Brain tumor-targeted drug delivery strategies

Despite the application of aggressive surgery, radiotherapy and chemotherapy in clinics, brain tumors are still a difficult health challenge due to their fast development and poor prognosis. Brain tumor-targeted drug delivery systems, which increase drug accumulation in the tumor region and reduce toxicity in normal brain and peripheral tissue, are a promising new approach to brain tumor treatments. Since brain tumors exhibit many distinctive characteristics relative to tumors growing in peripheral tissues, potential targets based on continuously changing vascular characteristics and the microenvironment can be utilized to facilitate effective brain tumor-targeted drug delivery. In this review, we briefly describe the physiological characteristics of brain tumors, including blood–brain/brain tumor barriers, the tumor microenvironment, and tumor stem cells. We also review targeted delivery strategies and introduce a systematic targeted drug delivery strategy to overcome the challenges.Key words: Barriers targeting, Tumor microenvironment, Tumor cells, Systematic targeted drug delivery     

Nanomedicine-based drug delivery towards tumor biological and immunological microenvironment

The complex tumor microenvironment is a most important factor in cancer development. The biological microenvironment is composed of a variety of barriers including the extracellular matrix and associated cells such as endothelia cells, pericytes, and cancer-associated fibroblasts. Different strategies can be utilized to enhance nanoparticle-based drug delivery and distribution into tumor tissues addressing the extracellular matrix or cellular components. In addition to the biological microenvironment, the immunological conditions around the tumor tissue can be very complicated and cancer cells have various ways of evading immune surveillance. Nanoparticle drug delivery systems can enhance cancer immunotherapy by tuning the immunological response and memory of various immune cells such as T cells, B cells, macrophages, and dendritic cells. In this review, the main components in the tumor biological and immunological environment are discussed. The focus is on recent advances in nanoparticle-based drug delivery systems towards targets within the tumor microenvironment to improve cancer chemotherapy and immunotherapy.     

Neural stem cells as novel drug delivery agents

Neural stem cells could be used as novel drug delivery agents after interleukin-expressing stem cells have been shown to track and kill gliomas as they spread through brain tissue.     

The interactions and communications in tumor resistance to radiotherapy: Therapy perspectives

Tumor microenvironment (TME) includes a wide range of cell types including cancer cells, cells which are involved in stromal structure and immune cells (tumor suppressor and tumor promoting cells). These cells have several interactions with each other that are mainly regulated via the release of intercellular mediators. Radiotherapy can modulate these interactions via shifting secretions into inflammatory or anti-inflammatory responses. Radiotherapy also can trigger resistance of cancer (stem) cells via activation of stromal cells. The main mechanisms of tumor resistance to radiotherapy is the exhaustion of anti-tumor immunity via suppression of CD4+ T cells and apoptosis of cytotoxic CD8+ T lymphocytes (CTLs). Cancer-associated fibroblasts (CAFs), mesenchymal-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) are the main suppressor of anti-tumor immunity via the release of several chemokines, cytokines and immune suppressors. In this review, we explain the main cellular and molecular interactions and secretions in TME following radiotherapy. Furthermore, the main signaling pathways and intercellular connections that can be targeted to improve therapeutic efficiency of radiotherapy will be discussed.     

主动靶向肿瘤的纳米递药系统改善肿瘤免疫治疗研究进展

近年来,免疫疗法在肿瘤临床治疗方面已取得巨大进展,但在免疫治疗药物体内递送过程中仍存在肿瘤特异性差、肿瘤深部渗透率低和细胞摄取率低等问题,导致其疗效和安全性较差,严重限制了免疫疗法的临床效果。通过表面偶联的抗体或配体与靶细胞膜受体间的相互作用,设计构建主动靶向肿瘤的纳米递药系统(aNDDS)可提高药物在靶细胞内的浓度,为实现特异高效的药物递送提供了可行的策略。此外,一些特定类型的细胞膜因具有天然的靶向能力被用于仿生纳米载体的构建,进而提高药物的递送效率。基于主动靶向肿瘤纳米载体的诸多优势,科研人员也设计了一系列用于促进抗肿瘤免疫应答的aNDDS,并证明其可以提高免疫治疗的有效性和安全性。本文回顾了近年来aNDDS改善肿瘤免疫治疗的研究进展,并对该领域的主要挑战和未来的发展进行了展望。     

