Nanoprobes Visualizing Gliomas by Crossing the Blood Brain Tumor Barrier

The difficulty in delineating the glioma margins in brain is a major obstacle for its completed resection, which leads to the disproportionately high recurrence and mortality. Besides the fast exertion rate, inadequate sensitivity and non‐targeting specificity, the main reason leading to failure of small molecular probes to define gliomas is their incapability to efficiently cross the blood brain tumor barrier (BBTB). Nanoprobes (NPs) show promise to precisely delineate the geographically irregular tumor margins due to their tunable size/circulation lifetime that maximize their passive intratumoral accumulation and their convenience for surface modification that increases the BBTB transcytosis efficacy, imaging sensitivity and receptor targeting specificity. In this work, the characteristics of the BBTB are addressed from biological and physiological perspectives, strategies are presented to deliver NPs across the BBTB, recent developments of NPs are reviewed for glioma visualization and finally the difficulty and promise for clinical translation of NPs are described. Overall, NPs hold great potential for glioma imaging and treatment by pre‐surgically delineating tumor margins and intra‐operatively guiding tumor excision.     

The blood-brain barrier and brain drug delivery

The present report encompasses a thorough review of drug delivery to the brain with a particular focus on using drug carriers such as liposomes and nanoparticles. Challenges in brain drug delivery arise from the presence of one of the strictest barriers in vivo-the blood-brain barrier (BBB). This barrier exists at the level of endothelial cells of brain vasculature and its role is to maintain brain homeostasis. To better understand the principles of brain drug delivery, relevant knowledge of the blood-brain barrier anatomy and physiology is briefly reviewed. Several approaches to overcome the BBB have been reviewed including the use of carrier systems. In addition, strategies to enhance brain drug delivery by specific brain targeting are discussed.     

Shuttle‐Mediated Nanoparticle Delivery to the Blood–Brain Barrier

Many therapeutic drugs are excluded from entering the brain due to their lack of transport through the blood–brain barrier (BBB). The development of new strategies for enhancing drug delivery to the brain is of great importance in diagnostics and therapeutics of central nervous diseases. To overcome this problem, a viral fusion peptide (gH625) derived from the glycoprotein gH of Herpes simplex virus type 1 is developed, which possesses several advantages including high cell translocation potency, absence of toxicity of the peptide itself, and the feasibility as an efficient carrier for delivering therapeutics. Therefore, it is hypothesized that brain delivery of nanoparticles conjugated with gH625 should be efficiently enhanced. The surface of fluorescent aminated polystyrene nanoparticles (NPs) is functionalized with gH625 via a covalent binding procedure, and the NP uptake mechanism and permeation across in vitro BBB models are studied. At early incubation times, the uptake of NPs with gH625 by brain endothelial cells is greater than that of the NPs without the peptide, and their intracellular motion is mainly characterized by a random walk behavior. Most importantly, gH625 peptide decreases NP intracellular accumulation as large aggregates and enhances the NP BBB crossing. In summary, these results establish that surface functionalization with gH625 may change NP fate by providing a good strategy for the design of promising carriers to deliver drugs across the BBB for the treatment of brain diseases.     

Brain targeted delivery of anticancer drugs: prospective approach using solid lipid nanoparticles

