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Emerging blood–brain-barrier-crossing nanotechnology for brain cancer theranostics
Abstract
Brain cancer, especially the most common type of glioblastoma, is highly invasive and known as one of the most devastating and deadly neoplasms. Despite surgical and medical advances, the prognosis for most brain cancer patients remains dismal and the median survival rarely exceeds 16 months. Drug delivery to the brain is significantly hindered by the existence of the blood-brain barrier (BBB), which serves as a protective semi-permeable membrane for the central nervous system. Recent breakthroughs in nanotechnology have yielded multifunctional theranostic nanoplatforms with the ability to cross or bypass the BBB, enabling accurate diagnosis and effective treatment of brain tumours. Herein, we make our efforts to present a comprehensive review on the latest remarkable advances in BBB-crossing nanotechnology, with an emphasis on the judicious design of multifunctional nanoplatforms for effective BBB penetration, efficient tumour accumulation, precise tumour imaging, and significant tumour inhibition of brain cancer. The detailed elucidation of BBB-crossing nanotechnology in this review is anticipated to attract broad interest from researchers in diverse fields to participate in the establishment of powerful BBB-crossing nanoplatforms for highly efficient brain cancer theranostics.
... Further, in intact condition, BBB restricts the entry of~99% of small drug molecules. BBB offers many transport mechanisms internally, i.e., via the transcellular lipophilic pathway, carrier-mediated transport (CMT), or receptor-mediated transport (RMT) [42,43]. However, the delivery of small molecules can be compromised by a large number of efflux pumps (such as adenosine triphosphate binding cassette transporters including multi-drug resistant protein (MRP) and p-glycoprotein (p-gp)), evade the foreign material into the bloodstream. ...
... However, the delivery of small molecules can be compromised by a large number of efflux pumps (such as adenosine triphosphate binding cassette transporters including multi-drug resistant protein (MRP) and p-glycoprotein (p-gp)), evade the foreign material into the bloodstream. Further, biological compounds, including inflammatory mediators (e.g., bradykinin, prostaglandin, vascular endothelial growth factors (VEGF)), signal receptors to increase BBB permeability [43]. ...
... Transient opening of BBB can be achieved by biological (e.g., VEGF) or chemical stimuli (e.g., mannitol, oleic acid, cyclodextrins) but could have non-specific uptake, causing unwanted side effects. Therefore, an ideal approach to disrupting BBB is essential, one that would be controllable, reversible, specific, transient, and selective [43]. ...
Pediatric brain tumors are the major cause of pediatric cancer mortality. They comprise a diverse group of tumors with different developmental origins, genetic profiles, therapeutic options, and outcomes. Despite many technological advancements, the treatment of pediatric brain cancers has remained a challenge. Treatment options for pediatric brain cancers have been ineffective due to non-specificity, inability to cross the blood-brain barrier, and causing off-target side effects. In recent years, nanotechnological advancements in the medical field have proven to be effective in curing challenging cancers like brain tumors. Moreover, nanoparticles have emerged successfully, particularly in carrying larger payloads, as well as their stability, safety, and efficacy monitoring. In the present review, we will emphasize pediatric brain cancers, barriers to treating these cancers, and novel treatment options.
... Currently, the most commonly utilized modalities in glioma diagnosis are magnetic resonance imaging (MRI), positron emission tomography (PET), and computed tomography. [2] In addition, several emerging imaging modalities have been applied to precisely delineate the demarcation between normal and neoplastic tissues, including fluorescence imaging (FI), Raman imaging (RI), and photoacoustic imaging (PAI). [3] Imaging guided surgical resection is the conventional treatment method of glioma, but it is impossible to excise tumor sites completely due to glioma's infiltrative growth features. ...
... Currently, several imaging methods including FI, MRI, computed tomography, PET, RI, and PAI, are frequently used for visualization and diagnosis of glioma. [2] The utilization of these imaging techniques can significantly contribute to enhancing the comprehension of fundamental pathological mechanisms, enabling early diagnosis, and evaluating therapeutic outcomes of brain tumors. [11] In this part, we will present the applications of biomimetic nanocomposites in diverse representative imaging methods, including FI, MRI, and multi-modal imaging, such as the combination of FI, MRI, and PAI. ...
Glioma, the most common primary brain tumor, is highly invasive and grows rapidly. As such, the survival of glioma patients is relatively short, highlighting the vital importance of timely diagnosis and treatment of glioma. However, the blood brain barrier (BBB) and the non‐targeting delivery systems of contrast agents and drugs greatly hinder the effective glioma imaging and therapy. Fortunately, in recent years, investigators have constructed various biomimetic delivery platforms utilizing the exceptional advantages of biomimetic nanocomposites, such as immune evasion, homologous targeting ability, and BBB penetrating ability, to achieve efficient and precise delivery of substances to glioma sites for improved diagnosis and treatment. In this concept, we present the application of these biomimetic nanocomposites in fluorescence imaging (FI), magnetic resonance imaging (MRI), and multi‐modal imaging, as well as in chemotherapy, phototherapy, and combined therapy for glioma. Lastly, we provide our perspective on this research field.
... The outcomes thus affirm that MNPs thermotherapy combined with a lower radiation dose is safe, effective, and extends OS-2 compared to traditional therapies [118]. The European Union approved this MNPbased thermotherapy in GBM patients based on the results obtained from clinical studies, yet the procedure has several drawbacks, including seizures and the requisition to remove all dental implants [119,120]. With exceptionally improved physicochemical properties, such as catalytic, optical, thermal, and electrical properties, MNPs have bactericidal, antiviral, fungicidal, and antioxidant potential. ...
... Due to its low level of invasiveness, the permutation of photothermal therapy (PTT) with chemotherapy is proving to be an effective method for treating GBM. Reduced undesirable side effects and increased treatment efficacy are two critical goals in improving innovative therapeutic compounds for chemo-photothermal therapy [119,120]. Due to their low toxicity and distinctive magnetic characteristics, iron oxide NPs are frequently utilized as efficient drug carriers. Fe 3 O 4 MNPs have recently been thoroughly proven to be efficient PTT agents for cancer therapy using nearinfrared (NIR) light. ...
Background
Glioblastoma multiforme (GBM) is recognized as the most lethal and most highly invasive tumor. The high likelihood of treatment failure arises from the presence of the blood-brain barrier (BBB) and stem cells around GBM, which avert the entry of chemotherapeutic drugs into the tumor mass.
Objective
Recently, several researchers have designed novel nanocarrier systems like liposomes, dendrimers, metallic nanoparticles, nanodiamonds, and nanorobot approaches, allowing drugs to infiltrate the BBB more efficiently, opening up innovative avenues to prevail over therapy problems and radiation therapy.
Methods
Relevant literature for this manuscript has been collected from a comprehensive and systematic search of databases, for example, PubMed, Science Direct, Google Scholar, and others, using specific keyword combinations, including “glioblastoma,” “brain tumor,” “nanocarriers,” and several others.
Conclusion
This review also provides deep insights into recent advancements in nanocarrier-based formulations and technologies for GBM management. Elucidation of various scientific advances in conjunction with encouraging findings concerning the future perspectives and challenges of nanocarriers for effective brain tumor management has also been discussed.
... One end of the polymer polyethylene glycol (PEG) is modi ed with mannose, facilitating transportation through glucose transporter protein 1 (GLUT1) in astrocytes, thereby achieving brain-targeted drug delivery [22]. The other end is connected to the LA, resulting in cross-linked nanomicelles mannose-PEG600-lipoic acid (Man-LA). ...
Autism spectrum disorder (ASD) presents cognitive and social deficits with a lacking brain-targeted medication landscape, notably in nanomedicine. Here, we introduce a novel brain-targeted H 2 S donor cross-linked nanomicelles named mannose-PEG600-lipoic acid (Man-LA). Man-LA exhibit enhanced stability and precise brain delivery through interaction with glucose transporter 1 (GLUT1) in astrocytes, facilitating gradual H 2 S release modulated by glutathione (GSH). In vivo , Man-LA improve symptoms of ASD by correlating with increased expression of aerobic glycolysis enzymes, lactate production, and H2S levels, while also preventing damage to hippocampal neurons. In vitro , Man-LA tightly bind to Aldh3b1 in astrocytes, upregulating its expression and promoting aerobic glycolysis and enhanced lactate production. Collectively, these findings suggest a link between ASD deficits and dysregulated astrocytic aerobic glycolysis, highlighting H 2 S's role. Notably, the identification of Aldh3b1 gene within aerobic glycolysis pathways presents a promising new target for ASD treatment.
... The most common primary malignancy in the CNS is glioma, which, due to its infiltrative growth and difficulty to be removed surgically, is associated with poor prognosis and short survival rates [135,136]. In this regard, extensive work has been done aiming at the development of anti-cancer medicines capable to overcome the BBB and target glioma using NPs as drug carriers [137][138][139][140]. ...
Neurodegenerative diseases are characterized by extensive loss of function or death of brain cells, hampering the life quality of patients. Brain-targeted drug delivery is challenging, with a low success rate this far. Therefore, the application of targeting ligands in drug vehicles, such as lipid-based and polymeric nanoparticles, holds the promise to overcome the blood-brain barrier (BBB) and direct therapies to the brain, in addition to protect their cargo from degradation and metabolization. In this review, we discuss the barriers to brain delivery and the different types of brain-targeting ligands currently in use in brain-targeted nanoparticles, such as peptides, proteins, aptamers, small molecules, and antibodies. Moreover, we present a detailed review of the different targeting ligands used to direct nanoparticles to specific brain cells, like neurons (C4-3 aptamer, neurotensin, Tet-1, RVG, and IKRG peptides), astrocytes (Aquaporin-4, D4, and Bradykinin B2 antibodies), oligodendrocytes (NG-2 antibody and the biotinylated DNA aptamer conjugated to a streptavidin core Myaptavin-3064), microglia (CD11b antibody), neural stem cells (QTRFLLH, VPTQSSG, and NFL-TBS.40–63 peptides), and to endothelial cells of the BBB (transferrin and insulin proteins, and choline). Reports demonstrated enhanced brain-targeted delivery with improved transport to the specific cell type targeted with the conjugation of these ligands to nanoparticles. Hence, this strategy allows the implementation of high-precision medicine, with reduced side effects or unwanted therapy clearance from the body. Nevertheless, the accumulation of some of these nanoparticles in peripheral organs has been reported indicating that there are still factors to be improved to achieve higher levels of brain targeting. This review is a collection of studies exploring targeting ligands for the delivery of nanoparticles to the brain and we highlight the advantages and limitations of this type of approach in precision therapies.
... It is possible to detect specific molecular changes at the organ, cellular, and even subcellular levels in a living state, while also guiding disease treatment at the molecular level. [33][34][35] The vascular endothelium has several important functions, including hemostasis. 36 In the process of thrombus formation and thrombolysis, endothelial damage occurs, leading to platelet activation and an excessive generation of ROS, intensifying oxidative stress. ...
The current treatment of venous thrombus during pregnancy is ineffective, primarily due to the unique physiology of pregnant women.
... The effective penetration of the BBB for drug or gene delivery in GBM treatment has long been a challenge for researchers [55]. Recent breakthroughs in nanotechnology have resulted in versatile therapeutic nanoplatforms that possess the ability to cross the BBB, allowing for precise diagnosis and effective treatment of GBM. ...
The blood-brain Barrier (BBB), combined with immune clearance, contributes to the low efficacy of drug delivery and suboptimal treatment outcomes in glioma. Here, we propose a novel approach that combines the self-assembly of mouse bone marrow-derived macrophage membrane with a targeted positive charge polymer (An-PEI), along with low-frequency ultrasound (LFU) irradiation, to achieve efficient and safe therapy for glioma. Our findings demonstrate the efficacy of a charge-induced self-assembly strategy, resulting in a stable co-delivery nanosystem with a high drug loading efficiency of 44.2 %. Moreover, this structure triggers a significant release of temozolomide in the acidic environment of the tumor microenvironment. Additionally, the macrophage membrane coating expresses Spyproteins, which increase the amount of An-BMP-TMZ that can evade the immune system by 40 %, while LFU irradiation treatment facilitates the opening of the BBB, allowing for enormously increased entry of An-BMP-TMZ (approximately 400 %) into the brain. Furthermore, after crossing the BBB, the Angiopep-2 peptide-modified An-BMP-TMZ exhibits the ability to selectively target glioma cells. These advantages result in an obvious tumor inhibition effect in animal experiments and significantly improve the survival of glioma-bearing mice. These results suggest that combining the macrophage membrane-coated drug delivery system with LFU irradiation offers a feasible approach for the accurate, efficient and safe treatment of brain disease.
... Among the various cases of brain cancer, almost 70% are high-grade and invasive. In particular, glioblastoma is characterized by an average survival that doesn't exceed 15 months [174]. ...
