Blood-brain Tumor Barrier Research Articles

Tailoring functional nanostructured lipid carriers for glioblastoma treatment with enhanced permeability through in-vitro 3D BBB/BBTB models

The blood-brain barrier (BBB) and blood-brain tumour barrier (BBTB) pose a significant challenge to drug delivery to brain tumours, including aggressive glioblastoma (GB). The present study rationally designed functional nanostructured lipid carriers (NLC) to tailor their BBB penetrating properties with high encapsulation of CNS negative chemotherapeutic drug docetaxel (DTX). We investigated the effect of four liquid lipids, propylene glycol monolaurate (Lauroglycol® 90), Capryol® propylene glycol monocaprylate, caprylocaproylmacrogol-8-glycerides (Labrasol®) and polyoxyl-15-hydroxystearate (Kolliphor® HS15) individually and in combination to develop NLCs with effective permeation across in-vitro 3D BBB model without alteration in the integrity of the barrier. With desirable spherical shape as revealed by TEM and an average particle size of 123.3 ± 0.642 nm and zeta potential of −32 mV, DTX-NLCs demonstrated excellent stability for six months in its freeze-dried form. The confocal microscopy along with flow cytometry data revealed higher internalisation of DTX-NLCs in U87MG over SVG P12 cells. Micropinocytosis was observed to be one of the dominant pathways for internalisation in U87MG cells while clathrin-mediated pathway was more predominat in patient-derived glioblastoma cells. The NLCs readily penetrated the actively proliferating peripheral cells on the surface of the 3D tumour spheroids as compared to the necrotic core. The DTX-NLCs induced cell arrest through G2/M phase with a significant decrease in the mitochondrial reserve capacity of cells. The NLCs circumvented BBTB with high permeability followed by accumulation in glioblastoma cells with patient-derived cells displaying ~2.4-fold higher uptake in comparison to U87MG when studied in a 3D in-vitro model of BBTB/GB. We envisage this simple and industrially feasible technology as a potential candidate to be developed as GB nanomedicine.

UPAR targeted phototheranostic metal-organic framework nanoprobes for MR/NIR-II imaging-guided therapy and surgical resection of glioblastoma

Glioblastoma (GBM) is the most malignant brain tumor. Owing to its highly infiltrative nature and restrictive blood-brain tumor barrier (BBTB), the current treatment strategies, including surgery and the following chemoradiotherapy, offer very low efficacy. Therefore, it is highly desirable to develop novel multifunctional theranostic agents for visualized diagnosis and treatment of GBM. In this work, a phototheranostic nanoprobe (CH4T@MOF-PEG-AE), constructed of Fe-based metal-organic framework (MOF) nanoparticles loaded with a small-molecule near-infrared II (NIR-II) fluorophore (CH4T), is rationally designed and modified with tumor-targeting AE105 peptide for efficiently targeting the over-expressed urokinase Plasminogen Activator Receptor (uPAR) on GBM. The nanoplatform combines advantages of high penetration depth of magnetic resonance (MR) imaging with high detection sensitivity and spatiotemporal resolution of NIR-II fluorescence imaging, enabling it to diagnose and delineate GBM accurately. Besides, in vivo studies reveal that CH4T@MOF-PEG-AE can realize MR/NIR-II imaging-guided photothermal therapy (PTT), achieving successful ablation of U87MG tumors. More importantly, the nanoprobes can efficiently transport across the BBTB facilitated by active tumor-targeting and enrich in the orthotopic GBM tumors, being capable of guiding the surgical resection of GBM via real-time intraoperative NIR-II imaging. Our work provides new insights into developing theranostic nanoplatforms for efficient diagnosis and treatment of GBM.

Blood-Brain Barrier Modulation to Improve Glioma Drug Delivery.