A brain tumour is amongst most devastating and challenging condition to overcome with suitable treatment as the drug has to cross the blood–brain barrier (BBB) with several physiological barriers like opsonisation by the reticuloendothelial system. Presently various techniques such as surgical, chemotherapeutic agents, and radiotherapy techniques have performed to extend the lifespan of patients diagnosed with glioblastoma, which did not maximise the overall survival of patients with a tumour. Nanotechnology is relied upon to diminish the requirement for intrusive methods for conveyance of therapeutics to the central nervous system. Colloidal nanocarriers sizing range 1–1000 nm have been utilised to cross BBB delivers the drug at cell levels with enhanced bioavailability and reduced toxicity. However, solid lipid nanoparticles (SLNs) are considered a highly flexible carrier for more successful remedially in brain tumour. The treatment of a brain tumour via SLNs is gaining greater potency due to its inimitable size and lipidic nature. This review focuses and represents the current strategies of SLNs in the brain tumour treatment with appropriate techniques adopted are highlighted. Based on this review, the authors concluded that SLNs embrace exclusive promising lipidic nanocarrier that could be utilised to target a brain tumour effectively.Inspec keywords: brain, cancer, nanoparticles, blood, molecular biophysics, tumours, nanomedicine, neurophysiology, radiation therapy, colloids, biomedical materials, drug delivery systems, nanofabrication, drugs, cellular biophysicsOther keywords: chemotherapeutic agents, radiotherapy techniques, central nervous system, colloidal nanocarriers sizing range 1–1000 nm, BBB, drug, solid lipid nanoparticles, brain tumour therapeutical uses, lipidic nature, brain tumour treatment, brain targeted delivery, anticancer drugs, prospective approach, blood–brain barrier, physiological barriers, reticuloendothelial system, surgical agents, lipidic nanocarrier, size 1.0 nm to 1000.0 nm     

Targeting orthotopic gliomas with renal-clearable luminescent gold nanoparticles

A major clinical translational challenge in nanomedicine is the potential of toxicity associated with the uptake and long-term retention of non-degradable nanoparticles (NPs) in major organs.The development of inorganic NPs that undergo renal clearance could potentially resolve this significant biosafety concern.However,it remains unclear whether inorganic NPs that can be excreted by the kidneys remain capable of targeting tumors with poor permeability.Glioblastoma multiforme,the most malignant orthotopic brain tumor,presents a unique challenge for NP delivery because of the blood-brain barrier and robust blood-tumor barrier of reactive microglia and macroglia in the tumor microenvironment.Herein,we used an orthotopic murine glioma model to investigate the passive targeting of glutathione-coated gold nanoparticles (AuNPs) of 3 nm in diameter that undergo renal clearance and 18-nm AuNPs that fail to undergo renal clearance.Remarkably, we report that 3-nm AuNPs were able to target intracranial tumor tissues with higher efficiency (2.3x relative to surrounding non-tumor normal brain tissues) and greater specificity (3.0x)than did the larger AuNPs.Pharmacokinetics studies suggested that the higher glioma targeting ability of the 3-nm AuNPs may be attributed to the longer retention time in circulation.The total accumulation of the 3-nm AuNPs in major organs was significantly less (8.4x) than that of the 18-nm AuNPs.Microscopic imaging of blood vessels and renal-clearable AuNPs showed extravasation of NPs from the leaky blood-tumor barrier into the tumor interstitium.Taken together,our results suggest that the 3-nm AuNPs,characterized by enhanced permeability and retention,are able to target brain tumors and undergo renal clearance.     

Focused Ultrasound Preconditioning for Augmented Nanoparticle Penetration and Efficacy in the Central Nervous System

Microbubble activation with focused ultrasound (FUS) facilitates the noninvasive and spatially‐targeted delivery of systemically administered therapeutics across the blood–brain barrier (BBB). FUS also augments the penetration of nanoscale therapeutics through brain tissue; however, this secondary effect has not been leveraged. Here, 1 MHz FUS sequences that increase the volume of transfected brain tissue after convection‐enhanced delivery of gene‐vector “brain‐penetrating” nanoparticles were first identified. Next, FUS preconditioning is applied prior to trans‐BBB nanoparticle delivery, yielding up to a fivefold increase in subsequent transgene expression. Magnetic resonance imaging (MRI) analyses of tissue temperature and K_trans confirm that augmented transfection occurs through modulation of parenchymal tissue with FUS. FUS preconditioning represents a simple and effective strategy for markedly improving the efficacy of gene vector nanoparticles in the central nervous system.     

