicated that the acid sensitivity, passive and active tumor targeting abilities were likely to act synergistically to enhance the drug delivery efficiency of DOX-hyd-PEG-FA NPs. Therefore, DOX-hyd-PEG-FA NPs are a promising drug delivery system for targeted cancer therapy.     

乳酸代谢——肿瘤治疗新靶点

恶性肿瘤严重危害人类健康,其治疗目前主要有手术、放疗和化疗三种方式,但疗效尚无法达到令人满意的程度,因此寻找肿瘤治疗新靶点、实现肿瘤的靶向治疗非常迫切. Warburg效应普遍存在于多种肿瘤中,其重要特征是在氧气充足的条件下,癌细胞的能量代谢仍以糖酵解为主. Warburg效应是糖酵解的典型过程,葡萄糖被大量吸收并通过糖酵解转化为乳酸.糖酵解产物乳酸可以激活癌细胞中许多重要的信号通路,促进癌细胞的存活、侵袭、免疫逃逸、转移和血管生成.因此,靶向乳酸代谢过程及其关键酶可能为肿瘤治疗提供新的靶点.本文对肿瘤细胞代谢方式的改变,乳酸对肿瘤细胞免疫逃逸、肿瘤转移、肿瘤血管生成的影响,以及以乳酸为靶点的肿瘤治疗等方面进行综述.     

Bacterially-Derived Nanocells for Tumor-Targeted Delivery of Chemotherapeutics and Cell Cycle Inhibitors

Chemotherapeutic drug therapy in cancer is seriously hampered by severe toxicity primarily due to indiscriminate drug distribution and consequent collateral damage to normal cells. Molecularly targeted drugs such as cell cycle inhibitors are being developed to achieve a higher degree of tumor cell specificity and reduce toxic side effects. Unfortunately, relative to the cytotoxics, many of the molecularly targeted drugs are less potent and the target protein is expressed only at certain stages of the cell cycle thus necessitating regimens like continuous infusion therapy to arrest a significant number of tumor cells in a heterogeneous tumor mass. Here we discuss targeted drug delivery nanovectors and a recently reported bacterially-derived 400nm sized minicell that can be packaged with therapeutically significant concentrations of chemotherapeutic drugs, targeted to tumor cell surface receptors and effect intracellular drug delivery with highly significant anti-tumor effects in-vivo. We also report that molecularly targeted drugs can also be packaged in minicells and targeted to tumor cells with highly significant tumor growth-inhibition and regression in mouse xenografts despite administration of minute amounts of drug. This targeted intracellular drug delivery may overcome many of the hurdles associated with the delivery of cytotoxic and molecularly targeted drugs.     

卟啉金属有机骨架材料在肿瘤治疗中的应用

目前,恶性肿瘤严重威胁人类健康和生命。临床上常用放疗法和化疗法治疗肿瘤,在一定程度上抑制肿瘤的生长和转移。但是,传统的化疗药物在给药过程中缺乏靶向性、副作用大,而且大多数化疗药物水溶性差,效果有限,高剂量的重复给药会导致耐药,单一模式的治疗策略效果不佳。因此通过构建靶向智能多功能纳米载药系统实现肿瘤精准诊断和治疗成为近年来的研究热点。卟啉金属有机骨架（MOFs）材料具有多孔性、大比表面积、表面可修饰等特性,有望成为良好的靶向刺激响应型药物载体。而且卟啉MOFs可以避免卟啉分子的自聚集以及在激发态的自猝灭,还具有卟啉分子的宽光谱响应范围,是一类具有广阔应用前景的固体光敏剂,因此卟啉MOFs近年来成为构建靶向智能多功能纳米载药系统的重要平台。本论文综述了近年来基于卟啉金属有机骨架材料的肿瘤治疗策略,特别是基于肿瘤内源性组分（pH、酶、氧化还原）和外源性物理信号（声、磁、光）刺激触发的多功能纳米平台用于肿瘤精准诊断和治疗的最新研究进展,并讨论了卟啉MOFs在未来肿瘤治疗中面临的挑战和机遇。     

肿瘤放化综合治疗中的靶向研究

放化疗综合应用是癌症治疗中的常用方法。研究表明,放化疗综合应用可以有效地控制杀伤肿瘤,但过程中对正常细胞的毒副作用严重制约着放化疗的剂量和疗效。如何在有效杀伤肿瘤细胞的同时减轻放化疗综合应用中对正常细胞的毒副作用已经成为探索更好的治疗策略的关键。随着研究的不断深入,各种相关的新药和新治疗思路层出不穷,比如针对肿瘤发生及代谢过程的靶向类新药、用于辐射增敏的新的基因靶点等都已进入研究者的视线。另外,近年来关于肿瘤细胞中药物转运蛋白的研究也为综合治疗靶点寻找提供了一定依据。本文根据当前研究现状,着重总结近年来放化疗综合治疗靶向研究在上述几方面的一些新进展。     

肿瘤放化综合治疗中的靶向研究

放化疗综合应用是癌症治疗中的常用方法。研究表明,放化疗综合应用可以有效地控制杀伤肿瘤,但过程中对正常细胞的毒副作用严重制约着放化疗的剂量和疗效。如何在有效杀伤肿瘤细胞的同时减轻放化疗综合应用中对正常细胞的毒副作用已经成为探索更好的治疗策略的关键。随着研究的不断深入,各种相关的新药和新治疗思路层出不穷,比如针对肿瘤发生及代谢过程的靶向类新药、用于辐射增敏的新的基因靶点等都已进入研究者的视线。另外,近年来关于肿瘤细胞中药物转运蛋白的研究也为综合治疗靶点寻找提供了一定依据。本文根据当前研究现状,着重总结近年来放化疗综合治疗靶向研究在上述几方面的一些新进展。     

Glioblastoma: Therapeutic challenges, what lies ahead

Glioblastoma (GBM) is one of the most aggressive human cancers. Despite current advances in multimodality therapies, such as surgery, radiotherapy and chemotherapy, the outcome for patients with high grade glioma remains fatal. The knowledge of how glioma cells develop and depend on the tumor environment might open opportunities for new therapies. There is now a growing awareness that the main limitations in understanding and successfully treating GBM might be bypassed by the identification of a distinct cell type that has defining properties of somatic stem cells, as well as cancer-initiating capacity - brain tumor stem cells, which could represent a therapeutic target. In addition, experimental studies have demonstrated that the combination of antiangiogenic therapy, based on the disruption of tumor blood vessels, with conventional chemotherapy generates encouraging results. Emerging reports have also shown that microglial cells can be used as therapeutic vectors to transport genes and/or substances to the tumor site, which opens up new perspectives for the development of GBM therapies targeting microglial cells. Finally, recent studies have shown that natural toxins can be conjugated to drugs that bind to overexpressed receptors in cancer cells, generating targeted-toxins to selectively kill cancer cells. These targeted-toxins are highly effective against radiation- and chemotherapy-resistant cancer cells, making them good candidates for clinical trials in GBM patients. In this review, we discuss recent studies that reveal new possibilities of GBM treatment taking into account cancer stem cells, angiogenesis, microglial cells and drug delivery in the development of new targeted-therapies.