Design of novel multifunctional targeting nano-carrier drug delivery system based on CD44 receptor and tumor microenvironment pH condition

In this study, to develop a multifunctional targeting nano-carrier drug delivery system for cancer therapy, the novel pH-sensitive ketal based oligosaccharides of hyaluronan (oHA) conjugates were synthesized by chemical conjugation of hydrophobic menthone 1,2-glycerol ketal (MGK) to the backbone of oHA with the histidine as the linker of proton sponge effect. The multifunctional oHA conjugates, oHA-histidine-MGK (oHM) carried the pH-sensitive MGK as hydrophobic moieties and oHA as the target of CD44 receptor. The oHM could self-assemble to nano-sized spherical shape with the average diameters of 128.6?nm at pH 7.4 PBS conditions. The oHM nanoparticles (oHMN) could release encapsulated curcumin (Cur) with 82.6% at pH 5.0 compared with 49.3% at pH 7.4. The results of cytotoxicity assay indicated that encapsulated Cur in oHMN (Cur-oHMN) were stable and have less toxicity compared to Cur suspension. The anti-tumor efficacy in vivo suggested that Cur-oHMN suppressed tumor growth most efficiently. These results present the promising potential of oHMN as a stable and effective nano-sized pH-sensitive drug delivery system for cancer treatment.     

Actively targeted nanocarriers for drug delivery to cancer cells

Introduction: Progressive breakthroughs in nanomedicine have been instrumental for the clinical translation of actively targeted drug-delivery approaches. Besides storing large payloads of drugs within the nanoparticle core, the conjugation of targeting moieties confers specific targeting ability to the nanoplatforms. In this respect, clinical results suggest that actively targeted nanocarriers can exhibit an overall improved antitumor efficacy, minimizing off-target toxicity.

Areas covered: This review article summarizes the advances in active targeting of nanocarriers to cancer cells. Specifically, we discuss the various types of nanocarriers, describe the receptors that are frequently overexpressed in solid tumors, and discuss how this approach can be used to improve clinical outcomes. We particularly focus on ongoing clinical trials of actively targeted nanoparticles that are yet to be clinically approved.

Expert opinion: Further investment in active targeting will likely pose clinical benefits. We envisage a future requiring the use of longitudinal measures in the clinical setting to profile the patients that are likely to benefit from actively targeted nanocarriers. At the preclinical stage, a complete picture of intratumoral barriers combined with a quantitative approach of the intratumoral fate of nanomaterials will be instrumental in defining more effective strategies to improve their clinical translation.     

Chemokines in bone-metastatic breast cancer: Therapeutic opportunities

Due to non-response to chemotherapy, incomplete surgical resection, and resistance to checkpoint inhibitors, breast cancer with bone metastasis is notoriously difficult to cure. Therefore, the development of novel, efficient strategies to tackle bone metastasis of breast cancer is urgently needed. Chemokines, which induce directed migration of immune cells and act as guide molecules between diverse cells and tissues, are small proteins indispensable in immunity. These complex chemokine networks play pro-tumor roles or anti-tumor roles when produced by breast cancer cells in the tumor microenvironment. Additionally, chemokines have diverse roles when secreted by various immune cells in the tumor microenvironment of breast cancer, which can be roughly divided into immunosuppressive effects and immunostimulatory effects. Recently, targeting chemokine networks has been shown to have potential for use in treatment of metastatic malignancies, including bone-metastatic breast cancer. In this review, we focus on the role of chemokines networks in the biology of breast cancer and metastasis to the bone. We also discuss the therapeutic opportunities and future prospects of targeting chemokine networks, in combination with other current standard therapies, for the treatment of bone-metastatic breast cancer.     

Towards crystal engineering via simulated pulmonary surfactant monolayers to optimise inhaled drug delivery

Purpose

To generate theophylline monohydrate crystals underneath Langmuir monolayers composed of material expressed at the alveolar air-liquid interface. Such monolayers can act as nucleation sites to direct crystallisation. The approach offers a novel route to rationally engineer therapeutic crystals and thereby optimise inhaled drug delivery.