Raman spectroscopy (RS) is a label-free molecular vibrational spectroscopy technique that is able to identify the molecular fingerprint of various samples making use of the inelastic scattering of monochromatic light. Because of its advantages of non-destructive and accurate detection, RS is finding more and more use for benign and malignant tissues, tumor differentiation, tumor subtype classification, and section pathology diagnosis, operating either
in vivo
or
in vitro
. However, the high specificity of RS comes at a cost. The acquisition rate is low, depth information cannot be directly accessed, and the sampling area is limited. Such limitations can be contained if data pre- and post-processing methods are combined with current methods of Artificial Intelligence (AI), essentially, Machine Learning (ML) and Deep Learning (DL). The latter is modifying the approach to cancer diagnosis currently used to automate many cancer data analyses, and it has emerged as a promising option for improving healthcare accuracy and patient outcomes by abiliting prediction diseases tools. In a very broad context, Artificial Intelligence applications in oncology include risk assessment, early diagnosis, patient prognosis estimation, and treatment selection based on deep knowledge. The application of autonomous methods to datasets generated by RS analysis of benign and malignant tissues could make RS a rapid and stand-alone technique to help pathologists diagnose cancer with very high accuracy. This review describes the current milestones achieved by applying AI-based algorithms to RS analysis, grouped according to seven major types of cancers (Pancreatic, Breast, Skin, Brain, Prostate, Ovarian and Oral cavity). Additionally, it provides a theoretical foundation to tackle both present and forthcoming challenges in this domain. By exploring the current achievements and discussing the relative methodologies, this review offers recapitulative insights on recent and ongoing efforts to position RS as a rapid and effective cancer screening tool for pathologists. Accordingly, we aim to encourage future research endeavors and to facilitate the realization of the full potential of RS and AI applications in cancer grading.
... This discovery promoted the progress of zinc selenide (ZnSe) nanoplatelet probes, enhancing PA imaging to detect in situ Cu 2+ exchange within the brains of AD mice in real-time. In order to enhance the transit of nano-platelets across the BBB, the Angiopep-2 (Ang) peptide, which serves as a ligand specifically targeting the overexpressed lipoprotein receptor-associated protein 1 (LRP1) on the BBB, was intricately modified on the surface of the nano-platelets (Tang et al., 2019). The synthetic nanoplatelet probes efficiently traversed the BBB and promptly interacted with Cu 2+ in brain, enhancing the ability of PA imaging to detect the level of copper ion in the brain (Figures 8D-G). ...
Alzheimer's disease (AD), referring to a gradual deterioration in cognitive function, including memory loss and impaired thinking skills, has emerged as a substantial worldwide challenge with profound social and economic implications. As the prevalence of AD continues to rise and the population ages, there is an imperative demand for innovative imaging techniques to help improve our understanding of these complex conditions. Photoacoustic (PA) imaging forms a hybrid imaging modality by integrating the high-contrast of optical imaging and deep-penetration of ultrasound imaging. PA imaging enables the visualization and characterization of tissue structures and multifunctional information at high resolution and, has demonstrated promising preliminary results in the study and diagnosis of AD. This review endeavors to offer a thorough overview of the current applications and potential of PA imaging on AD diagnosis and treatment. Firstly, the structural, functional, molecular parameter changes associated with AD-related brain imaging captured by PA imaging will be summarized, shaping the diagnostic standpoint of this review. Then, the therapeutic methods aimed at AD is discussed further. Lastly, the potential solutions and clinical applications to expand the extent of PA imaging into deeper AD scenarios is proposed. While certain aspects might not be fully covered, this mini-review provides valuable insights into AD diagnosis and treatment through the utilization of innovative tissue photothermal effects. We hope that it will spark further exploration in this field, fostering improved and earlier theranostics for AD.
... Nanodiamonds (NDs), a novel class of carbon-based nanomaterials, show promise in overcoming these difficulties. NDs are a viable remedy because of their chemical inertness, high biocompatibility, prolonged photostability, low toxicity, and capacity for surface modification (Tang et al. 2019). Hence, it is possible to create in vivo and in vitro monitoring devices to determine and analyze the dose and its consequences in real time. ...
The central nervous system (CNS) is imperative in maintaining a homeostatic balance between the mind and the physiological state of being. Any form of physical or biological impairment demonstrating a deteriorating nervous system condition is characterized as neurological disorders (NDs), primarily comprising neurodegenerative, immunogenic, neuro-muscular, trauma-induced, neuropathic, and psychological ailments. Conventional medications and nonspecific therapeutics available in the market either suppress the symptoms or delayed the disease progression rate. However, nothing has yet been developed to eradicate symptoms and revert to normal cerebral conditions. The conventional strategies have low efficacy and show limited mitigation of symptoms due to their inability to cross the blood-brain barrier (BBB). Since the dawn of materials sciences, nanotechnological interventions have been catering to fabricate biocompatible nanoformulations and actualize alternate drug delivery platforms, which specifically target prominent disease biomarkers associated with NDs, with limited toxicological implications. The drugs can also be nano-engineered to be delivered across the blood-brain barrier and perform specific functions. Therefore, this chapter tends to deliberate current understanding and recent findings on existing drug delivery routes and platforms using nanotechnological interventions. The chapter discusses challenges with nanomedicines developed for NDs and suggests personalized therapeutics as a solution.
... In order to facilitate the access of the drugs to their targets and to improve their efficiency, the development of new nanocarriers has been extensively investigated. A wide variety of nanocarriers have been designed, whether for the treatment of immune systemrelated pathologies [2], cancers and brain-related diseases [3,4], and various diseases or theragnostic agents [5]. Although a lot of nanomaterials are available in the field of drug delivery, this review focused on the supramolecular system known as drug-in-cyclodextrinin-liposome (DCLs) based on cyclodextrins (CDs) and liposomes. ...
The design of new drug delivery systems has been widely sought after. The stability, solubility, and difficulty of targeting active sites for new drugs have always been challenging and remain one of the major drawbacks to the efficiency of certain drugs. Liposomes are phospholipid vesicles enclosing one or more aqueous compartments. Depending on its properties, a drug is embedded in the lipid bilayer or the aqueous medium. Thus, liposomes can act as drug carriers for both lipo- and hydrophilic compounds. New strategies such as “drug-in-cyclodextrin-in liposomes” (DCLs) have been developed as safe and effective carriers for exploiting the inclusion properties of water-soluble cyclodextrins known to form host–guest complexes with lipophilic molecules. Once inclusion complexes are formed, they can be inserted into a liposome aqueous core in order to stabilize it and better control the drug release. Our review will provide an update on the use of DCLs in the field of drug delivery for various kinds of active compounds. While previous reviews focused on the interesting advantages of using this method, such as enhancing the solubility and stability of a drug or controlling and improving drug release, the authors intend to highlight the impact of these nanocarriers on the pharmacokinetic and/or pharmacodynamic properties of drugs.
... Feature extraction is the process of breaking down a segmented MRI picture into a collection of features. This method uses pre-processing to take care of the image's noise and artefacts [8,9]. The tumour region is then segmented using histogram and threshold approaches since its location is not consistent. ...
A brain cancer is an unexpected growth of nerves within the brain that interferes with the brain's normal function. Numerous lives have been lost as a result of it. It will take time to protect individuals from this illness by prompt discovery and the appropriate treatment. The search for tumor-affected brain cells is a difficult and time-consuming process. However, detecting brain cancer with the precision and speed necessary is a significant hurdle in the field of image processing. This study suggests a brand-new, precise, and enhanced method for finding brain cancer. Preprocessing, segmentation, feature extraction, optimization, and identification are some of the processes the system uses. A skull scripping constitutes one of the first steps in the procedure of finding anomalies in the brain and is used in the initial processing method. Discrete wavelet transform (DWT) is employed for feature extraction, while K-means algorithms are used for picture segmentation. In this section the optimised CNN method is used, which selects the best characteristics via dragon fly optimisation. The CNN classifier is used for identifying brain tumours. Utilising reliability, precision, and recall characteristics, this system evaluates its efficacy with that of another contemporary optimisation approach and declares that its work is superior.
... There are currently few drugs for the treatment of glioma, and progress in drug development in this area has been slow, as the physiological structure of the blood-brain barrier means that medicines are unable to effectively reach the tumor site [11,12]. However, developments in nanotechnology offer opportunities to overcome this barrier, and improved progress is expected in the development of drug treatments for glioma [13]. Immunotherapy is different from conventional treatments and is currently the most promising new treatment for glioma [10,14]. ...
The cell division cycle associated (CDCA) genes regulate the cell cycle; however, their relationship with prognosis in glioma has been poorly reported in the literature. The Cancer Genome Atlas (TCGA) was utilized to probe the CDCA family in relation to the adverse clinical features of glioma. Glioma single-cell atlas reveals specific expression of CDCA3, 4, 5, 8 in malignant cells and CDCA7 in neural progenitor cells (NPC)-like malignant cells. Glioma data from TCGA, the China Glioma Genome Atlas Project (CGGA) and the gene expression omnibus (GEO) database all demonstrated that CDCA2, 3, 4, 5, 7 and 8 are prognostic markers for glioma. Further analysis identified CDCA2, 5 and 8 as independent prognostic factors for glioma. Lasso regression-based risk models for CDCA families demonstrated that high-risk patients were characterized by high tumor mutational burden (TMB), low levels of microsatellite instability (MSI), and low tumor immune dysfunction and rejection (TIDE) scores. These pointed to immunotherapy for glioma as a potentially viable treatment option Further CDCA clustering suggested that the high CDCA subtype exhibited a high macrophage phenotype and was associated with a higher antigen presentation capacity and high levels of immune escape. In addition, hsa-mir-15b-5p was predicted to be common regulator of CDCA3 and CDCA4, which was validated in U87 and U251 cells. Importantly, we found that CDCAs may indicate response to drug treatment, especially rapamycin, in glioma. In summary, our results suggest that CDCAs have potential applications in clinical diagnosis and as drug sensitivity markers in glioma.
... Nowadays, it is still quite challenging to treat glioblastoma with conventional therapeutic paradigms like surgery and postoperative chemotherapy, leading to the low median life span (<2 years) for diagnosed patients (Omuro and DeAngelis, 2013;Grauwet and Chiocca, 2016;Aldape et al., 2019;Sampson et al., 2020;Qiao et al., 2022). The most probable reasons include (i) the existence of the blood-brain barrier hinders drug penetration and minimizes the efficacy of diagnosis and therapeutics; (ii) the surgery could not clear the tiny lesion tissues, which naturally prefer to penetrate deep of the central nerve system and this would lead to tumor recurrence; and (iii) while chemotherapy is the most often used therapeutic modality, the tumor gradually exhibits multidrug resistance under repeated treatment of drugs with high dosage, and the strong side effects of chemotherapy also severely compromise the health of patients Tang et al., 2019a;Agrawala et al., 2020;Bastiancich et al., 2021;Quader et al., 2022). ...
Nowadays, it is still quite difficult to combat glioblastoma, which is one of the most lethal cancers for human beings. Combinatory therapy, which could not only improve therapeutic efficacy and overcome multiple drug resistance but also decrease the threshold therapeutic drug dosage and minimize side effects, would be an appealing candidate for glioblastoma treatment. Herein, we report fluorescence imaging in the second near-infrared window (NIR-II)-guided combinatory photothermal therapy (PTT) and chemotherapy of glioblastoma with a newly formulated nanomedicine termed PATSL. It is composed of temperature-sensitive liposome (TSL) carriers, NIR-II emissive and photothermal aggregation-induced emission (AIE) dyes, and chemotherapeutic paclitaxel (PTX) as well. PATSL shows spherical morphology with diameters of approximately 55 and 85 nm by transmission electron microscopy and laser light scattering, respectively, a zeta potential of −14.83 mV, good stability in both size and photoactivity, strong light absorption with a peak of approximately 770 nm, and bright emission from 900 nm to 1,200 nm. After excitation with an 808-nm laser with good spatiotemporal controllability, PATSL emits bright NIR-II fluorescence signals for tumor diagnosis in vivo, exhibits high photothermal conversion efficiency (68.8%), and triggers drug release of PTX under hypothermia, which assists in efficient tumor ablation in vitro and in vivo. This research demonstrates that “all-in-one” theranostics with NIR-II fluorescence imaging-guided combinatory PTT and chemotherapy is an efficient treatment paradigm for improving the prognosis of brain cancers.
... Previous nanomedicine focused on high-potency drug encapsulation to reduce peripheral adverse reactions of clinical medication or promoting central delivery by utilizing the advantageous size or functionalized surface to achieve the blood-brain barrier crossing, thus promoting the effective enrichment of potential anti-AD active drugs in the lesion. 13,14 In recent years, as the elaboration of more detailed crosstalk relationship of AD pathogenic targets, the application of nanocarriers to efficiently support multiple therapeutic components has become a mainstream, especially the diverse drug carrying potential of the nanocarriers exhibits great advantages in the combinational delivery of biological macromolecules and active compounds. Meanwhile, with the successive approval of Aβ monoclonal antibodies, more studies have focused on the limitations of current antibody therapies, and a variety of synthetic nanoparticles have recently been demonstrated to act as highly efficient Aβ "chaperones" to regulate Aβ aggregation or facilitate clearance, attempting to provide alternatives to Aβ antibodies. ...
Recent successive approval of anti-amyloid-β (Aβ) monoclonal antibodies as disease-modifying therapies against Alzheimer’s disease (AD) has raised great confidence in the development of anti-AD therapies; however, the current therapies still face the dilemma of significant adverse reactions and limited effects. In this review, we summarized the therapeutic characteristics of the approved anti-Aβ immunotherapies and dialectically analyzed the gains and losses from clinical trials. The review further proposed the reasonable selection of animal models in preclinical studies from the perspective of different animal models of Aβ deposition and deals in-depth with the recent advances of exploring preclinical nanomedical application in Aβ targeted therapy, aiming to provide a reliable systematic summary for the development of novel anti-Aβ therapies. Collectively, this review comprehensively dissects the pioneering work of Aβ-targeted therapies and proposed perspective insight into AD-modified therapies.