The blood–brain barrier (BBB) is formed by brain microvascular endothelial cells that are sealed by tight junctions, making it a significant obstacle for most brain therapeutics. The poor BBB penetration of newly developed therapeutics has therefore played a major role in limiting their clinical success. A particularly challenging therapeutic target is glioma, which is the most frequently occurring malignant brain tumor. Thus, to enhance therapeutic uptake in tumors, researchers have been developing strategies to modulate BBB permeability. However, most conventional BBB opening strategies are difficult to apply in the clinical setting due to their broad, non-specific modulation of the BBB, which can result in damage to normal brain tissue. In this review, we have summarized strategies that could potentially be used to selectively and efficiently modulate the tumor BBB for more effective glioma treatment.

DDRE-32. ABC TRANSPORTERS RESTRICT THE BRAIN PENETRATION AND INTRACRANIAL EFFICACY OF ANTICANCER AGENTS EVEN WHEN BLOOD-BRAIN BARRIER INTEGRITY IS LOST

Abstract The impact of the blood-brain barrier (BBB) in brain tumors on the efficacy of anticancer drug therapy is controversial. In primary as well as metastatic brain tumors, the BBB is often disrupted. Yet, many intracranial cancers respond poorly to systemic therapies. We characterized the integrity of the BBB in a series of experimental intracranial tumor models using magnetic resonance imaging (MRI), fluorescent dyes and autoradiography. We also assessed the distribution and efficacy of docetaxel in healthy brain tissue and brain tumors that were grafted into P-glycoprotein (P-gp) proficient wild-type (WT) and deficient Abcb1a/b-/- recipient nude mice. Leakiness of the tumor vasculature varied from extensive to almost absent. Tumor blood vessels expressed P-gp and breast cancer resistance protein (BCRP). The leakiness of the vasculature resulted in higher docetaxel levels in tumors compared to normal brain. However, P-gp expression in tumor vessels reduced the drug distribution in tumors, which also translated into a reduced efficacy. Taken together, these studies demonstrate that leakiness of the BBB does not necessarily imply good accessibility to brain tumors of drugs that are substrates of P-gp and/or BCRP. Although therapeutic responses may be observed, the full potential of such therapeutics can still be attenuated by drug efflux pumps in the tumor vasculature. Therefore, only BBB-penetrable drugs with low to no affinity for efflux transporters should be considered for treatment of intracranial tumors.

DDRE-01. ACQUIRED AND INTRINSIC RESISTANCE TO VEMURAFENIB IN BRAFV600E-DRIVEN MELANOMA BRAIN METASTASES

Abstract BRAF V600-mutated melanoma brain metastases (MBMs) are responsive to BRAF inhibitors, but clinical responses are less durable than those of extracranial metastases. We studied the impact of the drug efflux proteins P-glycoprotein (P-gp; ABCB1) and breast cancer resistance protein (BCRP; ABCG2) at the blood-brain barrier (BBB) on the efficacy of vemurafenib against BRAFV600E-mutated A375 MBMs. We intracranially implanted A375 tumor cells in wild-type and Abcb1a/b;Abcg2-/- mice. We characterized the tumor BBB, analyzed drug levels in plasma and brain lesions after oral vemurafenib and determined the efficacy against brain metastases and subcutaneous lesions. MRI shows that A375 MBMs disrupt BBB integrity, but vemurafenib accumulation in MBMs was still reduced by P-gp/BCRP. Vemurafenib is also less efficacious against MBMs in wild-type mice compared to Abcb1a/b;Abcg2-/- mice. Vemurafenib efficacy against subcutaneous A375 tumors was similar in both strains. Even in Abcb1a/b;Abcg2-/- mice, A375 MBMs rapidly developed resistance, which was unrelated to pharmacokinetic issues or insufficient inhibition of MAPK/PI3K pathways. Taken together, these studies demonstrate that although the BBB is disrupted in MBMs, P-gp/BCRP still limit the efficacy of vemurafenib. Moreover, the response to vemurafenib is less and of shorter duration also due to rapidly acquired resistance, most likely by resorting to non-canonical growth signaling.

Magnetic Resonance Imaging-Guided Focused Ultrasound-Based Delivery of Radiolabeled Copper Nanoclusters to Diffuse Intrinsic Pontine Glioma.

