Recent advances in brain tumor-targeted nano-drug delivery systems

INTRODUCTION: Brain tumors represent one of the most challenging and difficult areas in unmet medical needs. Fortunately, the past decade has seen momentous developments in brain tumor research in terms of brain tumor-targeted novel nano-drug delivery systems with significant important superiority over conventional formulations with respect to decreased toxicity and improved pharmacokinetics/pharmacodynamics. AREA COVERED: This review first introduces the characteristics of the two major obstacles in brain-tumor targeted delivery, blood-brain barrier (BBB) and blood-brain tumor barrier (BBTB), and then reviews recent advances in brain tumor-targeted novel nano-drug delivery systems according to their targeting strategies aimed at different stages of brain tumor development and growth. EXPERT OPINION: Based on continuously changing vascular characteristics of brain tumors at different development and growth stages, we propose the concept of 'whole-process targeting' for brain tumor for nano-drug delivery systems, referring to a series of overall targeted drug delivery strategies aimed at key points during the whole development of brain tumors.     

Recent advances in brain tumor-targeted nano-drug delivery systems

Introduction: Brain tumors represent one of the most challenging and difficult areas in unmet medical needs. Fortunately, the past decade has seen momentous developments in brain tumor research in terms of brain tumor-targeted novel nano-drug delivery systems with significant important superiority over conventional formulations with respect to decreased toxicity and improved pharmacokinetics/pharmacodynamics.

Area covered: This review first introduces the characteristics of the two major obstacles in brain-tumor targeted delivery, blood–brain barrier (BBB) and blood–brain tumor barrier (BBTB), and then reviews recent advances in brain tumor-targeted novel nano-drug delivery systems according to their targeting strategies aimed at different stages of brain tumor development and growth.

Expert opinion: Based on continuously changing vascular characteristics of brain tumors at different development and growth stages, we propose the concept of ‘whole-process targeting’ for brain tumor for nano-drug delivery systems, referring to a series of overall targeted drug delivery strategies aimed at key points during the whole development of brain tumors.     

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.     

Drug development in oncology assisted by noninvasive optical imaging

Early and accurate detection of tumors, like the development of targeted treatments, is a major field of research in oncology. The generation of specific vectors, capable of transporting a drug or a contrast agent to the primary tumor site as well as to the remote (micro-) metastasis would be an asset for early diagnosis and cancer therapy. Our goal was to develop new treatments based on the use of tumor-targeted delivery of large biomolecules (DNA, siRNA, peptides, or nanoparticles), able to induce apoptosis while dodging the specific mechanisms developed by tumor cells to resist this programmed cell death. Nonetheless, the insufficient effectiveness of the vectorization systems is still a crucial issue. In this context, we generated new targeting vectors for drug and biomolecules delivery and developed several optical imaging systems for the follow-up and evaluation of these vectorization systems in live mice. Based on our recent work, we present a brief overview of how noninvasive optical imaging in small animals can accelerate the development of targeted therapeutics in oncology.     

信号素 3F及其受体神经纤毛蛋白在肿瘤微环境中的研究进展

肿瘤微环境可以经不同信号通路分泌多种血管生成因子、炎性细胞因子和趋化因子,利用多种间质细胞组成的庞杂系统加快肿瘤的进展.其中信号素(semaphorins,SEMA)是肿瘤微环境的重要调节因子,信号素-神经纤毛蛋白(SEMA-NRP)复合物参与肿瘤抑制途径,本研究期望通过对肿瘤微环境中信号素3F(semaphorins 3F,SEMA3F)及其受体神经纤毛蛋白(neuro?pilin,NRP)作用的综述,为将来对肿瘤进行早期靶向治疗提供依据.     

Thermally targeted delivery of chemotherapeutics and anti-cancer peptides by elastin-like polypeptide

Current chemotherapy treatment of solid tumors is limited due to a lack of specific delivery of the drugs to the tumor, leading to systemic toxicity. Therefore, it is necessary to develop targeted cancer therapies and tumor-targeted drug carriers. The authors review the development of elastin-like polypeptide (ELP) as a potential carrier for thermally targeted delivery of therapeutics. The authors searched Medline for articles concerning the application of ELP as a drug delivery vector for small molecule drugs and therapeutic peptides. ELP has been demonstrated to be a promising thermally targeted carrier. Further examination of the in vivo biodistribution and efficacy will provide the necessary data to advance ELP technology toward the ultimate goal of human therapeutics.     