The evolution of nanotechnology-driven lipid and metalloid-based nanoformulations has garnered significant attention for developing effective drug delivery systems with position/time precision and efficacy. This study focuses on challenges of blood-brain barrier (BBB) and their pivotal role in drug targeting in chronic diseases such as brain tumors (BTs). These formulations encapsulate therapeutic agents within lipidic matrices, enhancing drug solubility, bioavailability, and targeted delivery. The diverse lipid materials used in these nanoformulations highlight their biocompatibility and versatility, covering a wide range of drugs. Emphasis is placed on metal nanoparticles, liposomes, ethosomes, quantum dots, carbon nanotubes, nanorobots, and micelles. The analysis explores their drug loading, stability, release characteristics, and bioavailability modulation. It also delves into the enhanced-permeability and retention (EPR) effect, crucial for passive targeting of tumors. Recent nanocarrier systems enable better penetration of therapeutic compounds through the BBB, addressing treatment failures in invasive BTs.This review highlights the latest nanotechnology developments and potential therapeutic approaches, serving as a valuable resource for researchers, clinicians, and pharmaceutical scientists.
Ultrasmall nanoparticles have a diameter between 1 and 3 nm at the border between nanoparticles and large molecules. Usually, their core consists of a metal, and the shell of a capping ligand with sulfur or phosphorus as binding atoms. While the core structure can be probed by electron microscopy, electron and powder diffraction, and single-crystal structure analysis for atom-sharp clusters, it is more difficult to analyze the ligand shell. In contrast to larger nanoparticles, ultrasmall nanoparticles cause only a moderate distortion of the NMR signal, making NMR spectroscopy a qualitative as well as a quantitative probe to assess the nature of the ligand shell. The application of isotope-labelled ligands and of two-dimensional NMR techniques can give deeper insight into ligand-nanoparticle interactions. Applications of one- and two-dimensional NMR spectroscopy to analyze ultrasmall nanoparticles are presented with suitable examples, including a critical discussion of the limitations of NMR spectroscopy on nanoparticles.
Solid nanoparticle‐mediated drug delivery systems are usually confined to nanoscale due to the enhanced permeability and retention effect. However, they remain a great challenge for malignant glioma chemotherapy because of poor drug delivery efficiency and insufficient tumor penetration resulting from the blood–brain barrier/blood–brain tumor barrier (BBB/BBTB). Inspired by biological microparticles (e.g., cells) with excellent adaptive deformation, it is demonstrated that the adaptive microdrugs (even up to 3.0 µm in size) are more efficient than their nanodrugs (less than 200 nm in size) to cross BBB/BBTB and penetrate into tumor tissues, achieving highly efficient chemotherapy of malignant glioma. The distinct delivery of the adaptive microdrugs is mainly attributed to the enhanced interfacial binding and endocytosis via adaptive deformation. As expected, the obtained adaptive microdrugs exhibit enhanced accumulation, deep penetration, and cellular internalization into tumor tissues in comparison with nanodrugs, significantly improving the survival rate of glioblastoma mice. It is believed that the bioinspired adaptive microdrugs enable them to efficiently cross physiological barriers and deeply penetrate tumor tissues for drug delivery, providing an avenue for the treatment of solid tumors.
The application of metal-based nanoparticles (mNPs) in cancer therapy and diagnostics (theranostics) has been a hot research topic since the early days of nanotechnology, becoming even more relevant in recent years. However, the clinical translation of this technology has been notably poor, with one of the main reasons being a lack of understanding of the disease and conceptual errors in the design of mNPs. Strikingly, throughout the reported studies to date on in vivo experiments, the concepts of “tumor targeting” and “tumor cell targeting” are often intertwined, particularly in the context of active targeting. These misconceptions may lead to design flaws, resulting in failed theranostic strategies. In the context of mNPs, tumor targeting can be described as the process by which mNPs reach the tumor mass (as a tissue), while tumor cell targeting refers to the specific interaction of mNPs with tumor cells once they have reached the tumor tissue. In this review, we conduct a critical analysis of key challenges that must be addressed for the successful targeting of either tumor tissue or cancer cells within the tumor tissue. Additionally, we explore essential features necessary for the smart design of theranostic mNPs, where ‘smart design’ refers to the process involving advanced consideration of the physicochemical features of the mNPs, targeting motifs, and physiological barriers that must be overcome for successful tumor targeting and/or tumor cell targeting.
Glioblastoma is one of the most aggressive and invasive types of brain cancer with a 5-year survival rate of 6.8%. With limited options, patients often have poor quality of life and are moved to palliative care after diagnosis. As a result, there is an extreme need for a novel theranostic method that allows for early diagnosis and noninvasive treatment as current peptide-based delivery standards may have off-target effects. Prussian Blue nanoparticles (PBNPs) have recently been investigated as photoacoustic imaging (PAI) and photothermal ablation agents. However, due to their inability to cross the blood–brain barrier (BBB), their use in glioblastoma treatment is limited. By utilizing a hybrid, biomimetic nanoparticle composed of a PBNP interior and a U-87 cancer cell-derived exosome coating (Exo:PB), we show tumor-specific targeting within the brain and selective thermal therapy potential due to the strong photoconversion abilities. Particle characterization was carried out and showed a complete coating around the PBNPs that contains exosome markers. In vitro cellular uptake patterns are similar to native U-87 exosomes and when exposed to an 808 nm laser, show localized cell death within the specified region. After intravenous injection of Exo:PB into subcutaneously implanted glioblastoma mice, they have shown effective targeting and eradication of tumor volume compared to PEG-coated PBNPs (PEG:PB). Through systemic administration of Exo:PB particles into orthotopic glioblastoma-bearing mice, the PBNP signal was detected in the brain tumor region through PAI. It was seen that Exo:PB had preferential tumor accumulation with less off-targeting compared to the RGD:PB control. Ex vivo analysis validated specific targeting with a direct overlay of Exo:PB with the tumor by both H&E staining and Ki67 labeling. Overall, we have developed a novel biomimetic material that can naturally cross the BBB and act as a theranostic agent for systemic targeting of glioblastoma tissue and photothermal therapeutic effect.
Brain disorders represent a significant challenge in medical science due to the formidable blood–brain barrier (BBB), which severely limits the penetration of conventional therapeutics, hindering effective treatment strategies. This review delves into the innovative realm of biomimetic nanodelivery systems, including stem cell‐derived nanoghosts, tumor cell membrane‐coated nanoparticles, and erythrocyte membrane‐based carriers, highlighting their potential to circumvent the BBB's restrictions. By mimicking native cell properties, these nanocarriers emerge as a promising solution for enhancing drug delivery to the brain, offering a strategic advantage in overcoming the barrier's selective permeability. The unique benefits of leveraging cell membranes from various sources is evaluated and advanced technologies for fabricating cell membrane‐encapsulated nanoparticles capable of masquerading as endogenous cells are examined. This enables the targeted delivery of a broad spectrum of therapeutic agents, ranging from small molecule drugs to proteins, thereby providing an innovative approach to neurocare. Further, the review contrasts the capabilities and limitations of these biomimetic nanocarriers with traditional delivery methods, underlining their potential to enable targeted, sustained, and minimally invasive treatment modalities. This review is concluded with a perspective on the clinical translation of these biomimetic systems, underscoring their transformative impact on the therapeutic landscape for intractable brain diseases.
The precise targeted delivery of therapeutic agents to deep regions of the brain is crucial for the effective treatment of various neurological diseases. However, achieving this goal is challenging due to the presence of the blood‒brain barrier (BBB) and the complex anatomy of the brain. Here, a biomimetic self‐propelled nanomotor with cascade targeting capacity is developed for the treatment of neurological inflammatory diseases. The self‐propelled nanomotors are designed with biomimetic asymmetric structures with a mesoporous SiO2 head and multiple MnO2 tentacles. Macrophage membrane biomimetic modification endows nanomotors with inflammatory targeting and BBB penetration abilities The MnO2 agents catalyze the degradation of H2O2 into O2, not only by reducing brain inflammation but also by providing the driving force for deep brain penetration. Additionally, the mesoporous SiO2 head is loaded with curcumin, which actively regulates macrophage polarization from the M1 to the M2 phenotype. All in vitro cell, organoid model, and in vivo animal experiments confirmed the effectiveness of the biomimetic self‐propelled nanomotors in precise targeting, deep brain penetration, anti‐inflammatory, and nervous system function maintenance. Therefore, this study introduces a platform of biomimetic self‐propelled nanomotors with inflammation targeting ability and active deep penetration for the treatment of neurological inflammation diseases.
A novel micro-photoelectrode with selective molecular sieve was created for in vivo monitoring of O2 levels in mouse brain. The ITO optical fiber modified by graphitized carbon nitride (g-C3N4) in...
The blood-brain barrier (BBB) contains tightly connected brain microvascular endothelial cells (BMECs) that hinder drug delivery to the brain, which makes brain tumors difficult to treat. Previous studies have shown that nanoparticles coated with tumor cell membranes selectively target their homologous tumors. Therefore, this study investigated whether bEnd.3-line BMEC membrane-coated nanoparticles with poly(lactide-co-glycolide)-poly(ethylene glycol)-based doxorubicin-loaded cores (BM-PDs) can be used to target BMECs and cross the BBB. In vitro, the BM-PDs effectively target BMECs and cross a BBB model. The BM-PDs enter the BMECs via macropinocytosis, clathrin-mediated endocytosis, caveolin-mediated endocytosis, and membrane fusion, which result in excellent cellular uptake. The BM-PDs also show excellent cellular uptake in brain tumor cells. In vivo, the BM-PDs target BMECs, cross the BBB, accumulate in brain tumors, and efficiently kill tumor cells. Therefore, the proposed strategy has great therapeutic potential owing to its ability to cross the BBB to reach brain tumors.
Parkinson's disease (PD) is currently the second most incurable central neurodegenerative disease resulting from various pathogenesis. As the “energy factory” of cells, mitochondria play an extremely important role in supporting neuronal signal transmission and other physiological activities. Mitochondrial dysfunction can cause and accelerate the occurrence and progression of PD. How to effectively prevent and suppress mitochondrial disorders is a key strategy for the treatment of PD from the root. Therefore, the emerging mitochondria‐targeted therapy has attracted considerable interest. Herein, the relationship between mitochondrial dysfunction and PD, the causes and results of mitochondrial dysfunction, and major strategies for ameliorating mitochondrial dysfunction to treat PD are systematically reviewed. The study also prospects the main challenges for the treatment of PD.
The application of nanomedicines for glioblastoma (GBM) therapy is hampered by the blood–brain barrier (BBB) and the dense glioblastoma tissue. To achieve efficient BBB crossing and deep GBM penetration, this work demonstrates a strategy of active transcellular transport of a mitochondrion‐disturbing nanomedicine, pGBEMA22‐b‐pSSPPT9 (GBEPPT), in the GBM tissue through mitocytosis. GBEPPT is computer‐aided designed and prepared by self‐assembling a conjugate of an amphiphilic block polymer and a drug podophyllotoxin (PPT). When GBEPPT is delivered to the tumor site, overexpressed γ‐glutamyl transpeptidase (GGT) on the brain–blood endothelial cell, or the GBM cell triggered enzymatic hydrolysis of γ‐glutamylamide on GBEPPT to reverse its negative charge to positive. Positively charged GBEPPT rapidly enter into the cell and target the mitochondria. These GBEPPT disturb the homeostasis of mitochondria, inducing mitocytosis‐mediated extracellular transport of GBEPPT to the neighboring cells via mitosomes. This intracellular‐to‐intercellular delivery cycle allows GBEPPT to penetrate deeply into the GBM parenchyma, and exert sustainable action of PPT released from GBEPPT on the tumor cells along its penetration path at the tumor site, thus improving the anti‐GBM effect. The process of mitocytosis mediated by the mitochondrion‐disturbing nanomedicine may offer great potential in enhancing drug penetration through malignant tissues, especially poorly permeable solid tumors.
Vaccines have proven effective in the treatment and prevention of numerous diseases. However, traditional attenuated and inactivated vaccines suffer from certain drawbacks such as complex preparation, limited efficacy, potential risks and others. These limitations restrict their widespread use, especially in the face of an increasingly diverse range of diseases. With the ongoing advancements in genetic engineering vaccines, DNA vaccines have emerged as a highly promising approach in the treatment of both genetic diseases and acquired diseases. While several DNA vaccines have demonstrated substantial success in animal models of diseases, certain challenges need to be addressed before application in human subjects. The primary obstacle lies in the absence of an optimal delivery system, which significantly hampers the immunogenicity of DNA vaccines. We conduct a comprehensive analysis of the current status and limitations of DNA vaccines by focusing on both viral and non-viral DNA delivery systems, as they play crucial roles in the exploration of novel DNA vaccines. We provide an evaluation of their strengths and weaknesses based on our critical assessment. Additionally, the review summarizes the most recent advancements and breakthroughs in pre-clinical and clinical studies, highlighting the need for further clinical trials in this rapidly evolving field.
Brain infections, frequently accompanied by significant inflammation, necessitate comprehensive therapeutic approaches targeting both infections and associated inflammation. A major impediment to such combined treatment is the blood–brain barrier (BBB), which significantly restricts therapeutic agents from achieving effective concentrations within the central nervous system. Here, a neutrophil‐centric dual‐responsive delivery system, coined “CellUs,” is pioneered. This system is characterized by live neutrophils enveloping liposomes of dexamethasone, ceftriaxone, and oxygen‐saturated perfluorocarbon (Lipo@D/C/P). CellUs is meticulously engineered to co‐deliver antibiotics, anti‐inflammatory agents, and oxygen, embodying a comprehensive strategy against brain infections. CellUs leverages the intrinsic abilities of neutrophils to navigate through BBB, accurately target infection sites, and synchronize the release of Lipo@D/C/P with local inflammatory signals. Notably, the incorporation of ultrasound‐responsive perfluorocarbon within Lipo@D/C/P ensures the on‐demand release of therapeutic agents at the afflicted regions. CellUs shows considerable promise in treating Staphylococcus aureus infections in mice with meningitis, particularly when combined with ultrasound treatments. It effectively penetrates BBB, significantly eliminates bacteria, reduces inflammation, and delivers oxygen to the affected brain tissue, resulting in a substantial improvement in survival rates. Consequently, CellUs harnesses the natural chemotactic properties of neutrophils and offers an innovative pathway to improve treatment effectiveness while minimizing adverse effects.