Diffuse intrinsic pontine glioma (DIPG) is an invasive pediatric brainstem malignancy exclusively in children without effective treatment due to the often-intact blood-brain tumor barrier (BBTB), an impediment to the delivery of therapeutics. Herein, we used focused ultrasound (FUS) to transiently open BBTB and delivered radiolabeled nanoclusters (64Cu-CuNCs) to tumors for positron emission tomography (PET) imaging and quantification in a mouse DIPG model. First, we optimized FUS acoustic pressure to open the blood-brain barrier (BBB) for effective delivery of 64Cu-CuNCs to pons in wildtype mice. Then the optimized FUS pressure was used to deliver radiolabeled agents in DIPG mouse. Magnetic resonance imaging (MRI)-guided FUS-induced BBTB opening was demonstrated using a low molecular weight, short-lived 68Ga-DOTA-ECL1i radiotracer and PET/CT before and after treatment. We then compared the delivery efficiency of 64Cu-CuNCs to DIPG tumor with and without FUS treatment and demonstrated the FUS-enhanced delivery and time-dependent diffusion of 64Cu-CuNCs within the tumor.

Dual-Target Peptide-Modified Erythrocyte Membrane-Enveloped PLGA Nanoparticles for the Treatment of Glioma.

Penetration of the blood–brain barrier (BBB) and the blood–brain tumor barrier (BBTB) remains a significant challenge for the delivery of drugs in the treatment of glioma. Therefore, the development of targeted preparations with the ability to penetrate the BBB and BBTB, and target gliomas, is an important approach if we are to improve the efficacy of glioma treatment. In the current study, an active targeting preparation based on PLGA nanoparticles coated with erythrocyte membranes (RBCNPs) and dual-modified with DWSW and NGR peptide ligands (DWSW/NGR-RBCNPs). Euphorbia factor L1 (EFL1) extracted from euphorbiae semen was used as the model drug. The final nanoparticles were characterized by in vivo and in vitro tests. In vitro results showed that EFL1-loaded DWSW/NGR-RBCNPs were taken up by cells and had the ability to penetrate the BBB and BBTB and produce cytotoxic effects. Furthermore, in vivo studies in mice showed that when injected intravenously, these specialized NPs could enter the brain, target tumor tissue, and significantly extend life span. The results showed that dual-targeting EFL1-loaded DWSW/NGR-RBCNPs have significant potential as a nanotherapeutic tool for the treatment of brain glioma.

PSMA-targeted nanoparticles for specific penetration of blood-brain tumor barrier and combined therapy of brain metastases

Breast cancer brain metastases (BCBM) represent a major cause of morbidity and mortality among patients with breast cancer. Systemic drug therapy, which is usually effective against peripheral breast cancers, is often ineffective on BCBM due to its poor penetration through the blood-brain tumor barrier (BTB). In this study, prostate-specific membrane antigen (PSMA) with internalization function was found to be specifically up-regulated on BCBM-associated BTB while barely detectable in normal blood-brain barrier (BBB). Here, a nanotechnology approach is reported that can overcome the BTB through ACUPA (A) and cyclic TT1 (cT) co-functionalized nanoparticles (A-NPs-cT). A-NPs-cT selectively target PSMA on BTB for specific BTB crossing and specially bind with p32 for BCBM targeting. We disclosed the effectual synergism of doxorubicin (DOX) and lapatinib (LAP) for BCBM combined therapy. A-NPs-cT exhibited boosted uptake than integrin-targeting RGD-modified NPs in BTB endothelial cells and displayed about 4.57-fold stronger penetration through the BCBM-associated BTB as compared to the normal BBB. In vivo studies showed specific BTB crossing, and remission of BCBM and prolonged survival with DOX and LAP combinatorial regimen. A-NPs-cT based DOX and LAP innovative combined therapy envisioned improved therapeutic intervention for clinical management of BCBM, for which surgery is generally inapplicable and insufficient.