Influence of the surface properties on nanoparticle-mediated transport of drugs to the brain

Poly(alkyl cyanoacrylate) nanoparticles enable the delivery of a number of drugs, including doxorubicin, loperamide, tubocurarine, the NMDA receptor antagonist MRZ 2/576, and the peptides dalargin and kytorphin across the blood-brain barrier (BBB) after coating with surfactants. However, only the surfactants polysorbate (Tween) 20, 40, 60 and 80, and some poloxamers (Pluronic F 68) can induce this uptake. The mechanism for the delivery across the BBB most likely is endocytosis via the LDL receptor by the endothelial cells lining the brain blood capillaries after injection of the nanoparticles into the blood stream. This endocytotic uptake seems to be mediated by the adsorption of apolipoprotein B and/or E adsorption from the blood. Thus, the nanoparticles could mimic lipoprotein particles and act as "Trojan Horses." The drug, then, may be released either within these cells followed by passive diffusion into the brain or be transported into the brain by transcytosis.     

Transferrin-conjugated, fluorescein-loaded magnetic nanoparticles for targeted delivery across the blood–brain barrier

The blood–brain barrier (BBB) restricts the delivery of many potentially important therapeutic agents for the treatment of brain disorders. An efficient strategy for brain targeted delivery is the utilization of the targeting ligand conjugated nanoparticles to trigger the receptor-mediated transcytosis. In this study, transferrin (Tf) was employed as a brain targeting ligand to functionalize the fluorescein-loaded magnetic nanoparticles (FMNs). The Tf conjugated FMNs (Tf-FMNs) were characterized by transmission electron microscopy, thermal gravimetric analysis, Fourier transform infrared spectroscopy, and X-ray photoelectron spectroscopy. Using fluorescein as an optical probe, the potential of Tf-FMNs as brain targeting drug carriers was explored in vivo. It was demonstrated that Tf-FMNs were able to cross the intact BBB, diffuse into brain neurons, and distribute in the cytoplasm, dendrites, axons, and synapses of neurons. In contrast, magnetic nanoparticles without Tf conjugation cannot cross the BBB efficiently under the same conditions. Therefore, Tf-FMNs hold great potential in serving as an efficient multifunctional platform for the brain-targeted theranostics.     

Effect of Retro‐Inverso Isomer of Bradykinin on Size‐Dependent Penetration of Blood–Brain Tumor Barrier

Retro‐inverso bradykinin (RI‐BK) has better metabolic stability and higher affinity for the BK type 2 (B2) receptor, compared with bradykinin. At low doses, RI‐BK can selectively enhance the permeability of the blood–brain tumor barrier (BBTB) without harming normal brain tissue. In this study, gold nanoparticles (GNPs) of size ranging from 5 to 90 nm are synthesized to assess the optimal size of nanocarriers that achieves maximum brain accumulation after the treatment of RI‐BK. The ability of the GNPs to cross the BBTB is tested in a rat C6 glioma tumor model. The results of inductively coupled plasma–mass spectrometry and transmission electron microscopy indicate that GNPs with size of 70 nm achieve maximum permeability to the glioma. The present study supports the conclusion that RI‐BK can enhance the permeability of BBTB and provides fundamental information for further development of nanomedicines or nanoprobes for glioma therapy.     

Overcoming blood–brain barrier transport: Advances in nanoparticle-based drug delivery strategies

The blood–brain barrier (BBB), a unique structure in the central nervous system (CNS), protects the brain from bloodborne pathogens by its excellent barrier properties. Nevertheless, this barrier limits therapeutic efficacy and becomes one of the biggest challenges in new drug development for neurodegenerative disease and brain cancer. Recent breakthroughs in nanotechnology have resulted in various nanoparticles (NPs) as drug carriers to cross the BBB by different methods. This review presents the current understanding of advanced NP-mediated non-invasive drug delivery for the treatment of neurological disorders. Herein, the complex compositions and special characteristics of BBB are elucidated exhaustively. Moreover, versatile drug nanocarriers with their recent applications and their pathways on different drug delivery strategies to overcome the formidable BBB obstacle are briefly discussed. In terms of significance, this paper provides a general understanding of how various properties of nanoparticles aid in drug delivery through BBB and usher the development of novel nanotechnology-based nanomaterials for cerebral disease therapies.     