Brain tumors pose unique challenges for conventional therapies. Tumor heterogeneity and drug resistance hinder chemotherapy, while ill-defined tumor boundaries and the fragility of surrounding brain tissue limit surgical resection. Glioblastoma (GBM), the most common primary brain tumor, is an aggressive astrocyte-derived malignancy that exemplifies these characteristics. This chapter examines natural molecules as a potential means to mitigate or overcome the challenges of GBM therapy. Dietary natural molecules exert anti-GBM effects by enhancing apoptosis and autophagy, inducing cell cycle arrest, interfering with tumor metabolism, and inhibiting proliferation, neuroinflammation, chemoresistance, angiogenesis, and metastasis. Although these beneficial effects are promising, natural molecules’ efficacy in GBM remains constrained by their bioavailability and blood–brain barrier permeability; various chemical formulations are proposed to improve these properties. Many natural molecules are available in over-the-counter dietary supplements, underscoring their clinical potential. However, clinical trials are necessary to substantiate these molecules’ in vitro and in vivo properties.
The blood–brain barrier (BBB) is a tailored system of capillary endothelial cells intermixed with tight junctions and adherent junctions that regulates the transport of various materials and substances between the blood vasculature and the central nervous system (CNS). However, in cases of brain diseases, BBB's protective and regulatory effects hamper therapeutics from reaching affected sites in sufficient quantities. This has so far been a leading challenge in treating CNS diseases and disorders. For this problem to be overcome, recent research has sought to develop novel modalities to achieve efficient therapy and alleviate associated symptoms. Therefore, numerous strategies have operated in recent years to address the limitations of traditional and invasive methods, including poor brain penetration and serious side effects. As a desperately in‐demand technology, nanotheranostics has particularly shown promising results. Herein, this review reports recent advancements in CNS nanotheranostics and novel techniques and nanotechnology‐based strategies developed for treating neurodegenerative disorders. The study provides comprehensive data on the subject to be used for future studies for the therapy and management of CNS disorders and diseases.
Brain tumors, including primary gliomas and brain metastases, are one of the deadliest tumors because effective macromolecular antitumor drugs cannot easily penetrate the blood-brain barrier (BBB) and blood-brain tumor barrier (BTB). Magnetic nanoparticles (MNPs) are considered the most suitable nanocarriers for the delivery of brain tumor drugs because of their unique properties compared to other nanoparticles. Numerous preclinical and clinical studies have demonstrated the potential of these nanoparticles in magnetic targeting, nuclear magnetic resonance, magnetic thermal therapy, and ultrasonic hyperthermia. To further develop and optimize MNPs for the diagnosis and treatment of brain tumors, we attempt to outline recent advances in the use of MNPs to deliver drugs, with a particular focus on their efficacy in the delivery of anti-brain tumor drugs based on magnetic targeting and low-intensity focused ultrasound, magnetic resonance imaging for surgical real-time guidance, and magnetothermal and ultrasonic hyperthermia therapy. Furthermore, we summarize recent findings on the clinical application of MNPs and the research limitations that need to be addressed in clinical translation.
Acute encephalitis is a brain infection that can harm the nervous system if not recognized and treated promptly. However, the presence of the blood–brain barrier restricts therapeutic agent distribution from the bloodstream to the brain parenchyma, severely restricting effective therapy for this disease. Herein, a novel drug delivery system based on a macrophage (RAW 264.7 cells) artifactual diagnostic and therapeutic nanoparticles (IPD@RAW) drug‐loading approach is presented, which exploits RAW cells' ability to cross the blood–brain barrier and go toward inflammation, and efficiently realizes the targeted enrichment of diagnostic and therapeutic nanoparticles at the site of inflammation in the brain. This nano‐drug‐carrying technology can accurately depict the degree of inflammation in real time for an extended period due to the significant penetration depth and high signal‐to‐noise ratio of near‐infrared (NIR) imaging. Meanwhile, the modified polydopamine can trigger the controlled release of anti‐inflammatory drugs through photothermal conversion under NIR irradiation to reduce the expression of cellular inflammatory factors, such as TNF‐α, IL‐6, and IL‐1β, and alleviate the brain damage due to secretion of this inflammatory factor. As a result, this drug delivery system provides a reliable tool for overcoming the blood–brain barrier to achieve early diagnosis and treatment of acute encephalitis.
As the second-leading cause of human death, cancer has drawn attention to the area of biomedical research and therapy from all around the world. Certainly, the development of nanotechnology has...
Blood‐brain‐barrier (BBB) serves as a fatal guard of the central nervous system as well as a formidable obstacle for the treatment of brain diseases such as brain tumors. Cell membrane‐derived nanomedicines are promising drug carriers to achieve BBB‐penetrating and brain lesion targeting. However, the challenge of precise size control of such nanomedicines has severely limited their therapeutic effect and clinical application in brain diseases. To address this problem, this work develops a microfluidic mixing platform that enables the fabrication of cell membrane‐derived nanovesicles with precise controllability and tunability in particle size and component. Sub‐100 nm macrophage plasma membrane‐derived vesicles as small as 51 nm (nanoscale macrophage vesicles, NMVs), with a narrow size distribution (polydispersity index, PDI: 0.27) and a high drug loading rate (up to 89% for indocyanine green‐loaded NMVs, NMVs@ICG (ICG is indocyanine green)), are achieved through a one‐step process. Compared to beyond‐100 nm macrophage cell membrane vesicles (general macrophage vesicles, GMVs) prepared via the traditional methods, the new NMVs exhibits rapid (within 1 h post‐injection) and enhanced orthotopic glioma targeting (up to 78% enhancement), with no extra surface modification. This work demonstrates the great potential of such real‐nanoscale cell membrane‐derived nanomedicines in targeted brain tumor theranostics.
2D nanomaterials have attracted broad interest in the field of biomedicine owing to their large surface area, high drug‐loading capacity, and excellent photothermal conversion. However, few studies report their “enzyme‐like” catalytic performance because it is difficult to prepare enzymatic nanosheets with small size and ultrathin thickness by current synthetic protocols. Herein, a novel one‐step wet‐chemical method is first proposed for protein‐directed synthesis of 2D MnO2 nanosheets (M‐NSs), in which the size and thickness can be easily adjusted by the protein dosage. Then, a unique sono‐chemical approach is introduced for surface functionalization of the M‐NSs with high dispersity/stability as well as metal‐cation‐chelating capacity, which can not only chelate ⁶⁴Cu radionuclides for positron emission tomography (PET) imaging, but also capture the potentially released Mn²⁺ for enhanced biosafety. Interestingly, the resulting M‐NS exhibits excellent enzyme‐like activity to catalyze the oxidation of glucose, which represents an alternative paradigm of acute glucose oxidase for starving cancer cells and sensitizing them to thermal ablation. Featured with outstanding phototheranostic performance, the well‐designed M‐NS can achieve effective photoacoustic‐imaging‐guided synergistic starvation‐enhanced photothermal therapy. This study is expected to establish a new enzymatic phototheranostic paradigm based on small‐sized and ultrathin M‐NSs, which will broaden the application of 2D nanomaterials.
Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths that will occur in the United States and compiles the most recent data on cancer incidence, mortality, and survival. Incidence data, available through 2015, were collected by the Surveillance, Epidemiology, and End Results Program; the National Program of Cancer Registries; and the North American Association of Central Cancer Registries. Mortality data, available through 2016, were collected by the National Center for Health Statistics. In 2019, 1,762,450 new cancer cases and 606,880 cancer deaths are projected to occur in the United States. Over the past decade of data, the cancer incidence rate (2006‐2015) was stable in women and declined by approximately 2% per year in men, whereas the cancer death rate (2007‐2016) declined annually by 1.4% and 1.8%, respectively. The overall cancer death rate dropped continuously from 1991 to 2016 by a total of 27%, translating into approximately 2,629,200 fewer cancer deaths than would have been expected if death rates had remained at their peak. Although the racial gap in cancer mortality is slowly narrowing, socioeconomic inequalities are widening, with the most notable gaps for the most preventable cancers. For example, compared with the most affluent counties, mortality rates in the poorest counties were 2‐fold higher for cervical cancer and 40% higher for male lung and liver cancers during 2012‐2016. Some states are home to both the wealthiest and the poorest counties, suggesting the opportunity for more equitable dissemination of effective cancer prevention, early detection, and treatment strategies. A broader application of existing cancer control knowledge with an emphasis on disadvantaged groups would undoubtedly accelerate progress against cancer.
Photoacoustic (PA) imaging as a fast‐developing imaging technique has great potential in biomedical and clinical applications. It is a noninvasive imaging modality that depends on the light‐absorption coefficient of the imaged tissue and the injected PA‐imaging contrast agents. Furthermore, PA imaging provides superb contrast, super spatial resolution, and high penetrability and sensitivity to tissue functional characteristics by detecting the acoustic wave to construct PA images. In recent years, a series of PA‐imaging contrast agents are developed to improve the PA‐imaging performance in biomedical applications. Here, recent progress of PA contrast agents and their biomedical applications are outlined. PA contrast agents are classified according to their components and function, and gold nanocrystals, gold‐nanocrystal assembly, transition‐metal chalcogenides/MXene‐based nanomaterials, carbon‐based nanomaterials, other inorganic imaging agents, small organic molecules, semiconducting polymer nanoparticles, and nonlinear PA‐imaging contrast agents are discussed. The applications of PA contrast agents as biosensors (in the sensing of metal ions, pH, enzymes, temperature, hypoxia, reactive oxygen species, and reactive nitrogen species) and in bioimaging (lymph nodes, vasculature, tumors, and brain tissue) are discussed in detail. Finally, an outlook on the future research and investigation of PA‐imaging contrast agents and their significance in biomedical research is presented.
Delivery of imaging reagents and drugs to tumors is essential for cancer diagnosis and therapy. In addition to therapeutic and diagnostic functionalities, peptides have potential benefits such as biocompatibility, ease to synthesize, smaller size, by-passing off-target side effects, and achieving the beneficial effects with lower-administered dosages. A particular type of peptide known as cell penetrating peptides (CPP) have been predominantly studied during last twenty years as they are not only capable to translocate themselves across membranes but also allow carrier drugs to translocate across plasma membrane, by different mechanisms depending on the CPP. This is of great potential importance in drug delivery systems, as the ability to pass across membranes is crucial to many drug delivery systems. In spite of significant progress in design and application of CPP, more investigations are required to further improve their delivery to tumors, with reduced side-effect and enhanced therapeutic efficacy. In this review, we emphasis on current advancements in preclinical and clinical trials based on using CPP for more efficient delivery of anti-cancer drugs and imaging reagents to cancer tissues and individual cells associated with them. We discuss the evolution of the CPPs-based strategies for targeted delivery, their current status and strengths, along with summarizing the role of CPPs in targeted drug delivery. We also discuss some recently reported diagnostic applications of engineered protease-responsive substrates and activable imaging complexes. We highlight the recent clinical trial data by providing a road map for better design of the CPPs for future preclinical and clinical applications. © Tripathi et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Cell-based drug delivery systems have shown promising capability for tumor-targeted therapy owing to the intrinsic tumor-homing and drug-carrying property of some living cells. However, imaging tracking of their migration and bio-effects is urgently needed for clinical application, especially for glioma. Here, we report the inflammation-activatable engineered neutrophils by internalizing doxorubicin-loaded magnetic mesoporous silica nanoparticles (ND-MMSNs) which can provide the potential for magnetic resonance (MR) imaging tracking of the drug-loaded cells to actively target inflamed brain tumor after surgical resection of primary tumor. The phagocytized D-MMSNs possess high drug loading efficiency and do not affect the host neutrophils’ viability, thus remarkably improving intratumoral drug concentration and delaying relapse of surgically treated glioma. Our study offers a new strategy in targeted cancer theranostics through combining the merits of living cells and nanoparticle carriers.
Featured with large surface area, uniform interpenetrating mesopores, diverse organic framework hybridization, and well-defined surface properties, the hollow mesoporous organosilica nanoparticle (HMON) represents a promising paradigm of drug delivery system with excellent biocompatibility. However, effective tumor accumulation and precise cancer theranostics of the HMON still remain a challenge. In this study, an “ammonia-assisted hot water etching” method is applied for the successful construction of sub-50 nm thioether/phenylene dual-hybridized HMON with low hemolytic effect. Particularly, the surface modification with Mo(VI)-based polyoxometalate (POM) clusters drives the self-assembly of HMON in the mild acidic tumor microenvironment (TME) to achieve enhanced tumor retention and accumulation. More importantly, the reducibility-activated Mo(VI)-to-Mo(V) conversion within POM not only endows the POM-anchored HMON with outstanding TME-responsive photoacoustic (PA) imaging contrast and photothermal therapy (PTT) performance, but also plays an indispensable role in controllably triggering the decomposition of the Mn2(CO)10 payload for CO release, which gives rise to remarkable synergistic PTT-enhanced CO gas therapy for complete tumor eradication. By harnessing the unique acidic and redox properties of TME, the judiciously designed smart POM-anchored HMON nanoplatform is expected to act as a “magic bomb” to selectively destroy cancer without damaging normal tissues. This nanoplatform holds significant potential in realizing TME-responsive self-assembly for enhanced tumor accumulation and precise tumor-specific synergistic therapy, which is very promising for clinical translation.