Abstract 2883: A transformable delivery system for the effective treatment of pediatric central nervous system tumors

Abstract Malignancies of the central nervous system (CNS) are the most common type of solid tumor affecting children and a leading cause of cancer-related death in children. With the deterioration of brain tumors, blood-brain barrier (BBB)/blood-brain tumor barrier (BBTB) with poor permeability, and relatively weak enhanced permeability and retention effect become major obstacles in delivering therapeutics to brain tumors. Vincristine (VCR) is a mainstay of treatment of a variety of cancers including brain tumors due to its well-defined mechanism of action and demonstrated anticancer activity. However, the clinical application of VCR in brain tumors was limited by its neurotoxicity and inability to penetrate BBB/BBTB resulting in unsatisfactory anti-cancer efficacy. In this project, we developed a transformable nanoparticle, named Ninja-nanoparticle, which is capable overcoming several important barriers for drug delivery to CNS tumors resulting in better efficacy and toxicity profile. Ninja-NP was stable during circulation due to crosslinking and could transpass BBB/BBTB through glucose receptor-mediated transcytosis. Ninja-NP could further transform into smaller nanoparticle upon encountering acidic microenvironment and revealed hidden moiety to target tumor surface overexpressed sialic acid. Ninja-NP employed a unique strategy which could sequentially target BBB/BBTB and brain tumor cells. Our study confirmed that VCR loaded Ninja-NP significantly accumulated at the orthotopic brain tumor sites, and exhibited superior anti-cancer efficacy in orthotopic diffuse intrinsic pontine glioma (DIPG), the most deadly pediatric CNS tumor, then free VCR or Liposomal VCR with limited systemic toxicity. Ninja-NP addresses multiple challenges for CNS tumor treatment and exhibits great potential to be translated into an effective theranostic nano-platform which could be seamlessly integrated into standard human brain tumor management (imaging-guided drug delivery) with reduced long term toxicity. Citation Format: Tzu-yin Lin. A transformable delivery system for the effective treatment of pediatric central nervous system tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2883.

A pentapeptide enabled AL3810 liposome-based glioma-targeted therapy with immune opsonic effect attenuated

AL3810, a molecular dual inhibitor of the vascular endothelial growth factor receptor (VEGFR) and fibroblast growth factor receptor (FGFR), has earned the permission of phase II clinical trial for tumor treatment by China FDA. As a reversible ATP-competitive inhibitor, AL3810 targets ATP-binding site on intracellular region of VEGFR and FGFR, whereas, AL3810 lacking interplay with extracellular region of receptors rendered deficient blood–brain tumor barrier (BBTB) recognition, poor brain penetration and unsatisfactory anti-glioma efficacy. Integrin αvβ3 overexpressed on capillary endothelial cells of BBTB as well as glioma cells illuminated ligand-modified liposomes for pinpoint spatial delivery into glioma. The widely accepted peptide c(RGDyK)-modified liposome loading AL3810 of multiple dosing caused hypothermia, activated anti-c(RGDyK)-liposome IgG and IgM antibody and pertinent complements C3b and C5b-9, and experienced complement-dependent opsonization. We newly proposed a pentapeptide mn with superb αvβ3-binding affinity and tailored AL3810-loaded mn-modified liposome that afforded impervious blood circulation, targeting ability, and glioma therapeutic expertise as vastly alleviated immune opsonization on the underpinning of the finite antibodies and complements assembly. Stemming from attenuated immunogenicity, peptide mn strengthened liposome functions as a promising nanocarrier platform for molecular targeting agents.

Abstract 1962: Preclinical characterization of tucatinib in HER2-amplified xenograft and CNS implanted tumors