Emerging nanomedicine-based therapeutics for hematogenous metastatic cascade inhibition: Interfering with the crosstalk between “seed and soil”

Despite considerable progresses in cancer treatment, tumor metastasis is still a thorny issue, which leads to majority of cancer-related deaths. In hematogenous metastasis, the concept of “seed and soil” suggests that the crosstalk between cancer cells (seeds) and premetastatic niche (soil) facilitates tumor metastasis. Considerable efforts have been dedicated to inhibit the tumor metastatic cascade, which is a highly complicated process involving various pathways and biological events. Nonetheless, satisfactory therapeutic outcomes are rarely observed, since it is a great challenge to thwart this multi-phase process. Recent advances in nanotechnology-based drug delivery systems have shown great potential in the field of anti-metastasis, especially compared with conventional treatment methods, which are limited by serious side effects and poor efficacy. In this review, we summarized various factors involved in each phase of the metastatic cascade ranging from the metastasis initiation to colonization. Then we reviewed current approaches of targeting these factors to stifle the metastatic cascade, including modulating primary tumor microenvironment, targeting circulating tumor cells, regulating premetastatic niche and eliminating established metastasis. Additionally, we highlighted the multi-phase targeted drug delivery systems, which hold a better chance to inhibit metastasis. Besides, we demonstrated the limitation and future perspectives of nanomedicine-based anti-metastasis strategies.KEY WORDS: Tumor metastasis, Drug delivery systems, Nanomedicine, Metastatic cascade, Seed and soil, Tumor microenvironment, Circulating tumor cells, Premetastatic niche     

Role of tumor vascular architecture in drug delivery

Tumor targeted drug delivery has the potential to improve cancer care by reducing non-target toxicities and increasing the efficacy of a drug. Tumor targeted delivery of a drug from the systemic circulation, however, requires a thorough understanding of tumor pathophysiology. A growing or receding (under the impact of therapy) tumor represents a dynamic environment with changes in its angiogenic status, cell mass, and extracellular matrix composition. An appreciation of the salient characteristics of tumor vascular architecture and the unique biochemical markers that may be used for targeting drug therapy is important to overcome barriers to tumor drug therapy and to facilitate targeted drug delivery. This review discusses the unique aspects of tumor vascular architecture that need to be overcome or exploited for tumor targeted drug delivery.     

MDSCs参与肿瘤微环境免疫抑制的研究进展

肿瘤的发生、发展以及转移与其所处的肿瘤微环境密切相关,肿瘤细胞可以通过自分泌和旁分泌等方式对所处环境进行改造以维持自身的生存和发展。肿瘤免疫抑制是肿瘤微环境的重要特征,越来越多的研究表明骨髓来源的抑制性细胞（myeloid-derived suppressor cells,MDSCs）在肿瘤微环境免疫抑制中扮演了重要的角色,本文就MDSCs参与肿瘤微环境免疫抑制的研究进展进行综述,以期为进一步理解与干预肿瘤免疫抑制奠定基础。     

Barriers to Effective Drug Treatment for Brain Metastases: A Multifactorial Problem in the Delivery of Precision Medicine

The treatment of metastatic lesions in the brain represents a serious unmet medical need in the field of neuro-oncology. Even though many effective compounds have demonstrated success in treating peripheral (non-CNS) tumors with targeted agents, one aspect of this lack of success in the brain may be related to poor delivery of otherwise effective compounds. Many factors can influence the brain delivery of these agents, but one key barrier is a heterogeneously “leaky” BBB that expresses efflux transporters that limit the BBB permeability for many targeted agents. Future success in therapeutics for brain metastases must take into account the adequate delivery of “active, free drug” to the target, and may include combinations of targeted drugs that are appropriate to address each individual patient’s tumor type. This review discusses some issues that are pertinent to precision medicine for brain metastases, using specific examples of tumor types that have a high incidence of brain metastases.     

Influencing factors and strategies of enhancing nanoparticles into tumors in vivo

The administration of nanoparticles (NPs) first faces the challenges of evading renal filtration and clearance of reticuloendothelial system (RES). After that, NPs infiltrate through the expanded endothelial space and penetrated the dense stroma of tumor microenvironment to tumor cells. As long as possible to prolong the time of NPs remaining in tumor tissue, NPs release active agent and induce pharmacological action. This review provides a comprehensive summary of the physical and chemical properties of NPs and the influence of various biological factors in tumor microenvironment, and discusses how to improve the final efficacy through adjusting the characteristics and structure of NPs. Perspectives and future directions are also provided.KEY WORDS: Nanoparticles, Drug delivery, Reticuloendothelial system, Tumor microenvironment, Tumor stroma, Cancer-associated fibroblasts, Extracellular matrix, Tumor vascular endothelial cells     