2D materials are considered as intriguing building blocks for next‐generation optoelectronic devices. However, their photoresponse performance still needs to be improved for practical applications. Here, ultrasensitive 2D phototransistors are reported employing chemical vapor deposition (CVD)‐grown 2D Bi2O2Se transferred onto silicon substrates with a noncorrosive transfer method. The as‐transferred Bi2O2Se preserves high quality in contrast to the serious quality degradation in hydrofluoric‐acid‐assisted transfer. The phototransistors show a responsivity of 3.5 × 10⁴ A W⁻¹, a photoconductive gain of more than 10⁴, and a time response in the order of sub‐millisecond. With back gating of the silicon substrate, the dark current can be reduced to several pA. This yields an ultrahigh sensitivity with a specific detectivity of 9.0 × 10¹³ Jones, which is one of the highest values among 2D material photodetectors and two orders of magnitude higher than that of other CVD‐grown 2D materials. The high performance of the phototransistor shown here together with the developed unique transfer technique are promising for the development of novel 2D‐material‐based optoelectronic applications as well as integrating with state‐of‐the‐art silicon photonic and electronic technologies.
Treatment of malignant glioma is a challenge facing cancer therapy. In addition to surgery, and chemotherapy, radiotherapy (RT) is one of the most effective modalities of glioma treatment. However, there are two crucial challenges for RT facing malignant glioma therapy: first, gliomas are known to be resistant to radiation due to their intratumoral hypoxia; second, radiosensitizers may exhibit a lack of target specificity, which may cause a lower concentration of radiosensitizers in tumors and toxic side effects in normal tissues. Thus, novel angiopep-2-lipid-poly-(metronidazoles)n (ALP-(MIs)n) hypoxic radiosensitizer-polyprodrug nanoparticles (NPs) were designed to enhance the radiosensitizing effect on gliomas.
Methods: In this study, different degrees and biodegradabilites of hypoxic radiosensitizer MIs-based polyprodrug (P-(MIs)n) were synthesized as a hydrophobic core. P-(MIs)n were mixed with DSPE-PEG2000, angiopep-2-DSPE-PEG2000 and lecithin to self-assemble ALP-(MIs)n through a single-step nanoprecipitation method. The ALP-(MIs)n encapsulate doxorubicin (DOX) (ALP-(MIs)n/DOX) and provoke the release of DOX under hypoxic conditions for glioma chemo- and radiotherapy. In vivo glioma targeting was tested in an orthotopic glioma using live animal fluorescence/bioluminescence imaging. The effect on sensitization to RT of ALP-(MIs)n and the combination of chemotherapy and RT of ALP-(MIs)n/DOX for glioma treatment were also investigated both in vitro and in vivo.
Results: ALP-(MIs)n/DOX effectively accumulated in gliomas and could reach the hypoxic glioma site after systemic in vivo administration. These ALP-(MIs)n showed a significant radiosensitizing effect on gliomas and realized combination chemotherapy and RT for glioma treatment both in vitro and in vivo.
Conclusions: In summary, we constructed a lipid-poly-(hypoxic radiosensitized polyprodrug) nanoparticles for enhancing the RT sensitivity of gliomas and achieving the combination of radiation and chemotherapy for gliomas.
Malignant glioblastoma (GBM) is the most aggressive brain cancer that has a very low survival rate. With the rapid development of nanotechnology in the past few decades, the use of nanoparticles (NPs) for nucleic acid delivery is expected to have a revolutionary impact on GBM therapy. However, clinical success in GBM therapy remains a formidable challenge, mainly due to suboptimal in vivo delivery of therapeutics to glioma cells. Herein, we developed an aptamer-like peptide (aptide)-decorated liposomal nanoplatform for systemic small interfering RNA (siRNA) delivery and targeted GBM therapy. This nanoplatform is mainly composed of the following key components: (i) classic liposome structure with an aqueous core that can encapsulate therapeutic siRNA; (ii) hydrophilic polyethylene glycol (PEG) chains on the outer shell to prolong blood circulation; and (iii) surface-encoded aptide to specifically target the extra-domain B (EDB) of fibronectin that over-expressed on glioma cells. After systemic administration of these new siRNA delivery NPs, they can target the glioma cells and efficiently inhibit the GBM tumor growth by silencing the expression of cyclophilin A (CypA), which is up-regulated in brain cancer and plays an important role in malignant transformation of brain cancer and maintaining glioma cell stemness. These results suggest that the reported RNA interference (RNAi) NP platform herein could become an effective tool for targeted GBM therapy.
Background
Mesenchymal stem cells (MSCs) possess inherent tropism towards tumor cells, and so have attracted increased attention as targeted-therapy vehicles for glioma treatment.
Purpose
The objective of this study was to demonstrate the injection of MSCs loaded with paclitaxel (Ptx)-encapsulated poly(d,l-lactide-co-glycolide) (PLGA) nanoparticles (NPs) for orthotopic glioma therapy in rats.
Methods
Ptx-PLGA NP-loaded MSC was obtained by incubating MSCs with Ptx-PLGA NPs. The drug transfer and cytotoxicity of Ptx-PLGA NP-loaded MSC against tumor cells were investigated in the transwell system. Biodistribution and antitumor activity was evaluated in the orthotopic glioma rats after contralateral injection.
Results
The optimal dose of MSC-loaded Ptx-PLGA NPs (1 pg/cell Ptx) had little effect on MSC-migration capacity, cell cycle, or multilineage-differentiation potential. Compared with Ptx-primed MSCs, Ptx-PLGA NP-primed MSCs had enhanced sustained Ptx release in the form of free Ptx and Ptx NPs. Ptx transfer from MSCs to glioma cells could induce tumor cell death in vitro. As for distribution in vivo, NP-loaded fluorescent MSCs were tracked throughout the tumor mass for 2 days after therapeutic injection. Survival was significantly longer after contralateral implantation of Ptx-PLGA NP-loaded MSCs than those injected with Ptx-primed MSCs or Ptx-PLGA NPs alone.
Conclusion
Based on timing and sufficient Ptx transfer from the MSCs to the tumor cells, Ptx-PLGA NP-loaded MSC is effective for glioma treatment. Incorporation of chemotherapeutic drug-loaded NPs into MSCs is a promising strategy for tumor-targeted therapy.
Drug delivery by nanocarriers (NCs) has long been stymied by dominant liver uptake and limited target organ deposition, even when NCs are targeted using affinity moieties. Here we report a universal solution: red blood cell (RBC)-hitchhiking (RH), in which NCs adsorbed onto the RBCs transfer from RBCs to the first organ downstream of the intravascular injection. RH improves delivery for a wide range of NCs and even viral vectors. For example, RH injected intravenously increases liposome uptake in the first downstream organ, lungs, by ~40-fold compared with free NCs. Intra-carotid artery injection of RH NCs delivers >10% of the injected NC dose to the brain, ~10× higher than that achieved with affinity moieties. Further, RH works in mice, pigs, and ex vivo human lungs without causing RBC or end-organ toxicities. Thus, RH is a clinically translatable platform technology poised to augment drug delivery in acute lung disease, stroke, and several other diseases.
Engineered nanoparticles offer the chance to improve drug transport and delivery through biological barriers, exploiting the possibility to leave the blood circulation and traverse the endothelial vascular bed, blood-brain barrier (BBB) included, to reach their target. It is known that nanoparticles gather molecules on their surface upon contact with biological fluids, forming the “protein corona”, which can affect their fate and therapeutic/diagnostic performance, yet no information its evolution across the barrier has been gathered so far. Using a cellular model of the BBB and gold nanoparticles, we show that the composition of the corona undergoes dramatic quantitative and qualitative molecular modifications during passage from the “blood” to the “brain” side, while it is stable once beyond the BBB. Thus, for the first time, we show that the nanoparticle corona dynamically and drastically evolves upon crossing the BBB, and that its initial composition is not predictive of nanoparticle fate and performance once beyond the barrier at the target organ.
Effective treatment for glioblastoma (GBM) is limited by the presence of the blood-brain barrier (BBB) and rapid resistance to single agent therapies. To address these issues, we developed a transferrin-functionalized nanoparticle (Tf-NP) that can deliver dual combination therapies. Using intravital imaging, we show the ability of Tf-NPs to traverse intact BBB in mice as well as achieve direct tumor binding in two intracranial orthotopic models of GBM. Treatment of tumor-bearing mice with Tf-NPs loaded with temozolomide and the bromodomain inhibitor JQ1 leads to increased DNA damage and apoptosis that correlates with a 1.5- to 2-fold decrease in tumor burden and corresponding increase in survival compared to equivalent free-drug dosing. Immunocompetent mice treated with Tf-NP-loaded drugs also show protection from the effects of systemic drug toxicity, demonstrating the preclinical potential of this nanoscale platform to deliver novel combination therapies to gliomas and other central nervous system tumors.
Nanoparticles have enormous applications in textiles, cosmetics, electronics, and pharmaceuticals. But due to their exceptional physical and chemical properties, particularly antimicrobial, anticancer, antibacterial, anti-inflammatory properties, nanoparticles have many potential applications in diagnosis as well as in the treatment of various diseases. Over the past few years, nanoparticles have been extensively used to investigate their response on the neuronal cells. These nanoparticles cause stem cells to differentiate into neuronal cells and promote neuronal cell survivability and neuronal cell growth and expansion. The nanoparticles have been tested both in in vitro and in vivo models. The nanoparticles with various shapes, sizes, and chemical compositions mostly produced stimulatory effects on neuronal cells, but there are few that can cause inhibitory effects on the neuronal cells. In this review, we discuss stimulatory and inhibitory effects of various nanoparticles on the neuronal cells. The aim of this review was to summarize different effects of nanoparticles on the neuronal cells and try to understand the differential response of various nanoparticles. This review provides a bird’s eye view approach on the effects of various nanoparticles on neuronal differentiation, neuronal survivability, neuronal growth, neuronal cell adhesion, and functional and behavioral recovery. Finally, this review helps the researchers to understand the different roles of nanoparticles (stimulatory and inhibitory) in neuronal cells to develop effective therapeutic and diagnostic strategies for neurodegenerative diseases.
Background
Demarcation of malignant brain tumor boundaries is critical to achieve complete resection and to improve patient survival. Contrast-enhanced brain magnetic resonance imaging (MRI) is the gold standard for diagnosis and pre-surgical planning, despite limitations of gadolinium (Gd)-based contrast agents to depict tumor margins. Recently, solid metal-based nanoparticles (NPs) have shown potential as diagnostic probes for brain tumors. Gold nanoparticles (GNPs) emerged among those, because of their unique physical and chemical properties and biocompatibility. The aim of the present study is to review the application of GNPs for in vitro and in vivo brain tumor diagnosis.
Methods
We performed a PubMed search of reports exploring the application of GNPs in the diagnosis of brain tumors in biological models including cells, animals, primates, and humans. The search words were “gold” AND “NP” AND “brain tumor.” Two reviewers performed eligibility assessment independently in an unblinded standardized manner. The following data were extracted from each paper: first author, year of publication, animal/cellular model, GNP geometry, GNP size, GNP coating [i.e., polyethylene glycol (PEG) and Gd], blood-brain barrier (BBB) crossing aids, imaging modalities, and therapeutic agents conjugated to the GNPs.
Results
The PubMed search provided 100 items. A total of 16 studies, published between the 2011 and 2017, were included in our review. No studies on humans were found. Thirteen studies were conducted in vivo on rodent models. The most common shape was a nanosphere (12 studies). The size of GNPs ranged between 20 and 120 nm. In eight studies, the GNPs were covered in PEG. The BBB penetration was increased by surface molecules (nine studies) or by means of external energy sources (in two studies). The most commonly used imaging modalities were MRI (four studies), surface-enhanced Raman scattering (three studies), and fluorescent microscopy (three studies). In two studies, the GNPs were conjugated with therapeutic agents.
Conclusion
Experimental studies demonstrated that GNPs might be versatile, persistent, and safe contrast agents for multimodality imaging, thus enhancing the tumor edges pre-, intra-, and post-operatively improving microscopic precision. The diagnostic GNPs might also be used for multiple therapeutic approaches, namely as “theranostic” NPs.
Difficulty in visualizing glioma margins intraoperatively remains a major issue in the achievement of gross total tumor resection and, thus, better clinical outcome of glioblastoma (GBM) patients. Here, the potential of a new combined optical + optoacoustic imaging method for intraoperative brain tumor delineation is investigated. A strategy using a newly developed gold nanostar synthesis method, Raman reporter chemistry, and silication method to produce dual‐modality contrast agents for combined surface‐enhanced resonance Raman scattering (SERRS) and multispectral optoacoustic tomography (MSOT) imaging is devised. Following intravenous injection of the SERRS‐MSOT‐nanostars in brain tumor bearing mice, sequential MSOT imaging is performed in vivo and followed by Raman imaging. MSOT is able to accurately depict GBMs three‐dimensionally with high specificity. The MSOT signal is found to correlate well with the SERRS images. Because SERRS enables uniquely sensitive high‐resolution surface detection, it could represent an ideal complementary imaging modality to MSOT, which enables real‐time, deep tissue imaging in 3D. This dual‐modality SERRS‐MSOT‐nanostar contrast agent reported here is shown to enable high precision depiction of the extent of infiltrating GBMs by Raman‐ and MSOT imaging in a clinically relevant murine GBM model and could pave new ways for improved image‐guided resection of brain tumors.