Abstract Tucatinib is an investigational, oral, small molecule tyrosine kinase inhibitor that is highly selective for the kinase domain of HER2, without significant inhibition of EGFR. Recently, HER2CLIMB (NCT02614794), a pivotal, randomized, international, double-blind trial that evaluated tucatinib or placebo in combination with trastuzumab and capecitabine in patients with HER2+ metastatic breast cancer (MBC) with or without brain metastases, after progression with trastuzumab, pertuzumab, and ado-trastuzumab emtansine (T-DM1), showed superior progression-free and overall survival in patients treated on the tucatinib arm. Adverse events in the tucatinib arm were primarily low grade and occurred at rates similar to what was observed in the placebo arm. In this report, we characterize the in vitro and in vivo activity of tucatinib alone and in combination with T-DM1 in HER2-amplified preclinical models. In vitro assays demonstrate that tucatinib potently suppresses HER2-meditated signaling pathways, including phosphorylation of HER2, HER3, AKT and ERK. Ex vivo analysis of tucatinib-treated xenografts shows similar suppression of signal transduction pathways. Tucatinib inhibits the proliferation of HER2+ breast cancer (BC) cell lines in vitro with single digit nanomolar potencies, but was inactive in blocking cell proliferation of BC cell lines lacking amplified HER2. In HER2-amplified BC cell line derived- and patient-derived xenograft models, tucatinib suppresses growth of tumors as a single agent and shows improved activity when combined with T-DM1. To evaluate activity and drug penetration in HER2+ metastatic CNS tumors, we developed and characterized a red-shifted luciferase-expressing BT-474 BC cell line which was stereotaxically implanted into the brain. In vivo bioluminescence imaging was used to evaluate the efficacy of tucatinib and T-DM1 in CNS tumors as single agents and in combination. Histological assessment of treated tumors suggests that tucatinib can penetrate the blood-brain tumor barrier to suppress HER2 signaling. These data are further supported by a drug penetration study of CNS-implanted BT-474 tumors. Quantitative autoradiography analysis demonstrates that 14C-labeled tucatinib penetrates the CNS tumor mass with drug concentration levels exceeding measurements in normal brain regions. These data demonstrate that tucatinib is a uniquely selective and highly potent inhibitor of HER2 signaling, with activity against HER2+ breast cancer xenograft and brain metastasis models. Tucatinib is effective against implanted CNS tumors, suggesting that therapeutically relevant drug concentrations are achievable. These preclinical findings are consistent with clinical data showing tucatinib activity in patients with HER2+ MBC with brain metastases and support the continued development of tucatinib in patients with HER2+ BC. Citation Format: Devra J. Olson, Anita Kulukian, Janelle D. Taylor, Margo C. Zaval, Albina Nesterova, Kelly M. Hensley, Michelle L. Ulrich, Nicole S. Stevens, Scott R. Peterson. Preclinical characterization of tucatinib in HER2-amplified xenograft and CNS implanted tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1962.

Lnc00462717 regulates the permeability of the blood-brain tumor barrier through interaction with PTBP1 to inhibit the miR-186-5p/Occludin signaling pathway.

Blood-brain tumor barrier (BTB) severely restricts the efficient delivery of chemotherapeutic drugs into brain tumor tissue, which is a critical obstacle for glioma treatment. Recently, long noncoding RNAs (lncRNAs) have shown as regulation factors of numerous biological processes. In this study, we identified that Lnc00462717 was upregulated in glioma endothelial cells (GECs), and that knockdown of Lnc00462717 significantly increased the BTB permeability. Both bioinformatics and RNA immunoprecipitation (RIP) results revealed that Lnc00462717 interacts with polypyrimidine tract binding protein (PTBP1). Moreover, overexpression of PTBP1 significantly reversed the increase in BTB permeability caused by siLnc00462717. Furthermore, the binding sites between miR-186 and PTBP1 as well as between miR-186 and 3'UTR of Occludin mRNA were confirmed by RIP and luciferase assays, respectively. And the interaction of Lnc00462717 and PTBP1 significantly facilitated the binding of PTBP1 to 3'UTR of Occludin mRNA and then blocked the miR-186-5p-induced downregulation of Occludin. In addition, we identified that knockdown of Lnc00462717 or overexpression of miR-186-5p increased the accumulation of doxorubicin (Dox) in brain glioma via the ultrafast liquid chromatography-mass spectrometry system (UFLC-MS/MS system) and decreased the intracranial glioma volume in BALB/c nude mice. Taken together, these results show a novel molecular pathway in BTB that may provide a potential innovative strategy for glioma therapy.

Recent Strategies for Targeted Brain Drug Delivery.