A Bioinspired Platform for Effective Delivery of Protein Therapeutics to the Central Nervous System

Central nervous system (CNS) diseases are the leading cause of morbidity and mortality; their treatment, however, remains constrained by the blood–brain barrier (BBB) that impedes the access of most therapeutics to the brain. A CNS delivery platform for protein therapeutics, which is achieved by encapsulating the proteins within nanocapsules that contain choline and acetylcholine analogues, is reported herein. Mediated by nicotinic acetylcholine receptors and choline transporters, such nanocapsules can effectively penetrate the BBB and deliver the therapeutics to the CNS, as demonstrated in mice and non‐human primates. This universal platform, in general, enables the delivery of any protein therapeutics of interest to the brain, opening a new avenue for the treatment of CNS diseases.     

Hsp70-Targeting and Size-Tunable Nanoparticles Combine with PD-1 Checkpoint Blockade to Treat Glioma

Invasive glioma usually disrupts the integrity of the blood-brain barrier (BBB), making the delivery of nanodrugs across the BBB possible, but sufficient targeting ability is still avidly needed to improve drug accumulation in glioma. Membrane-bound heat shock protein 70 (Hsp70) is expressed on the membrane of glioma cells rather than adjacent normal cells, therefore it can serve as a specific glioma target. Meanwhile, prolonging the retention in tumors is important for active-targeting nanoparticles to overcome receptor-binding barriers. Herein, the Hsp70-targeting and acid-triggered self-assembled gold nanoparticles (D-A-DA/TPP) are proposed to realize selective delivery of doxorubicin (DOX) to glioma. In the weakly acidic glioma matrix, D-A-DA/TPP formed aggregates to prolong retention, improve receptor-binding efficiency and facilitate acid-responsive DOX release. DOX accumulation in glioma induced immunogenic cell death (ICD) to promote antigen presentation. Meanwhile, combination with the PD-1 checkpoint blockade further activate T cells and provokes robust anti-tumor immunity. The results showed that D-A-DA/TPP can induce more glioma apoptosis. Furthermore, in vivo studies indicated D-A-DA/TPP plus PD-1 checkpoint blockade significantly improved median survival time. This study offeres a potential nanocarrier combining size-tunable strategy with active targeting ability to increase drug enrichment in glioma and synergizes with PD-1 checkpoint blockade to achieve chemo-immunotherapy.     

Nanoneurotherapeutics approach intended for direct nose to brain delivery

Abstract

Context: Brain disorders remain the world's leading cause of disability, and account for more hospitalizations and prolonged care than almost all other diseases combined. The majority of drugs, proteins and peptides do not readily permeate into brain due to the presence of the blood–brain barrier (BBB), thus impeding treatment of these conditions.

Objective: Attention has turned to developing novel and effective delivery systems to provide good bioavailability in the brain.

Methods: Intranasal administration is a non-invasive method of drug delivery that may bypass the BBB, allowing therapeutic substances direct access to the brain. However, intranasal administration produces quite low drug concentrations in the brain due limited nasal mucosal permeability and the harsh nasal cavity environment. Pre-clinical studies using encapsulation of drugs in nanoparticulate systems improved the nose to brain targeting and bioavailability in brain. However, the toxic effects of nanoparticles on brain function are unknown.

Result and conclusion: This review highlights the understanding of several brain diseases and the important pathophysiological mechanisms involved. The review discusses the role of nanotherapeutics in treating brain disorders via nose to brain delivery, the mechanisms of drug absorption across nasal mucosa to the brain, strategies to overcome the blood brain barrier, nanoformulation strategies for enhanced brain targeting via nasal route and neurotoxicity issues of nanoparticles.     