Fluoromagnetic systems are recognized as an emerging class of materials with great potential in the biomedical field. Here, it is shown how to fabricate fluoromagnetic nanotubes that can serve as multimodal probes for the imaging and targeting of brain cancer. An ionic self-assembly strategy is used to functionalize the surface of synthetic chrysotile nanotubes with pH-sensitive fluorescent chromophores and ferromagnetic nanoparticles. The acquired magnetic properties permit their use as contrast agent for magnetic resonance imaging, and enable the tracking of tumor cell migration and infiltration responsible for metastatic growth and disease recurrence. Their organic component, changing its fluorescence attitude as a function of local pH, targets the cancer distinctive acidity, and allows localizing and monitoring the tumor occurrence and progression by mapping the acidic spatial distribution within biopsy tissues. The fluoromagnetic properties of nanotubes are preserved from the in vitro to the in vivo condition and they show the ability to migrate across the blood brain barrier, thus spontaneously reaching the brain tumor after injection. The simplicity of the synthesis route of these geomimetic nanomaterials combined with their demonstrated affinity with the in vivo condition strongly highlights their potential for developing effective functional materials for multimodal theranostics of brain cancer.
Tumor adaptive treatment tolerance associated with chemotherapy originates from low tumor accumulation and adverse effects and remains a formidable challenge for cancer therapy. Herein, human serum albumin (HSA)-based nanomedicines modified with diazirine and loaded with indocyanine green (ICG) and tirapazamine (TPZ), denoted as ICG/TPZ@HSA dNMs are developed. The obtained ICG/TPZ@HSA dNMs can efficiently eradicate the tumors through a cascade of synergistic events triggered by the sequential irradiation of lasers in the tumor area. Upon a 405 nm laser irradiation, the ICG/TPZ@HSA dNMs are able to form aggregates via crosslinking and thus realized enhanced tumor site accumulation and prolonged retention time. The following irradiation at tumor area with an 808 nm laser-generated local hyperthermia and reactive oxygen species, which results in efficient tumor ablation and increased local hypoxia in the tumor microenvironment. The resulted local hypoxia further activates the initially nontoxic TPZ to a highly cytotoxic derivative, by which precisely bioactivated chemotherapy is achieved following the phototherapy. Thus, upon the laser irradiations, a cascade of aggregation, phototherapy, and bioactivated chemotherapy is successfully triggered, which achieves efficient precise eradication of tumors without detectable side effects in vivo.
Objective:
To evaluate the feasibility of visualizing bone marrow-derived human mesenchymal stem cells (MSCs) labeled with a gold-coated magnetic resonance (MR)-active multifunctional nanoparticle (SPIO@Au) for assessing the extent of MSC homing in glioma- bearing mice following carotid artery MSC injection.
MATERIALS AND METHODS: Nanoparticle containing superparamagnetic iron oxide coated with gold (SPIO@Au) having a diameter of ~82 nm and maximum absorbance in the near infrared (NIR) region was synthesized. Bone marrow-derived mesenchymal stem cells (MSCs) conjugated with GFP were successfully labeled with SPIO@Au at 4 μg/mL, and injected via the internal carotid artery of six mice bearing orthotopic U87 tumor. Unlabeled MSCs were used as control. The ability of SPIO@Au-loaded MSCs to be imaged using magnetic resonance (MR) and photoacoustic (PA) imaging at t = 0 h, t=2 h, 24 h, and 72 h was accomplished using a 7T Bruker Biospec Experimental MR Scanner and Vevo LAZR PAT Imaging System with a 5 ns laser as the excitation source, respectively. Histological analysis of the brain was done at t = 72 h post-injection via GFP fluorescence, Prussian Blue, and hematoxylin/eosin (H&E) staining.
RESULTS: MSCs labeled with SPIO@Au at 4 ug/mL did not show cell death nor any adverse effects on differentiation or migration. After SPIO@Au-loaded MSC injection, the PA signal in the tumor was clearly more enhanced compared to the tumor injected with MSCs alone at t = 72 h. Using the same mice, T2-weighted MR imaging results taken before and at t=2 h, 24 h, and 72 h, are consistent with the PA imaging results, showing significant darkening of the tumor in the presence of SPIO@Au-loaded MSCs. Histological analysis showed co-localization of GFP fluorescence and iron at the location of the tumor.
CONCLUSIONS: In conclusion, our results demonstrated the feasibility of tracking carotid artery injected SPIO@Au-labeled MSCs in vivo via MR and PA imaging.
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Therapeutic efficacy of glioblastoma multiforme (GBM) is often severely limited by poor penetration of therapeutics through blood-brain barrier (BBB) into brain tissues and lack of tumor targeting. In this regard, a functionalized upconversion nanoparticle (UCNP)-based delivery system which can target brain tumor and convert deep tissue-penetrating near-infrared (NIR) light into visible light for precise phototherapies on brain tumor was developed in this work.
Methods: The UCNP-based phototherapy delivery system was acquired by assembly of oleic acid-coated UCNPs with angiopep-2/cholesterol-conjugated poly(ethylene glycol) and the hydrophobic photosensitizers. The hybrid nanoparticles (ANG-IMNPs) were characterized by DLS, TEM, UV/vis and fluorescence spectrophotometer. Cellular uptake was examined by laser scanning confocal microscopy and flow cytometry. The PDT/PTT effect of ANG-IMNPs was evaluated using MTT assay. Tumor accumulation of NPs was determined by a non-invasive in vivo imaging system (IVIS). The in vivo anti-glioma effect of ANG-IMNPs was evaluated by immunohistochemical (IHC) examination of tumor tissues and Kaplan-Meier survival analysis.
Results: In vitro data demonstrated enhanced uptake of ANG-IMNPs by murine astrocytoma cells (ALTS1C1) and pronounced cytotoxicity by combined NIR-triggered PDT and PTT. In consistence with the increased penetration of ANG-IMNPs through endothelial monolayer in vitro, the NPs have also shown significantly enhanced accumulation at brain tumor by IVIS. The IHC tissue examination confirmed prominent apoptotic and necrotic effects on tumor cells in mice receiving targeted dual photo-based therapies, which also led to enhanced median survival (24 days) as compared to the NP treatment without angiopep-2 (14 days).
Conclusion: In vitro and in vivo data strongly indicate that the ANG-IMNPs were capable of selectively delivering dual photosensitizers to brain astrocytoma tumors for effective PDT/PTT in conjugation with a substantially improved median survival. The therapeutic efficacy of ANG-IMNPs demonstrated in this study suggests their potential in overcoming BBB and establishing an effective treatment against GBM.
Adoptive cellular therapy using T cells with tumor specificity derived from either natural T cell receptors (TCRs) or an artificial chimeric antigen receptor (CAR) has reached late phase clinical testing, with two CAR T cell therapies achieving regulatory approval within the United States in 2017. The effective use of these therapies depends upon an understanding of their pharmacology, which is quite divergent from traditional small molecule or biologic drugs. We review the different types of T cell therapy under clinical development, the factors affecting cellular kinetics following infusion, and the relationship between these cellular kinetics and anti-cancer activity. We also discuss the toxicity associated with T cell therapies, with an emphasis on cytokine release syndrome and neurotoxicity, and the gaps in knowledge regarding these frequent and unique adverse effects.
The blood brain barrier is the main obstacle to delivering diagnostic and therapeutic agents to the diseased sites of brain. It is still of great challenge for the combined use of focused ultrasound (FUS) and theranostic nanotechnology to achieve noninvasive and localized delivery of chemotherapeutic drugs into orthotopic brain tumor. In this work, a unique theranostic nanoplatform for highly efficient photoacoustic imaging-guided chemotherapy of brain tumor both in vitro and in vivo, which is based on the utilization of hollow mesoporous organosilica nanoparticles (HMONs) to integrate ultrasmall Cu2-
x
Se particles on the surface and doxorubicin inside the hollow interior, is synthesized. The developed multifunctional theranostic nanosystems exhibit tumor-triggered programmed destruction due to the reducing microenvironment-responsive cleavage of disulfide bonds that are incorporated into the framework of HMONs and linked between HMONs and Cu2-
x
Se, resulting in tumor-specific biodegradation and on-demand drug-releasing behavior. Such tumor microenvironment-responsive biodegradable and biocompatible theranostic nanosystems in combination with FUS provide a promising delivery nanoplatform with high performance for orthotopic brain tumor imaging and therapy.
Fluorescence bioimaging in the second near-infrared spectral region (NIR-II, 1000–1700 nm) can provide advantages of high spatial resolution and large penetration depth, due to low light scattering. However, NIR-II fluorophores simultaneously possessing high brightness, good stability, and biocompatibility are very rare. Hydrophobic NIR-II emissive PbS@CdS quantum dots (QDs) are surface-functionalized, via a silica and amphiphilic polymer (Pluronic F-127) dual-layer coating method. The as-synthesized PbS@CdS@SiO2@F-127 nanoparticles (NPs) are aqueously dispersible and possess a quantum yield of ≈5.79%, which is much larger than those of most existing NIR-II fluorophores. Thanks to the dual-layer protection, PbS@CdS@SiO2@F-127 NPs show excellent chemical stability in a wide range of pH values. The biocompatibility of PbS@CdS@SiO2@F-127 NPs is studied, and the results show that the toxicity of the NPs in vivo could be minimal. PbS@CdS@SiO2@F-127 NPs are then utilized for in vivo and real-time NIR-II fluorescence microscopic imaging of mouse brain. The architecture of blood vessels is visualized and the imaging depth reaches 950 µm. Furthermore, in vivo NIR-II fluorescence imaging of gastrointestinal tract is achieved, by perfusing PbS@CdS@SiO2@F-127 NPs into mice at a rather low dosage. This work illustrates the potential of ultrastable, biocompatible, and bright NIR-II QDs in biomedical and clinical applications, which require deep tissue imaging.
A series of novel reduction-responsive micelles with tailored size were designed and prepared to release doxorubicin (DOX) for treating glioma, which were developed based on amphiphilic block copolymer poly (2-ethyl-2-oxazoline)-b-poly (ε-caprolactone) (PEtOz-SS-PCL) and the micelle size could be regulated by designing the polymer structure. The DOX-loaded PEtOz-SS-PCL micelles had small size and rapid drug release in reductive intracellular environments. Biodistribution and in vivo imaging studies in C6 glioma mice tumor model showed that DOX loaded PEtOz-SS-PCL43 micelles with the smallest size had superior accumulation and fast drug release in tumor sites. In vivo antitumor activity demonstrated that DOX-loaded PEtOz-SS-PCL43 micelles improved antitumor efficacy in contrast to PEtOz-SS-PCL micelles with larger size toward the orthotopic C6-Luci cells-bearing mice. This study shows great potential in tailoring the micelle size and introducing the responsive bonds or compartment for intracellular drug delivery and release in glioma treatment by designing the architecture of the polymer.
Advances in phototheranostics revolutionized glioma intraoperative fluorescence imaging and phototherapy. However, the lack of desired active targeting agents for crossing the blood brain barrier (BBB) significantly compromises the theranostic efficacy. In this study, biomimetic proteolipid nanoparticles (NPs) with U.S. Food and Drug Administration (FDA)-approved indocyanine green (ICG) were constructed to allow fluorescence imaging, tumor margin detection and phototherapy of orthotopic glioma in mice. By embedding glioma cell membrane proteins into NPs, the obtained BLIPO-ICG NPs could cross BBB and actively reach glioma at the early stage thanks to their specific binding to glioma cells due to their excellent homotypic targeting and immune escaping characteristics. High accumulation in the brain tumor with a signal to background ratio of 8.4 was obtained at 12 h post injection. At this time point, the glioma and its margin were clearly visualized by near-infrared fluorescence imaging. Under the imaging guidance, the glioma tissue could be completely removed as a proof of concept. In addition, after NIR laser irradiation (1 W/cm2, 5 min), the photothermal effect exerted by BLIPO-ICG NPs efficiently suppressed glioma cell proliferation with a 94.2% tumor growth inhibition. No photothermal damages of normal brain tissue and treatment-induced side effects were observed. These results suggest that the biomimetic proteolipid NP is a promising phototheranostic nanoplatform for brain-tumor-specific imaging and therapy.
The blood brain barrier (BBB) selectively controls the passage of endogenous and exogenous molecules between systemic circulation and the brain parenchyma. Nano-carrier based drugs such as liposomes and nanoparticles are an attractive prospect for cancer therapy since they can carry a drug payload and be modified to improve targeting and retention at the desired site. However, the BBB prevents most therapeutic drugs from entering the brain, including physically restricting the passage of liposomes and nanoparticles. In this paper, we show that a low dose of systemically injected recombinant human vascular endothelial growth factor induces a short period of increased BBB permeability. We have shown increased delivery of a range of nanomedicines to the brain including contrast agents for imaging, varying sizes of nanoparticles, small molecule chemotherapeutics, tracer dyes, and liposomal chemotherapeutics. However, this effect was not uniform across all brain regions, and permeability varied depending on the drug or molecule measured. We have found that this window of BBB permeability effect is transient, with normal BBB integrity restored within four hours. This strategy, combined with liposomal doxorubicin, was able to significantly extend survival in a mouse model of human glioblastoma. We have found no evidence of systemic toxicity, and the technique was replicated in pigs, demonstrating that this technique could be scaled up and potentially be translated to the clinic, thus allowing the use of nanocarrier-based therapies for brain disorders.