Because the brain is the most important human organ, many brain disorders can cause severe symptoms. For example, glioma, one type of brain tumor, is progressive and lethal, while neurodegenerative diseases cause severe disability. Nevertheless, medical treatment for brain diseases remains unsatisfactory, and therefore innovative therapies are desired. However, the development of therapies to treat some cerebral diseases is difficult because the blood-brain barrier (BBB) or blood-brain tumor barrier prevents drugs from entering the brain. Hence, drug delivery system (DDS) strategies are required to deliver therapeutic agents to the brain. Recently, brain-targeted DDS have been developed, which increases the quality of therapy for cerebral disorders. This review gives an overview of recent brain-targeting DDS strategies. First, it describes strategies to cross the BBB. This includes BBB-crossing ligand modification or temporal BBB permeabilization. Strategies to avoid the BBB using local administration are also summarized. Intrabrain drug distribution is a crucial factor that directly determines the therapeutic effect, and thus it is important to evaluate drug distribution using optimal methods. We introduce some methods for evaluating drug distribution in the brain. Finally, applications of brain-targeted DDS for the treatment of brain tumors, Alzheimer's disease, Parkinson's disease, and stroke are explained.

Blood-Brain Barrier, Blood-Brain Tumor Barrier, and Fluorescence-Guided Neurosurgical Oncology: Delivering Optical Labels to Brain Tumors.

Recent advances in maximum safe glioma resection have included the introduction of a host of visualization techniques to complement intraoperative white-light imaging of tumors. However, barriers to the effective use of these techniques within the central nervous system remain. In the healthy brain, the blood-brain barrier ensures the stability of the sensitive internal environment of the brain by protecting the active functions of the central nervous system and preventing the invasion of microorganisms and toxins. Brain tumors, however, often cause degradation and dysfunction of this barrier, resulting in a heterogeneous increase in vascular permeability throughout the tumor mass and outside it. Thus, the characteristics of both the blood-brain and blood-brain tumor barriers hinder the vascular delivery of a variety of therapeutic substances to brain tumors. Recent developments in fluorescent visualization of brain tumors offer improvements in the extent of maximal safe resection, but many of these fluorescent agents must reach the tumor via the vasculature. As a result, these fluorescence-guided resection techniques are often limited by the extent of vascular permeability in tumor regions and by the failure to stain the full volume of tumor tissue. In this review, we describe the structure and function of both the blood-brain and blood-brain tumor barriers in the context of the current state of fluorescence-guided imaging of brain tumors. We discuss features of currently used techniques for fluorescence-guided brain tumor resection, with an emphasis on their interactions with the blood-brain and blood-tumor barriers. Finally, we discuss a selection of novel preclinical techniques that have the potential to enhance the delivery of therapeutics to brain tumors in spite of the barrier properties of the brain.

Development of a human in vitro blood\u2013brain tumor barrier model of diffuse intrinsic pontine glioma to better understand the chemoresistance

BackgroundPediatric diffuse intrinsic pontine glioma (DIPG) represents one of the most devastating and lethal brain tumors in children with a median survival of 12 months. The high mortality rate can be explained by the ineligibility of patients to surgical resection due to the diffuse growth pattern and midline localization of the tumor. While the therapeutic strategies are unfortunately palliative, the blood–brain barrier (BBB) is suspected to be responsible for the treatment inefficiency. Located at the brain capillary endothelial cells (ECs), the BBB has specific properties to tightly control and restrict the access of molecules to the brain parenchyma including chemotherapeutic compounds. However, these BBB specific properties can be modified in a pathological environment, thus modulating brain exposure to therapeutic drugs. Hence, this study aimed at developing a syngeneic human blood–brain tumor barrier model to understand how the presence of DIPG impacts the structure and function of brain capillary ECs.MethodsA human syngeneic in vitro BBB model consisting of a triple culture of human (ECs) (differentiated from CD34+-stem cells), pericytes and astrocytes was developed. Once validated in terms of BBB phenotype, this model was adapted to develop a blood–brain tumor barrier (BBTB) model specific to pediatric DIPG by replacing the astrocytes by DIPG-007, -013 and -014 cells. The physical and metabolic properties of the BBTB ECs were analyzed and compared to the BBB ECs. The permeability of both models to chemotherapeutic compounds was evaluated.ResultsIn line with clinical observation, the integrity of the BBTB ECs remained intact until 7 days of incubation. Both transcriptional expression and activity of efflux transporters were not strongly modified by the presence of DIPG. The permeability of ECs to the chemotherapeutic drugs temozolomide and panobinostat was not affected by the DIPG environment.ConclusionsThis original human BBTB model allows a better understanding of the influence of DIPG on the BBTB ECs phenotype. Our data reveal that the chemoresistance described for DIPG does not come from the development of a “super BBB”. These results, validated by the absence of modification of drug transport through the BBTB ECs, point out the importance of understanding the implication of the different protagonists in the pathology to have a chance to significantly improve treatment efficiency.