Methods

Langmuir monolayers consisting of either dipalmitoylphosphatidylcholine (DPPC) or a surfactant mix reflecting pulmonary surfactant were supported on an aqueous theophylline (5.7 mg/ml) subphase. The monolayers were compressed to surface pressures reflecting inhalation and exhalation (i.e. 5 mN m⁻¹ or 55 mN m⁻¹) with a period of 16 h to allow crystallisation. Analysis involved scanning electron microscopy (SEM), atomic force microscopy (AFM) and powder X-ray diffraction (PXRD).

Results

Condensed isotherms were acquired, which signified surfactant-theophylline interaction. Theophylline monohydrate crystals were obtained and exhibited needle-like morphology. SEM and AFM data highlighted regions of roughened growth along with smooth, stepwise growth on the same crystal face. The surfactant monolayers appeared to influence crystal morphology over time.

Conclusions

The data indicate a favourable interaction between each species. The principal mechanism of interaction is thought to be an ion-dipole association. This approach may be applied to generate material with improved complementarity with pulmonary surfactant thus enhancing the interaction between inhaled drug particles and internal lung surfaces.     

CD30L/CD30 signaling regulates the formation of the tumor immune microenvironment and inhibits intestinal tumor development of colitis-associated colon cancer in mice

Inflammatory bowel disease is one of the major causes of colitis-associated colon cancer (CAC). Therefore, it is necessary to explore new therapies to prevent colon cancer (CRC) in view of the relationship between chronic inflammation and tumor development. Previous studies on the correlation between CD30L/CD30 and cancer were mostly limited to lymphoid or homogenous tumors, while there have been only a few reports on the role of CD30L/CD30 signal transduction in the pathogenesis of CAC. In this study, we established an AOM/DSS-induced CAC model with CD30LKO mice to explore the effect of CD30L/CD30 signal transduction on the formation of the intestinal tumor immune microenvironment (TIME) during the development of intestinal tumors. Our results revealed that CD30L deficiency promoted the accumulation of myeloid derived suppressor cells (MDSCs), increased the expression of PD-L1 on MDSCs and tumor associated macrophages (TAMs), and enhanced the secretion of various inflammatory and immunosuppressive factors in the intestinal mucosa of CAC mice. Furthermore, CD30L gene deletion could selectively promote the upregulation of PD-1 expression on CD4⁺ and CD8⁺ T cells and inhibit their activation, differentiation and secretion of effector cytokines, which led to an attenuation of antitumor immune responses mediated by T_EM (CD44⁺CD62L^-) cells. Thus, our data suggest that CD30L/CD30 signaling might be a potential candidate target for immunological therapy in CAC.     

Bioadhesive film formed from a novel organic-inorganic hybrid gel for transdermal drug delivery system

A novel organic-inorganic hybrid film-forming agent for TDDS was developed by a modified poly(vinyl alcohol) (PVA) gel using γ-(glycidyloxypropyl)trimethoxysilane (GPTMS) as an inorganic-modifying agent, poly(N-vinyl pyrrolidone) (PVP) as a tackifier and glycerol (GLY) as a plasticizer. The prepared gels can be applied to the skin by a coating method and in situ form very thin and transparent films with good performance, comfortable feel and cosmetic attractiveness. The key properties of the bioadhesive films produced from the hybrid gels were investigated and the results showed that the incorporation of appropriate GPTMS (GPTMS/(PVA + GPTMS) in the range of 20-30%) into the PVA matrix not only can significantly enhance mechanical strength and skin adhesion properties of the resultant film, but also can decrease the crystalline regions of PVA and hence facilitate the diffusion of water vapor and drug. Furthermore, the investigations into in vivo skin irritation suggested the films caused non-irritation to skin after topical application for 120 h. In conclusion, the bioadhesive films formed from organic-inorganic hybrid gels possessed very good qualities for application on the skin and may provide a promising formulation for TDDS, especially when the patient acceptability from an aesthetic perspective of the dosage form is a prime consideration.     