Reconciling the conflicting needs for prolonged circulation time, enhanced cellular uptake by bulk tumor cells and cancer stem cells (CSCs), and extensive tumor tissue penetration remains a major challenge for current nano drug delivery systems. Here we describe smart poly(N-isopropylacrylamide)-based nanogels with fast adaptive hydrophobicity to solve these contradictory requirements for enhanced cancer chemotherapy. The nanogels are hydrophilic in the blood to prolong their circulation time. Once they accumulate at tumor sites, they rapidly become hydrophobic in response to tumor extracellular acidity. The adaptive hydrophobicicty of the nanogels facilitates tumor accumulation, deep tumor penetration and efficient uptake by bulk tumor cells and CSCs, resulting in greater in vivo enrichment in tumor cells and side population cells. Together with lysosomal pH-regulated charge reversal and redox-responsive intracellular drug release, the nanogels escape from lysosomes and release their cargo doxorubicin. Thus, the nanogels significantly improve the in vivo anticancer efficacy and decrease side effects of doxorubicin. Strikingly, the ratio of CSCs is greatly decreased after treatment with the nanogels loaded with doxorubicin. Our current study provides new insights into designing effective anticancer drug delivery systems.
Inability to cross blood brain barrier (BBB) refrains nearly all chemotherapeutics and biotherapeutics from effective treatment of brain tumors, rendering little improvement of patient survival rates to date. Here, we report that apolipoprotein E peptide (ApoE, (LRKLRKRLL)2C), which specifically binds to low-density lipoprotein receptor members (LDLRs), mediates superb BBB crossing and highly efficient glioblastoma (GBM)-targeted protein therapy in vivo. The in vitro BBB model studies reveal that ApoE induces 2.2-fold better penetration of the immortalized mouse brain endothelial cell line (bEnd.3) monolayer for chimeric polymersomes (CP) compared with Angiopep-2, a best-known BBB crossing peptide used in clinical trials for GBM therapy. ApoE-installed CP (ApoE-CP) carrying saporin (SAP) displays highly specific and potent antitumor effect toward U-87 MG cells with a low IC50 of 14.2 nM SAP. Notably, ApoE-CP shows efficient BBB crossing as well as accumulation and penetration in orthotopic U-87 MG glioblastoma. The systemic administration of SAP-loaded ApoE-CP causes complete growth inhibition of orthotopic U-87 MG GBM without eliciting any observable adverse effects, affording markedly improved survival benefits. ApoE peptide provides an ultrahigh-efficiency targeting strategy for GBM therapy.
Glioblastoma with intracranial infiltrative growth remains an incurable disease mainly owing to existence of blood brain barrier (BBB) and off-target drug toxicity. RNA interference (RNAi) with a high specificity and low toxicity emerges as a new treatment modality for glioblastoma. The clinical application of RNAi technology is, however, hampered by the absence of safe and brain-targeting transfection agents. Here, we report on angiopep-2 peptide-decorated chimaeric polymersomes (ANG-CP) as a nontoxic and brain-targeting non-viral vector to boost the RNAi therapy for human glioblastoma in vivo. ANG-CP shows excellent packaging and protection of anti-PLK1 siRNA (siPLK1) in its lumen while quickly releasing payloads in a cytoplasmic reductive environment. Notably, in vitro experiments demonstrate that ANG-CP can effectively permeate the bEnd.3 monolayer, transport siRNA into the cytosol of U-87 MG glioblastoma cells via the LRP-1-mediated pathway, and significantly silence PLK1 mRNA and corresponding oncoprotein in U-87 MG cells. ANG-CP greatly prolongs the siPLK1 circulation time and enhances its accumulation in glioblastoma. RNAi with siPLK1 induces a strong anti-glioblastoma effect and significantly improves the survival time of glioblastoma carrying mice.
Cancer is one of the leading causes of morbidity and mortality in the world. But more cancer therapies are needed to complement existing regimens due to problems of existing cancer therapies. Herein, we term ferroptosis therapy (FT) as a form of cancer therapy, and hypothesize that the FT efficacy can be significantly improved via accelerating the Fenton reaction by simultaneously increasing the local concentrations of all reactants (Fe2+, Fe3+, and H2O2) in cancer cells. Thus, Fenton-reaction-accelerable magnetic nanoparticles, i.e., cisplatin (CDDP) loaded Fe3O4/Gd2O3 hybrid nanoparticles with conjugation of lactoferrin (LF) and RGD dimer (RGD2) (FeGd-HN@Pt@LF/RGD2), were exploited in this study for FT of orthotopic brain tumors. FeGd-HN@Pt@LF/RGD2 nanoparticles were able to cross the blood-brain barrier (BBB) because of its small size (6.6 nm) and LF-receptor-mediated transcytosis. FeGd-HN@Pt@LF/RGD2 can be internalized into cancer cells by integrin αvβ3-mediated endocytosis, and then release Fe2+, Fe3, and CDDP upon endosomal uptake and degradation. Fe2+ and Fe3+ can directly participate in the Fenton reaction, while the CDDP can indirectly produce H2O2 to further accelerate the Fenton reaction. The acceleration of Fenton reaction generates reactive oxygen species to induce cancer cell death. FeGd-HN@Pt@LF/RGD2 successfully delivered reactants involved in the Fenton reaction to the tumor site, and led to significant inhibition of tumor growth. Finally, the intrinsic magnetic resonance imaging (MRI) capability of the nanoparticles was used to assess and monitor tumor response to FT (self-MRI-monitoring).
The aim of this study was to evaluate the global scientific output of neurotoxicity of nanoparticles (NPs) and explore their hot spots and research trends. Articles about the neurotoxicity of NPs between 2008 and 2017 were taken from the Web of Science Core Collection database. The VOSviewer was used to analyze annual publications, countries/institutions, funding agencies, research objects, major journals, and international cooperation. The reference co-citation map and keywords were used to analyze the mechanisms of neurotoxicity of NPs. Six hundred and forty-one eligible studies were included for analysis, and the annual publications increased with time in the past decade. Based on the bibliometric analysis, China and the United States were the main countries in this field. Metals and metal oxides were the main types of NPs. Cell, rat, and mouse were the primary research objects of NPs. The main research hot spots might focus on the pathogenesis of NPs, such as oxidative stress and apoptosis. This study will help researchers understand the research status, hot spots, and trends of neurotoxicity of NPs.
Brain tumor is one of the most lethal cancers owing to the existence of blood-brain barrier and blood-brain tumor barrier as well as the lack of highly effective brain tumor treatment paradigms. Herein, cyclo(Arg-Gly-Asp-D-Phe-Lys(mpa)) decorated biocompatible and photostable conjugated polymer nanoparticles with strong absorption in the second near-infrared (NIR-II) window are developed for precise photoacoustic imaging and spatiotemporal photothermal therapy of brain tumor through scalp and skull. Evidenced by the higher efficiency to penetrate scalp and skull for 1064 nm laser as compared to common 808 nm laser, NIR-II brain-tumor photothermal therapy is highly effective. In addition, via a real-time photoacoustic imaging system, the nanoparticles assist clear pinpointing of glioma at a depth of almost 3 mm through scalp and skull with an ultrahigh signal-to-background ratio of 90. After spatiotemporal photothermal treatment, the tumor progression is effectively inhibited and the survival spans of mice are significantly extended. This study demonstrates that NIR-II conjugated polymer nanoparticles are promising for precise imaging and treatment of brain tumors.
Introduction: Valrubicin [AD-32 (N-trifluoroacetyladriamycin-14-valerate)], a cancer therapeutic agent, is used for treating bacillus Calmette Guerin (BCG)-resistant bladder cancer. Although valrubicin has been found to be less toxic to normal tissues than doxorubicin during preclinical studies, its therapeutic applications have been restricted to nonsystemic administration due to its poor aqueous solubility. Its proven antineoplastic properties make it a promising candidate to serve as an effective chemotherapeutic agent for systemic use as a soluble nanoparticle formulation with injectable excipients. The current study was undertaken to formulate valrubicin as nanoparticle formulation using our proprietary Quanticle™ Technology. Here we report the use of biocompatible and injectable phospholipid and protein to produce a stable nanoparticle formulation of valrubicin for systemic use.
Methods: We developed Quanticle manufacturing process, which subjected the nanoparticle to a minimum number of fixed passes to avoid the deterioration of excipients by microfluidization process. This was possible through judicious combination of proprietary ternary solvent mixture and excipients. A Quality by Design (QbD) approach was utilized to design the experimental study and understand the effect of process variables on critical quality attributes (CQAs) during our proprietary medicinization of valrubicin. Drug loading, nanoparticle size (before and after filtration), particle size distribution, ease of filtration, and physical stability of particle during storage at room temperature were evaluated as CQA. The process variables being evaluated were aqueous to organic phase ratio, ratios of solvents constituting the total organic phase, amount of drug, microfluidizer pressure, number of passes, and evaporation temperature. Valrubicin was also examined for its incorporation into whole human plasma or human plasma components (HDL, LDL and serum albumin (HSA).
Results: Quanticle formulation with human serum albumin as excipients produced nanoparticle formulation of very small size of ~100 nm. The formulation was stable for 24 h at RT. This formulation was also lyophilizable and reconstitutionable to its original size and the reconstituted formulation is stable for more than 24 at RT. The formulation was reconstitutionable in less than 3 minutes with 0.9% (w/v) saline; the final conc. of the formulation was ~2 mg/mL and the drug recovery was very high. Valrubicin distributes itself in the particles of HDL, LDL and HSA, with the maximum being in HSA.
Conclusions: A new nanoparticle valrubicin (LM-401) was formulated using injectable excipients. The formulation is sterile filterable, lyophilizable and stable at RT for 24h before and after lyophilization. We are planning for in vitro and in vivo application of this new LM-401 formulation in ovarian (SKOV-3) and prostate (PC-3) cancer cell lines.
Citation Format: Tapas De, Steve Miller, Zachary Yim, Vuong Trieu. An injectable nanoparticle formulation of valrubicin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3718.
Effective treatment of malignant glioma still remains formidable challenge due to lack of the effective BBB-permeable drugs and efficient brain delivery methods, and the pharmacotherapy options are very limited. Therefore, to develop an effective therapeutic strategy is a pressing need. In this work, a noncytotoxic drug combination (i.e., simvastatin and fenretinide) was revealed to be potent for treating glioma, which was co-encapsulated into a TPGS-TAT-embedded lactoferrin nanoparticle system for achieving brain-targeted biomimetic delivery via the LRP-1 receptor. It was shown that the lactoferrin nanoparticle repolarized the tumor-associated macrophages from the M2 phenotype to M1 via regulating the STAT6 pathway, as well as induced the ROS-mediated mitochondrial apoptosis by inhibiting the Ras/Raf/p-Erk pathway in the glioma cells. The anti-glioma efficacy was further demonstrated in both the subcutaneous and orthotopic glioma models. The repolarization of tumor-associated macrophages not only prompted the ROS generation but also induced the innate immunity (e.g., antitumor cytokine release). This delivery and therapeutic strategy provides a novel modality for the glioma treatment.
Designing nanomaterials with advanced functions and physical properties to improve cancer diagnosis and treatment has been an enormous challenge. In this work, we report the synthesis of magnetic gold nanowreaths (AuNWs) by combining wet-chemical synthesis with layer-by-layer self-assembly. The presence of Au branches, small junctions, and central holes in AuNWs led to improved photothermal effect compared with Au nanoring seeds and thick Au nanoring with smooth surface. The self-assembly of exceedingly small magnetic iron oxide nanoparticles (ES-MIONs) on the surfaces of AuNWs not only effectively quenched the T1-weighted magnetic resonance imaging (MRI) ability due to the enhanced T2 decaying effect, but also provided the responsiveness to glutathione (GSH). After intravenous injection, the T1 signal of magnetic AuNWs initially in the “OFF” state can be intelligently switched on in response to the relatively high GSH concentration in tumor. And the formation of larger assemblies of ES-MIONs improved their tumor delivery compared to ES-MIONs themselves. Thus, the magnetic AuNWs showed higher MRI contrast than ES-MIONs or commercial Magneveist in T1-weighted MR imaging of tumor. Furthermore, the magnetic AuNWs have absorption in near infrared range, leading to strong photoacoustic signal and effective photoablation of tumor. Therefore, our GSH-responsive self-assembled magnetic AuNWs could enhance T1-weighted MRI and photoacoustic imaging of tumor and be used for imaging-guided photothermal therapy.
Currently, glioma treatment is limited by two main factors: timely detection at onset or relapse and restriction of drugs by the blood-brain barrier (BBB) from entering the brain and influencing tumor growth. However, a safe BBB-traversing drug delivery system has brought new hope to glioma treatment. Exosomes have strong cargo-loading capacity and have the ability to cross the BBB. They can also be conferred with the ability for targeted delivery. Therefore, exosomes have great promise to be a targeted drug delivery vehicles. In this study, we firstly loaded superparamagnetic iron oxide nanoparticles (SPIONs) and curcumin (Cur) into exosomes and then conjugated the exosome membrane with neuropilin-1-targeted peptide (RGERPPR, RGE) by click chemistry to obtain glioma-targeting exosomes with imaging and therapeutic functions. When administered to glioma cells and orthotopic glioma models, we found that these engineered exosomes could cross the BBB smoothly and provided good results for targeted imaging and therapy of glioma. Furthermore, SPION-mediated magnetic flow hyperthermia (MFH) and Cur-mediated therapy also showed a potent synergistic antitumor effect. Therefore, the diagnostic and therapeutic effects on glioma were significantly improved, while reducing the side effects. We have designed a new type of glioma-targeting exosomes, which can carry nanomaterials and chemical agents for simultaneous diagnosis and treatment of glioma, thus providing a potential approach for improving the diagnosis and treatment effects of intracranial tumors.