In Situ Formation of Nanotheranostics to Overcome the Blood-Brain Barrier and Enhance Treatment of Orthotopic Glioma.

Glioblastoma is one of the most lethal cancers and needs effective therapeutics. The development of coordination-driven metal-organic nanoassemblies, which can cross the blood-brain barrier (BBB) and blood-brain tumor barrier (BBTB) and have multiple desired functions, may provide a promising solution to this issue. Here, we report an in situ assembled nanoplatform based on RGD peptide-modified bisulfite-zincII-dipicolylamine-Arg-Gly-Asp (Bis(DPA-Zn)-RGD) and ultrasmall Au-ICG nanoparticles. Attributed to its positive charges and neovascular targeting properties, Bis(DPA-Zn)-RGD can be selectively delivered to the tumor site, and then assembled in situ into large nanoclusters with subsequently administered Au-ICG nanoparticles. Au nanoparticles with ultrasmall size (∼7 nm) can successfully cross the BBB. The obtained nanoclusters exhibit strong near-infrared-red (NIR) absorption and an enhanced tumor retention effect, enabling precise orthotopic fluorescence/photoacoustic imaging. With the aid of image guidance, the photothermal effect of the nanoclusters is observed to suppress tumor progression with the inhibition efficiency reaching up to 93.9%. Meanwhile, no photothermal damage can be found for normal brain tissues. These results, herein, suggest a feasible nanotheranostic agent with the ability to overcome the BBB and BBTB for imaging and therapy of orthotopic brain tumors.

A Mini-review on HER2 Positive Breast Cancer and its Metastasis: Resistance and Treatment Strategies

HER2 positive breast cancer is an aggressive breast cancer followed by brain metastasis, which emerges at the later stage of breast cancer or after a few years of treatment. HER2+ breast cancer brain metastasis is a complex fatal disease with short survival and resistance to first-line drugs such as Trastuzumab, lapatinib, etc. The resistance can be due to the upregulation/downregulation of various proteins of downstream pathways mainly PI3K/AKT pathway and MAPK pathway. In addition, the Blood-brain Barrier (BBB) and Blood Tumor Barrier (BTB) also hinder the delivery to brain metastases. Thus controlling the altered proteins of the downstream pathway can be a targeted approach to control breast cancer and its brain metastasis. At the same time, targeted delivery to metastatic sites can give a synergistic effect in controlling brain metastasis and increasing the survival period. Various type of targeted nanocarriers such as single, dual, or multitargeted, pH specific, or stimuli sensitive nanocarriers can be employed for providing specific delivery to HER2+ cancer cells. Furthermore, combinations such as Trastuzumab with tyrosine kinase inhibitors (lapatinib, neratinib, afatinib), chemotherapeutic drugs (paclitaxel, doxorubicin, capecitabine), or some natural compounds (curcumin, Lycorine, berberine) with anti-apoptotic activity can provide an additional effect in the management of HER2 positive breast cancer and its metastasis.

Nanoparticle Drug Delivery System for Glioma and Its Efficacy Improvement Strategies: A Comprehensive Review.