Pathophysiological response to hypoxia - from the molecular mechanisms of malady to drug discovery: drug discovery for targeting the tumor microenvironment

The tumor microenvironment, characterized by regions of hypoxia, low nutrition, and acidosis due to incomplete blood vessel networks, has been recognized as a major factor that influences not only the response to conventional anti-cancer therapies but also malignant progression and metastasis. However, exploiting such a cumbersome tumor microenvironment for cancer treatment could provide tumor-specific therapeutic approaches. In particular, hypoxia is now considered a fundamentally important characteristic of the tumor microenvironment in which hypoxia inducible factor (HIF)-1-mediated gene regulation is considered essential for angiogenesis and tumor development. Additional oxygen sensitive signaling pathways including mammalian target of rapamycin (mTOR) signaling and signaling through activation of the unfolded protein response (UPR) also contribute to the adaptation in the tumor microenvironment. This in turn has led to the current extensive interest in the signal molecules related to adaptive responses in the tumor microenvironment as potential molecular targets for cancer therapy against refractory cancer and recurrence in preparation for the aging society. Therefore, we should focus on the drug discovery for targeting the tumor microenvironment to develop tumor-specific cytostatic agents including angiogenesis inhibitors. In this paper, the development of hypoxia-selective prodrugs, HIF-1 inhibitors, and modulators of the tumor microenvironment will be discussed.     

From nanoemulsions to self-nanoemulsions,with recent advances in self-nanoemulsifying drug delivery systems (SNEDDS)

Introduction: Lipid-based drug delivery systems (LBDDS) are the most promising technique to formulate the poorly water soluble drugs. Nanotechnology strongly influences the therapeutic performance of hydrophobic drugs and has become an essential approach in drug delivery research. Self-nanoemulsifying drug delivery systems (SNEDDS) are a vital strategy that combines benefits of LBDDS and nanotechnology. SNEDDS are now preferred to improve the formulation of drugs with poor aqueous solubility.

Areas covered: The review in its first part shortly describes the LBDDS, nanoemulsions and clarifies the ambiguity between nanoemulsions and microemulsions. In the second part, the review discusses SNEDDS and elaborates on the current developments and modifications in this area without discussing their associated preparation techniques and excipient properties.

Expert opinion: SNEDDS have exhibit the potential to increase the bioavailability of poorly water soluble drugs. The stability of SNEDDS is further increased by solidification. Controlled release and supersaturation can be achieved, and are associated with increased patient compliance and improved drug loads, respectively. Presence of biodegradable ingredients and ease of large-scale manufacturing combined with a lot of ‘drug-targeting opportunities’ give SNEDDS a clear distinction and prominence over other solubility enhancement techniques.     

Targeting the TCR signaling checkpoint: a therapeutic strategy to reactivate memory T cells in the tumor microenvironment

Background: One of the major conundrums in cancer immunotherapy is why human tumors are not rejected, and progress despite the presence of inflammatory leukocytes in the tumor microenvironment. While studies addressing the mechanisms responsible for the failure of immunocompetent cells to control tumor progression have shed considerable light upon this issue, not enough is known about the mechanisms contributing to the regulation of tumor-associated T cells in the microenvironment of human tumors. Objective: A persistent and robust response is likely to be required for the complete eradication of tumors. Such a durable immune response will require the development and persistence of functional tumor-reactive memory T cells. Methods: Various studies have investigated the mechanisms of suppression in the tumor microenvironment. However, very few studies have investigated the hyporesponsiveness of tumor-associated T cells at the molecular level. This review focuses on the hyporesponsiveness of tumor-associated T cells and how this relates to the T cell receptor signaling cascade. Results/conclusions: We postulate that this hyporesponsiveness results from a normal regulatory mechanism or TCR signaling checkpoint that is initiated by the persistence of antigen. If the TCR checkpoint is defined, it will be possible to design therapeutic strategies that reverse the TCR arrest. Essentially, this will reactivate the T cells in situ, leading to the killing and lysis of tumors locally, the release of tumor antigens and the generation of a systemic antitumor immunity.     