Overcoming the blood–brain barrier in neurodegenerative disorders and brain tumours

Drug delivery is one of the major challenges in the treatment of central nervous system disorders. The brain needs to be protected from harmful agents, which are done by the capillary network, the so‐called blood–brain barrier (BBB). This protective guard also prevents the delivery of therapeutic agents to the brain and limits the effectiveness of treatment. For this reason, various strategies have been explored by scientists for overcoming the BBB from disruption of the BBB to targeted delivery of nanoparticles (NPs) and cells and immunotherapy. In this review, different promising brain drug delivery strategies including disruption of tight junctions in the BBB, enhanced transcellular transport by peptide‐based delivery, local delivery strategies, NP delivery, and cell‐based delivery have been fully discussed.Inspec keywords: drugs, tumours, neurophysiology, blood, biochemistry, brain, drug delivery systems, nanoparticles, biomedical materials, molecular biophysics, cellular biophysics, nanomedicine, diseases, proteins, reviewsOther keywords: blood–brain barrier, neurodegenerative disorders, central nervous system disorders, BBB, therapeutic agents, targeted delivery, peptide‐based delivery, local delivery strategies, NP delivery, cell‐based delivery, brain drug delivery strategies, brain tumours, nanoparticles, immunotherapy, review     

HDL‐Mimicking Peptide–Lipid Nanoparticles with Improved Tumor Targeting

Targeted delivery of intracellularly active diagnostics and therapeutics in vivo is a major challenge in cancer nanomedicine. A nanocarrier should possess long circulation time yet be small and stable enough to freely navigate through interstitial space to deliver its cargo to targeted cells. Herein, it is shown that by adding targeting ligands to nanoparticles that mimic high‐density lipoprotein (HDL), tumor‐targeted sub‐30‐nm peptide–lipid nanocarriers are created with controllable size, cargo loading, and shielding properties. The size of the nanocarrier is tunable between 10 and 30 nm, which correlates with a payload of 15–100 molecules of fluorescent dye. Ligand‐directed nanocarriers targeting epidermal growth factor receptor (EGFR) are confirmed both in vitro and in vivo. The nanocarriers show favorable circulation time, tumor accumulation, and biodistribution with or without the targeting ligand. The EGFR targeting ligand is proved to be essential for the EGFR‐mediated tumor cell uptake of the nanocarriers, a prerequisite of intracellular delivery. The results demonstrate that targeted HDL‐mimetic nanocarriers are useful delivery vehicles that could open new avenues for the development of clinically viable targeted nanomedicine.     

Single siRNA Nanocapsules for Effective siRNA Brain Delivery and Glioblastoma Treatment

Small interfering RNA (siRNA) has been considered as a highly promising therapeutic agent for human cancer treatment including glioblastoma (GBM), which is a fatal disease without effective therapy methods. However, siRNA-based GBM therapy is seriously hampered by a number of challenges in siRNA brain delivery including poor stability, short blood circulation, low blood–brain barrier (BBB) penetration, and tumor accumulation, as well as inefficient siRNA intracellular release. Herein, an Angiopep-2 (Ang) functionalized intracellular-environment-responsive siRNA nanocapsule (Ang-NC_ss(siRNA)) is successfully developed as a safe and efficient RNAi agent to boost siRNA-based GBM therapy. The experimental results demonstrate that the developed Ang-NC_ss(siRNA) displays long circulation in plasma, efficient BBB penetration capability, and GBM accumulation and retention, as well as responsive intracellular siRNA release due to the unique design of small size (25 nm) with polymeric shell for siRNA protection, Ang functionalization for BBB crossing and GBM targeting, and disulfide bond as a linker for intracellular-environment-responsive siRNA release. Such superior properties of Ang-NC_ss(siRNA) result in outstanding growth inhibition of orthotopic U87MG xenografts without causing adverse effects, achieving remarkably improved survival benefits. The developed siRNA nanocapsules provide a new strategy for RNAi therapy of GBM and beyond.     