Gliomas are the most common tumor of the central nervous system. However, the presence of the brain barrier blocks the effective delivery of drugs and leads to the treatment failure of various drugs. The development of a nanoparticle drug delivery system (NDDS) can solve this problem. In this review, we summarized the brain barrier (including blood–brain barrier (BBB), blood–brain tumor barriers (BBTB), brain–cerebrospinal fluid barrier (BCB), and nose-to-brain barrier), NDDS of glioma (such as passive targeting systems, active targeting systems, and environmental responsive targeting systems), and NDDS efficacy improvement strategies and deficiencies. The research prospect of drug-targeted delivery systems for glioma is also discussed.

Overcoming the Blood-Brain Barrier: Successes and Challenges inDeveloping Nanoparticle-Mediated Drug Delivery Systems for the Treatment of Brain Tumours.

High-grade gliomas are still characterized by a poor prognosis, despite recent advances in surgical treatment. Chemotherapy is currently practiced after surgery, but its efficacy is limited by aspecific toxicity on healthy cells, tumour cell chemoresistance, poor selectivity, and especially by the blood–brain barrier (BBB). Thus, despite the large number of potential drug candidates, the choice of effective chemotherapeutics is still limited to few compounds. Malignant gliomas are characterized by high infiltration and neovascularization, and leaky BBB (the so-called blood–brain tumour barrier); surgical resection is often incomplete, leaving residual cells that are able to migrate and proliferate. Nanocarriers can favour delivery of chemotherapeutics to brain tumours owing to different strategies, including chemical stabilization of the drug in the bloodstream; passive targeting (because of the leaky vascularization at the tumour site); inhibition of drug efflux mechanisms in endothelial and cancer cells; and active targeting by exploiting carriers and receptors overexpressed at the blood–brain tumour barrier. Within this concern, a suitable nanomedicine-based therapy for gliomas should not be limited to cytotoxic agents, but also target the most important pathogenetic mechanisms, including cell differentiation pathways and angiogenesis. Moreover, the combinatorial approach of cell therapy plus nanomedicine strategies can open new therapeutical opportunities. The major part of attempted preclinical approaches on animal models involves active targeting with protein ligands, but, despite encouraging results, a few number of nanomedicines reached clinical trials, and most of them include drug-loaded nanocarriers free of targeting ligands, also because of safety and scalability concerns.

Long non-coding RNA MALAT1 as a key target in pathogenesis of glioblastoma. Janus faces or Achilles’ heal?

Glioblastomas (GBMs) are primary brain tumors with extremely bad prognosis and therefore; discovery of novel regulators of their pathology is of immense importance. LncRNAs (long noncoding RNAs) regulate nuclear structure, embryonic pluripotency, cell differentiation, development and carcinogenesis. Many lncRNAs have weak evolutionary conservation; however, a nuclear lncRNA, MALAT1 (metastasis-associated lung adenocarcinoma transcript 1), is exceptionally conserved and is among the most abundant lncRNAs in benign tissues. The majority of cell culture studies and clinico-epidemiological studies demonstrated that MALAT1 acts a tumor promoter in GBMs and inhibition of MALAT1 suppressed tumor growth in various preclinical models of GBM. MALAT1 involves in stemness of GBM cells by regulating SOX2, nestin and members of WNT pathway. MALAT1 induces protective autophagy and suppresses apoptosis in GBM cells via sponging miRNA-101 and increases temozolomide chemoresistance via enhancing epithelial-mesenchymal transition, suppressing miR-203 and promoting thymidilate synthase. Moreover, knockdown of MALAT1 expression enhances blood-brain tumor barrier permeability via miR-140, which may provide a double benefit of MALAT1 suppression by increasing the delivery of chemotherapy agents into the GBM tissues. On the other hand, there also exist some cell culture and animal studies showing that MALAT1 acts as a tumor suppressor in GBMs by suppression of ERK/MAPK and MMP2 signaling and by repression of miR-155 with subsequent increase of FBXW7. Whether protective or detrimental, MALAT1 seems to be an important component of GBM pathogenesis and hence; novels studies are needed in versatile models, including many different primary GBM cultures, orthotopic and xenogreft in vivo models and transgenic mice.