卡莫氟-聚乳酸纳米纤维缓释体系的制备及体外缓释性能

目的：以聚乳酸纳米纤维为载体,制备卡莫氟-聚乳酸纳米纤维药物缓释体系,研究其体外药物释放性能.方法：用静电纺丝制备卡莫氟-聚乳酸纳米纤维药物缓释体系,用紫外分光光度法研究药物的在37℃模拟体液中的释放性能.结果：溶剂不同,纤维的形貌有很大差别;纳米纤维体外药物释放速度也大不相同,缓释曲线符合Higuchi方程.结论：随着溶液的导电性和介电常数的增加,静电纺丝纤维的直径明显变小,纤维表面也逐渐光滑;纳米纤维的形貌对体外药物释放速度有较大影响.     

Reassembling of albumin-bound paclitaxel mitigates myelosuppression and improves its antitumoral efficacy via neutrophil-mediated targeting drug delivery

Albumin-bound paclitaxel (abPTX) has been widely used in cancer treatment. However, dose-related side effects, such as myelosuppression, restrict its clinical application. Cell-based targeting drug delivery is a promising way to mitigate systematic side-effects and improve antitumoral efficacy. In this study, we demonstrated that reassembled abPTX could be engulfed by neutrophils in vivo and delivered to tumor site, thus improving therapeutic efficacy and mitigating myelosuppression. First, in vitro analysis confirmed that reassembling of abPTX formed uniform and stable serum albumin nanoparticles (NP-abPTX) with size of 107.5 ± 2.29 nm and reserved the ability to kill tumor cells. Second, we found that NP-abPTX could be engulfed by activated neutrophil in vitro and in vivo but do not affect neutrophils’ function, such as chemotaxis and activation. In a murine tumor model, we further proved that local radiotherapy (RT) induced inflammation activated peripheral neutrophils to capture venous infused NP-abPTX and carry them into tumor tissue. As compared to abPTX, infusion of NP-abPTX dramatically enhanced inhibition of tumor growth treated by local RT and mitigated hematotoxicity. Therefore, our study demonstrated a novel strategy to mitigate side-effects and to improve tumor killing efficacy of abPTX through neutrophil-mediated targeting drug delivery.     

自微乳化给药系统增加索拉非尼的口服吸收生物利用度

目的:为了增加难溶性药物索拉非尼(Sorafenib)的口服吸收,本研究制备索拉非尼自微乳化给药系统并测定其口服相对生物利用度。方法:以油酸乙酯(20%,w/w)为油相,聚山梨酯-80(48%,w/w)为主要乳化剂,聚乙二醇400(16%,w/w)和乙醇(16%,w/w)为助乳化剂制备索拉非尼自微乳化给药系统,以大鼠为实验动物测定其口服相对生物利用度。结果:自微乳化给药系统中索拉非尼的终浓度为20 mg.mL-1。该制剂乳化后粒径为20～25 nm,并可在去离子水,生理盐水及5%葡萄糖溶液中稳定存在8 h。与索拉非尼混悬液相比,自微乳化给药系统可以显著增加索拉非尼的血药浓度-时间曲线下面积(AUC0～72 h),峰浓度(Cmax)和平均滞留时间(MRT),降低清除率(CL)。尤其是与口服混悬液相比,其相对生物利用度提高约25倍。结论:索拉非尼自微乳化给药系统可以显著提高索拉非尼的口服吸收相对生物利用度,有望开发成为增加其口服吸收的药物制剂。     

Combining stem cell-derived hepatocytes with impedance sensing to better predict human drug toxicity

Background: The liver plays a central role in human drug metabolism. To model drug metabolism, the major cell type of the liver, the hepatocyte, is commonly used. Hepatocytes can be derived from human and animal sources, including pluripotent stem cells. Cell-based models have shown promise in modeling human drug exposure. The assays used in those studies are normally ‘snap-shot’ in nature, and do not provide the complete picture of human drug exposure.

Research design and methods: In this study, we employ stem cell-derived hepatocytes and impedance sensing to model human drug toxicity. This impedance-based stem cell assay reports hepatotoxicity in real time after treatment with compounds provided by industry.

Results: Using electric cell-substrate impedance Sensing (ECIS), we were able to accurately measure drug toxicity post-drug exposure in real time and more quickly than gold standard biochemical assays.

Conclusions: ECIS is robust and non-destructive methodology capable of monitoring human drug exposure with superior performance to current gold standard ‘snapshot’ assays. We believe that the methodology presented within this article could prove valuable in the quest to better predict off-target effects of drugs in humans.