药物载体用于递送肿瘤坏死因子相关凋亡诱导配体的研究进展

肿瘤坏死因子相关凋亡诱导配体（Tumor necrosis factor-related apoptosis-inducing ligand,TRAIL）是肿瘤坏死因子家族的成员之一,可与肿瘤细胞膜表面过度表达的死亡受体4或5结合,特异性诱导肿瘤细胞凋亡,且对正常细胞无明显影响,因此被认为是临床最有发展前景的蛋白药物之一。然而,由于肿瘤坏死因子相关凋亡诱导配体存在体内稳定性差和生物利用度低等缺点,限制了其在临床中的应用。运用药物载体对肿瘤坏死因子相关凋亡诱导配体进行递送,成为目前解决此弊端的有效策略。本综述简要介绍了近年来药物载体在肿瘤坏死因子相关凋亡诱导配体递送方面的研究进展。     

Remodeling “cold” tumor immune microenvironment via epigenetic-based therapy using targeted liposomes with in situ formed albumin corona

There is a close connection between epigenetic regulation, cancer metabolism, and immunology. The combination of epigenetic therapy and immunotherapy provides a promising avenue for cancer management. As an epigenetic regulator of histone acetylation, panobinostat can induce histone acetylation and inhibit tumor cell proliferation, as well as regulate aerobic glycolysis and reprogram intratumoral immune cells. JQ1 is a BRD4 inhibitor that can suppress PD-L1 expression. Herein, we proposed a chemo-free, epigenetic-based combination therapy of panobinostat/JQ1 for metastatic colorectal cancer. A novel targeted binary-drug liposome was developed based on lactoferrin-mediated binding with the LRP-1 receptor. It was found that the tumor-targeted delivery was further enhanced by in situ formation of albumin corona. The lactoferrin modification and endogenous albumin adsorption contribute a dual-targeting effect on the receptors of both LRP-1 and SPARC that were overexpressed in tumor cells and immune cells (e.g., tumor-associated macrophages). The targeted liposomal therapy was effective to suppress the crosstalk between tumor metabolism and immune evasion via glycolysis inhibition and immune normalization. Consequently, lactic acid production was reduced and angiogenesis inhibited; TAM switched to an anti-tumor phenotype, and the anti-tumor function of the effector CD8⁺ T cells was reinforced. The strategy provides a potential method for remodeling the tumor immune microenvironment (TIME).KEY WORDS: Tumor immune microenvironment, Tumor-associated macrophage, Epigenetic therapy, Immune checkpoint, Angiogenesis, Panobinostat, JQ1, Liposome     

Advances in Targeted Drug Delivery Approaches for the Central Nervous System Tumors: The Inspiration of Nanobiotechnology

At present, brain tumor is among the most challenging diseases to treat and the therapy is limited by the lack of effective methods to deliver anticancer agents across the blood-brain barrier (BBB). BBB is a selective barrier that separates the circulating blood from the brain extracellular fluid. In its neuroprotective function, BBB prevents the entry of toxins, as well as most of anticancer agents and is the main impediment for brain targeted drug delivery approaches. Nanotechnology-based delivery systems provide an attractive strategy to cross the BBB and reach the central nervous system (CNS). The incorporation of anticancer agents in various nanovehicles facilitates their delivery across the BBB. Moreover, a more powerful tool in brain tumor therapy has relied surface modifications of nanovehicles with specific ligands that can promote their passage through the BBB and favor the accumulation of the drug in CNS tumors. This review describes the physiological and anatomical features of the brain tumor and the BBB, and summarizes the recent advanced approaches to deliver anticancer drugs into brain tumor using nanobiotechnology-based drug carrier systems. The role of specific ligands in the design of functionalized nanovehicles for targeted delivery to brain tumor is reviewed. The current trends and future approaches in the CNS delivery of therapeutic molecules to tumors are also discussed.     

肿瘤微环境对乳腺癌发生发展的影响

摘要： 肿瘤微环境 （TME） 在局部耐药性、 免疫逃脱和远端转移等多个肿瘤发生、 发展的步骤中起关键作用。依据 不同个体的 TME, 准确评估和选择临床用药, 可有效控制原位癌和转移癌的恶性转化。目前, 治疗癌症的主要方法 是化疗, 由于 TME 中良性细胞可调节癌细胞对标准化疗和靶向药物治疗的反应, 因此, 结合靶向 TME 治疗会取得更 理想的临床疗效。本文就乳腺癌 TME 中细胞外基质 （ECM）、 肿瘤相关成纤维细胞、 肿瘤相关巨噬细胞、 调节性 T 细 胞和骨髓间质干细胞对肿瘤发生、 发展的作用机制进行综述。     