Stimuli-Responsive Multifunctional Nanomedicine for Enhanced Glioblastoma Chemotherapy Augments Multistage Blood-to-Brain Trafficking and Tumor Targeting

Minimal therapeutic advances have been achieved over the past two decades for glioblastoma (GBM), which remains an unmet clinical need. Here, hypothesis-driven stimuli-responsive nanoparticles (NPs) for docetaxel (DTX) delivery to GBM are reported, with multifunctional features that circumvent insufficient blood-brain barrier (BBB) trafficking and lack of GBM targeting—two major hurdles for anti-GBM therapies. NPs are dual-surface tailored with a i) brain-targeted acid-responsive Angiopep-2 moiety that triggers NP structural rearrangement within BBB endosomal vesicles, and ii) L-Histidine moiety that provides NP preferential accumulation into GBM cells post-BBB crossing. In tumor invasive margin patient cells, the stimuli-responsive multifunctional NPs target GBM cells, enhance cell uptake by 12-fold, and induce three times higher cytotoxicity in 2D and 3D cell models. Moreover, the in vitro BBB permeability is increased by threefold. A biodistribution in vivo trial confirms a threefold enhancement of NP accumulation into the brain. Last, the in vivo antitumor efficacy is validated in GBM orthotopic models following intratumoral and intravenous administration. Median survival and number of long-term survivors are increased by 50%. Altogether, a preclinical proof of concept supports these stimuli-responsive multifunctional NPs as an effective anti-GBM multistage chemotherapeutic strategy, with ability to respond to multiple fronts of the GBM microenvironment.     

Nanoparticulate strategies for the treatment of polyglutamine diseases by halting the protein aggregation process†

Polyglutamine (polyQ) diseases are a class of neurodegenerative disorders that cause cellular dysfunction and, eventually, neuronal death in specific regions of the brain. Neurodegeneration is linked to the misfolding and aggregation of expanded polyQ-containing proteins, and their inhibition is one of major therapeutic strategies used commonly. However, successful treatment has been limited to date because of the intrinsic properties of therapeutic agents (poor water solubility, low bioavailability, poor pharmacokinetic properties), and difficulty in crossing physiological barriers, including the blood–brain barrier (BBB). In order to solve these problems, nanoparticulate systems with dimensions of 1–1000?nm able to incorporate small and macromolecules with therapeutic value, to protect and deliver them directly to the brain, have recently been developed, but their use for targeting polyQ disease-mediated protein misfolding and aggregation remains scarce. This review provides an update of the polyQ protein aggregation process and the development of therapeutic strategies for halting it. The main features that a nanoparticulate system should possess in order to enhance brain delivery are discussed, as well as the different types of materials utilized to produce them. The final part of this review focuses on the potential application of nanoparticulate system strategies to improve the specific and efficient delivery of therapeutic agents to the brain for the treatment of polyQ diseases.     

Drug delivery to the brain--realization by novel drug carriers

Delivery of drugs to the brain is still a major challenge. Successful delivery across the bloodbrain barrier has only been achieved in some cases, e.g., using pro-drugs. The review describes the delivery to the brain using nanoparticulate drug carriers in combination with the novel targeting principle of "differential protein adsorption" (PathFinder technology). The PathFinder technology exploits proteins in the blood which adsorb onto the surface of intravenously injected carriers for targeting. Apolipoprotein E is the targeting moiety for the delivery of particles to the endothelials of the blood-brain barrier. To reach therapeutic drug level in the brain, nanoparticulate drug carriers with sufficiently high loading capacity are reviewed, including drug nanocrystals (nanosuspensions), lipid drug conjugate (LDC) nanoparticles and lipid nanoparticles (solid lipid nanoparticles-SLN, nanostructured lipid carriers-NLC). The features are described, including regulatory aspects and large scale production.