Despite our growing molecular understanding of glioblastoma (GBM), treatment modalities remain limited. Recent developments in mechanisms of cell fate regulation and nanomedicine provide new avenues to treat and manage brain tumors via delivery of molecular therapeutics. Here we have developed bioreducible poly(beta-amino ester) nanoparticles that demonstrate high intracellular delivery efficacy, low cytotoxicity, escape from endosomes, and promotion of cytosol-targeted environmentally-triggered cargo release for miRNA delivery to tumor-propagating human cancer stem cells. In this report, we combined this nanobiotechnology with newly discovered cancer stem cell inhibiting miRNAs to develop self-assembled miRNA-containing polymeric nanoparticles (nano-miRs) to treat gliomas. We show that these nano-miRs effectively intracellularly deliver single and combination miRNA mimics that inhibit the stem cell phenotype of human GBM cells in vitro. Following direct intratumoral infusion, these nano-miRs were found to distribute through the tumors, inhibit the growth of established orthotopic human GBM xenografts, and cooperatively enhance response to standard-of-care gamma radiation. Co-delivery of two miRNAs, miR-148a and miR-296-5p, within the bioreducible nano-miR particles enabled long-term survival from GBM in mice.
Treatment of glioblastoma multiforme (GBM) is a predominant challenge in chemotherapy due to the existence of blood–brain barrier (BBB) which restricts delivery of chemotherapeutic agents to the brain together with the problem of drug penetration through hard parenchyma of the GBM. With the structural and mechanistic elucidation of the BBB under both physiological and pathological conditions, it is now viable to target central nervous system (CNS) disorders utilizing the presence of transferrin (Tf) receptors (TfRs). However, overexpression of these TfRs on the GBM cell surface can also help to avoid restrictions of GBM cells to deliver chemotherapeutic agents within the tumor. Therefore, targeting of TfR-mediated delivery could counteract drug delivery issues in GBM and create a delivery system that could cross the BBB effectively to utilize ligand-conjugated drug complexes through receptor-mediated transcytosis. Hence, approach towards successful delivery of antitumor agents to the gliomas has been making possible through targeting these overexpressed TfRs within the CNS and glioma cells. This review article presents a thorough analysis of current understanding on Tf-conjugated nanocarriers as efficient drug delivery system.
Glioblastoma is a most intractable and high‐mortality malignancy because of its extremely low drug accessibility resulting from the blood–brain barrier (BBB). Here, it is reported that angiopep‐2‐directed and redox‐responsive virus‐mimicking polymersomes (ANG‐PS) (angiopep‐2 is a peptide targeting to low‐density lipoprotein receptor‐related protein‐1 (LRP‐1)) can efficiently and selectively chaperone saporin (SAP), a highly potent natural protein toxin, to orthotopic human glioblastoma xenografts in nude mice. Unlike chemotherapeutics, free SAP has a low cytotoxicity. SAP‐loaded ANG‐PS displays, however, a striking antitumor activity (half‐maximal inhibitory concentration, IC50 = 30.2 × 10⁻⁹m) toward U‐87 MG human glioblastoma cells in vitro as well as high BBB transcytosis and glioblastoma accumulation in vivo. The systemic administration of SAP‐loaded ANG‐PS to U‐87 MG orthotopic human‐glioblastoma‐bearing mice brings about little side effects, effective tumor inhibition, and significantly improved survival rate. The protein toxins chaperoned by LRP‐1‐targeted virus‐mimicking vesicles emerge as a novel and highly promising treatment modality for glioblastoma.
The intracellular delivery of biofunctional enzymes or therapeutic proteins through systemic administration is of great importance in therapeutic intervention of various diseases. However, current strategies face substantial challenges owing to various biological barriers, including susceptibility to protein degradation and denaturation, poor cellular uptake, and low transduction efficiency into the cytosol. Here, we developed a biomimetic nanoparticle platform for systemic and intracellular delivery of proteins. Through a biocompatible strategy, guest proteins are caged in the matrix of metal–organic frameworks (MOFs) with high efficiency (up to ∼94%) and high loading content up to ∼50 times those achieved by surface conjunction, and the nanoparticles were further decorated with the extracellular vesicle (EV) membrane with an efficiency as high as ∼97%. In vitro and in vivo study manifests that the EV-like nanoparticles can not only protect proteins against protease digestion and evade the immune system clearance but also selectively target homotypic tumor sites and promote tumor cell uptake and autonomous release of the guest protein after internalization. Assisted by biomimetic nanoparticles, intracellular delivery of the bioactive therapeutic protein gelonin significantly inhibits the tumor growth in vivo and increased 14-fold the therapeutic efficacy. Together, our work not only proposes a new concept to construct a biomimetic nanoplatform but also provides a new solution for systemic and intracellular delivery of protein.
Precise diagnostics are of significant importance to the optimal treatment outcomes of patients bearing brain tumors. NIR‐II fluorescence imaging holds great promise for brain‐tumor diagnostics with deep penetration and high sensitivity. This requires the development of organic NIR‐II fluorescent agents with high quantum yield (QY), which is difficult to achieve. Herein, the design and synthesis of a new NIR‐II fluorescent molecule with aggregation‐induced‐emission (AIE) characteristics is reported for orthotopic brain‐tumor imaging. Encapsulation of the molecule in a polymer matrix yields AIE dots showing a very high QY of 6.2% with a large absorptivity of 10.2 L g⁻¹ cm⁻¹ at 740 nm and an emission maximum near 1000 nm. Further decoration of the AIE dots with c‐RGD yields targeted AIE dots, which afford specific and selective tumor uptake, with a high signal/background ratio of 4.4 and resolution up to 38 µm. The large NIR absorptivity of the AIE dots facilitates NIR‐I photoacoustic imaging with intrinsically deeper penetration than NIR‐II fluorescence imaging and, more importantly, precise tumor‐depth detection through intact scalp and skull. This research demonstrates the promise of NIR‐II AIE molecules and their dots in dual NIR‐II fluorescence and NIR‐I photoacoustic imaging for precise brain cancer diagnostics.
A major obstacle to the success rate of chimeric antigen receptor (CAR-) T-cell therapy against solid tumors is the microenvironment antagonistic to T cells that solid tumors create. Conventional checkpoint blockade can silence lymphocyte antisurvival pathways activated by tumors, but because they are systemic, these treatments disrupt immune homeostasis and induce autoimmune side effects. Thus, new technologies are required to remodel the tumor milieu without causing systemic toxicities. Here, we demonstrate that targeted nanocarriers that deliver a combination of immune-modulatory agents can remove protumor cell populations and simultaneously stimulate antitumor effector cells. We administered repeated infusions of lipid nanoparticles coated with the tumor-targeting peptide iRGD and loaded with a combination of a PI3K inhibitor to inhibit immune-suppressive tumor cells and an α-GalCer agonist of therapeutic T cells to synergistically sway the tumor microenvironment of solid tumors from suppressive to stimulatory. This treatment created a therapeutic window of 2 weeks, enabling tumor-specific CAR-T cells to home to the lesion, undergo robust expansion, and trigger tumor regression. CAR-T cells administered outside this therapeutic window had no curative effect. The lipid nanoparticles we used are easy to manufacture in substantial amounts, and we demonstrate that repeated infusions of them are safe. Our technology may therefore provide a practical and low-cost strategy to potentiate many cancer immunotherapies used to treat solid tumors, including T-cell therapy, vaccines, and BITE platforms.
Significance: A new nanotechnology approach can promote T-cell therapy for solid tumors. Cancer Res; 78(13); 3718–30. ©2018 AACR.
In recent years, CRISPR (clustered regularly interspaced short palindromic repeat)/Cas (CRISPR-associated) genome editing systems have become one of the most robust platforms in basic biomedical research and therapeutic applications. To date, efficient in vivo delivery of the CRISPR/Cas9 system to the targeted cells remains a challenge. Although viral vectors have been widely used in the delivery of the CRISPR/Cas9 system in vitro and in vivo, their fundamental shortcomings, such as the risk of carcinogenesis, limited insertion size, immune responses and difficulty in large-scale production, severely limit their further applications. Alternative non-viral delivery systems for CRISPR/Cas9 are urgently needed. With the rapid development of non-viral vectors, lipid- or polymer-based nanocarriers have shown great potential for CRISPR/Cas9 delivery. In this review, we analyze the pros and cons of delivering CRISPR/Cas9 systems in the form of plasmid, mRNA, or protein and then discuss the limitations and challenges of CRISPR/Cas9-based genome editing. Furthermore, current non-viral vectors that have been applied for CRISPR/Cas9 delivery in vitro and in vivo are outlined in details. Finally, critical obstacles for non-viral delivery of CRISPR/Cas9 system are highlighted and promising strategies to overcome these barriers are proposed.
Over the last decades, considerable efforts have been put into developing active nanocarrier systems that cross the blood brain barrier (BBB) to treat brain-related diseases such as glioma tumors. However, to date none have been approved for clinical usage. Here, we show that a human H-ferritin (HFn) nanocarrier both successfully crosses the BBB and kills glioma tumor cells. Its principle point of entry is the HFn receptor (transferrin receptor 1), which is overexpressed both in BBB endothelial cells (ECs) and glioma cells. Importantly, we found that HFn enters and exits the BBB via the endosome compartment. In contrast, upon specifically targeting and entering glioma cells, nearly all of the HFn accumulated in the lysosomal compartment, resulting in the killing of glioma tumor cells, with no HFn accumulation in the surrounding healthy brain tissue. Thus, HFn is an ideal nanocarrier for glioma therapy, and possesses the potential to serve as a therapeutic approach against a broad range of central nervous system (CNS) diseases.
Combination of photoacoustic (PA) and ultrasound (US) imaging offers high spatial resolution images with deep tissue penetration, which shows great potentials in applications in medical imaging. Development of PA/US dual-contrast agents with high contrast and excellent biocompatible is of great interest. Herein, an organic semiconducting photoacoustic nanodroplet, PS-PDI-PAnD, is developed by stabilizing low-boiling-point perfluorocarbon (PFC) droplet with a photoabsorber and photoacoustic agent of perylene diimide (PDI) molecules and co-encapsulating the droplet with photosensitizers of ZnF16Pc molecules. Upon irradiation, the PDI acts as an efficient photoabsorber to trigger the liquid-to-gas phase transition of the PFC, resulting in dual-modal PA/US imaging contrast as well as photothermal heating. On the other hand, PFC can serve as an O2 reservoir to overcome the hypoxia-associated resistance in cancer therapies, especially in photodynamic therapy. The encapsulated photosensitizers will benefit from the sustained oxygen release from the PFC, leading to promoted photodynamic efficacy regardless of pre-existing hypoxia in the tumors. When intravenously injected into tumor-bearing mice, the PS-PDI-PAnDs show a high tumor accumulation via EPR effect. With a single 671-nm laser irradiation, the PS-PDI-PAnDs exhibit a dual-modal PA/US imaging-guided synergistic photothermal and oxygen self-enriched photodynamic treatment, resulting in complete tumor eradication and minimal side effects. The PS-PDI-PAnDs represents a type of PFC nanodroplets for synergistic PDT/PTT treatment upon a single laser irradiation, which is expected to hold great potential in the clinical translation in dual-modal PA/US imaging-guided combinational cancer therapy.
Glioblastoma multiforme (GBM), a prevalent brain cancer with high mortality, is resistant to the conventional single-agent chemotherapy. In this study, we employed a combination chemotherapy strategy to inhibit GBM growth and addressed its possible beneficial effects. The synergistic effect of lauroyl-gemcitabine (Gem-C12) and honokiol (HNK) was firstly tested and optimized using U87 cells in vitro. Then, the hyaluronic acid-grafted micelles (HA-M) encapsulating optimal mole ratio (1:1) of Gem-C12 and HNK were prepared, and characterized. Cell based studies demonstrated that HA-M could be transported into cells by CD44 receptor-mediated endocytosis, which could penetrate deeper into tumor spheroids and enhance the cytotoxicity of payloads to glioma cells. In vivo, drug loaded HA-M significantly increased the survival rate of mice bearing orthotopic xenograft GBM compared with the negative control (1.85-fold). Immunohistochemical analysis indicated that the enhanced efficacy of HA-M was attributed to the stronger inhibition of glioma proliferation and induction of apoptosis. Altogether, our findings showed advantages of combination chemotherapy of GBM using HA-grafted micelles.
Ferroptosis, a new form of regulated cell death that is iron- and reactive oxygen species dependent, has attracted much attention in the research communities of biochemistry, oncology, and especially material sciences. Since the first demonstration in 2012, a series of strategies have been developed to induce ferroptosis of cancer cells, including the use of nanomaterials, clinical drugs, experimental compounds, and genes. A plethora of research work has outlined the blueprint of ferroptosis as a new option for cancer therapy. However, the published ferroptosis-related reviews have mainly focused on the mechanisms and pathways of ferroptosis, which motivated this contribution to bridge the gap between biological significance and material design. Therefore, it is timely to summarize the previous efforts on the emerging strategies for inducing ferroptosis and shed light on future directions for using such a tool to fight against cancer. Here, the current strategies of cancer therapy based on ferroptosis will be elaborated, the design considerations and the advantages and limitations are highlighted, and finally a future perspective on this emerging field is given.