Emerging nanomedicine-based therapeutics for hematogenous metastatic cascade inhibition: Interfering with the crosstalk between “seed and soil”

Despite considerable progresses in cancer treatment, tumor metastasis is still a thorny issue, which leads to majority of cancer-related deaths. In hematogenous metastasis, the concept of “seed and soil” suggests that the crosstalk between cancer cells (seeds) and premetastatic niche (soil) facilitates tumor metastasis. Considerable efforts have been dedicated to inhibit the tumor metastatic cascade, which is a highly complicated process involving various pathways and biological events. Nonetheless, satisfactory therapeutic outcomes are rarely observed, since it is a great challenge to thwart this multi-phase process. Recent advances in nanotechnology-based drug delivery systems have shown great potential in the field of anti-metastasis, especially compared with conventional treatment methods, which are limited by serious side effects and poor efficacy. In this review, we summarized various factors involved in each phase of the metastatic cascade ranging from the metastasis initiation to colonization. Then we reviewed current approaches of targeting these factors to stifle the metastatic cascade, including modulating primary tumor microenvironment, targeting circulating tumor cells, regulating premetastatic niche and eliminating established metastasis. Additionally, we highlighted the multi-phase targeted drug delivery systems, which hold a better chance to inhibit metastasis. Besides, we demonstrated the limitation and future perspectives of nanomedicine-based anti-metastasis strategies.     

分子靶向抗肿瘤药物的研究进展

恶性肿瘤是严重威胁人类生命的疾病之一,而传统的治疗方法和治疗药物已远远不能满足临床需要。随着分子生物学的发展,分子靶向药物载体系统和靶向抗肿瘤药物的研究取得了突破性进展,为恶性肿瘤患者带来了新的希望。许多靶向药物已在临床试验中显示出极大的优势并被批准用于恶性肿瘤的临床治疗,获得了较好的效果。还有一些恶性肿瘤的潜在治疗药物正处于研究之中。本文主要针对分子靶向药物的载体系统和其在肿瘤治疗方面的应用进行综述。     

Combinatorial therapeutic strategies for enhanced delivery of therapeutics to brain cancer cells through nanocarriers: current trends and future perspectives

Brain cancer is the most aggressive one among various cancers. It has a drastic impact on people''s lives because of the failure in treatment efficacy of the currently employed strategies. Various strategies used to relieve pain in brain cancer patients and to prolong survival time include radiotherapy, chemotherapy, and surgery. Nevertheless, several inevitable limitations are accompanied by such treatments due to unsatisfactory curative effects. Generally, the treatment of cancers is very challenging due to many reasons including drugs’ intrinsic factors and physiological barriers. Blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB) are the two additional hurdles in the way of therapeutic agents to brain tumors delivery. Combinatorial and targeted therapies specifically in cancer show a very promising role where nanocarriers’ based formulations are designed primarily to achieve tumor-specific drug release. A dual-targeting strategy is a versatile way of chemotherapeutics delivery to brain tumors that gets the aid of combined ligands and mediators that cross the BBB and reaches the target site efficiently. In contrast to single targeting where one receptor or mediator is targeted, the dual-targeting strategy is expected to produce a multiple-fold increase in therapeutic efficacy for cancer therapy, especially in brain tumors. In a nutshell, a dual-targeting strategy for brain tumors enhances the delivery efficiency of chemotherapeutic agents via penetration across the blood-brain barrier and enhances the targeting of tumor cells. This review article highlights the ongoing status of the brain tumor therapy enhanced by nanoparticle based delivery with the aid of dual-targeting strategies. The future perspectives in this regard have also been highlighted.     

In vitro models of tumor vessels and matrix: Engineering approaches to investigate transport limitations and drug delivery in cancer

Tumor–stroma interactions have emerged as critical determinants of drug efficacy. However, the underlying biological and physicochemical mechanisms by which the microenvironment regulates therapeutic response remain unclear, due in part to a lack of physiologically relevant in vitro platforms to accurately interrogate tissue-level phenomena. Tissue-engineered tumor models are beginning to address this shortcoming. By allowing selective incorporation of microenvironmental complexity, these platforms afford unique access to tumor-associated signaling and transport dynamics. This review will focus on engineering approaches to study drug delivery as a function of tumor-associated changes of the vasculature and extracellular matrix (ECM). First, we review current biological understanding of these components and discuss their impact on transport processes. Then, we evaluate existing microfluidic, tissue engineering, and materials science strategies to recapitulate vascular and ECM characteristics of tumors, and finish by outlining challenges and future directions of the field that may ultimately improve anti-cancer therapies.