Brain Tumor Targeting Research Articles

An Overview of Current Progress and Challenges in Brain Cancer Therapy Using Advanced Nanoparticles.

Brain tumors pose significant challenges in terms of complete cure and early-stage prognosis. The complexity of brain tumors, including their location, infiltrative nature, and intricate tumor microenvironment (TME), contributes to the difficulties in achieving a complete cure. The primary objective of brain cancer therapy is to effectively treat brain tumors and improve the patient's quality of life. Nanoparticles (NPs) have emerged as promising tools in this regard. They can be designed to deliver therapeutic drugs to the brain tumor site while also incorporating imaging agents. The NPs with the 10-200 nm range can cross the blood-brain barrier (BBB) and blood-brain tumor barrier (BBTB) and facilitate drug bioavailability. NPs can be designed by several methods to improve the pharmaceutical and pharmacological aspects of encapsulated therapeutic agents. NPs can be developed in various dosage forms to suit different administration routes in brain cancer therapy. The unique properties and versatility of NPs make them essential tools in the fight against brain tumors, offering new opportunities to improve patient outcomes and care. Having the ability to target brain tumors directly, overcome the BBB, and minimize systemic side effects makes NPs valuable tools in improving patient outcomes and care. The review highlights the challenges associated with brain tumor treatment and emphasizes the importance of early detection and diagnosis. The use of NPs for drug delivery and imaging in brain tumors is a promising approach to improving patient outcomes and quality of life. The versatility and unique properties of NPs make them valuable tools in the fight against brain tumors, and NPs have the potential to revolutionize healthcare.

Galectin-9 Mediates the Functions of Microglia in the Hypoxic Brain Tumor Microenvironment.

Galectin-9 is a multifaceted regulator of various pathophysiological processes that exerts positive or negative effects in a context-dependent manner. Here, we elucidated the distinctive functional properties of galectin-9 on myeloid cells within the brain tumor microenvironment. Galectin-9-expressing cells were abundant at the hypoxic tumor edge in the tumor-bearing ipsilateral hemisphere compared to the contralateral hemisphere in an intracranial mouse brain tumor model. Galectin-9 was highly expressed in microglia and macrophages in tumor-infiltrating cells. In primary glia, both the expression and secretion of galectin-9 were influenced by tumors. Analysis of a human glioblastoma bulk RNA-sequencing dataset and a single-cell RNA-sequencing dataset from a murine glioma model revealed a correlation between galectin-9 expression and glial cell activation. Notably, the galectin-9high microglial subset was functionally distinct from the galectin-9neg/low subset in the brain tumor microenvironment. Galectin-9high microglia exhibited properties of inflammatory activation and higher rates of cell death, whereas galectin-9neg/low microglia displayed a superior phagocytic ability against brain tumor cells. Blockade of galectin-9 suppressed tumor growth and altered the activity of glial and T cells in a mouse glioma model. Additionally, glial galectin-9 expression was regulated by Hif-2α in the hypoxic brain tumor microenvironment. Myeloid-specific Hif-2α deficiency led to attenuated tumor progression. Together, these findings reveal that galectin-9 on myeloid cells is an immunoregulator and putative therapeutic target in brain tumors.

Transcriptomic observations of intra and extracellular immunotherapy targets for pediatric brain tumors

ABSTRACT Objectives Despite surgical resection, chemoradiation, and targeted therapy, brain tumors remain a leading cause of cancer-related death in children. Immunotherapy has shown some promise and is actively being investigated for treating childhood brain tumors. However, a critical step in advancing immunotherapy for these patients is to uncover targets that can be effectively translated into therapeutic interventions. Methods In this study, our team performed a transcriptomic analysis across pediatric brain tumor types to identify potential targets for immunotherapy. Additionally, we assessed components that may impact patient response to immunotherapy, including the expression of genes essential for antigen processing and presentation, inhibitory ligands and receptors, interferon signature, and overall predicted T cell infiltration. Results We observed distinct expression patterns across tumor types. These included elevated expression of antigen genes and antigen processing machinery in some tumor types while other tumors had elevated inhibitory checkpoint receptors, known to be associated with response to checkpoint inhibitor immunotherapy. Conclusion These findings suggest that pediatric brain tumors exhibit distinct potential for specific immunotherapies. We believe our findings can guide investigators in their assessment of appropriate immunotherapy classes and targets in pediatric brain tumors.

Single-Domain Antibodies as Antibody-Drug Conjugates: From Promise to Practice-A Systematic Review.

Antibody-drug conjugates (ADCs) represent potent cancer therapies that deliver highly toxic drugs to tumor cells precisely, thus allowing for targeted treatment and significantly reducing off-target effects. Despite their effectiveness, ADCs can face limitations due to acquired resistance and potential side effects. This study focuses on advances in various ADC components to improve both the efficacy and safety of these agents, and includes the analysis of several novel ADC formats. This work assesses whether the unique features of VHHs-such as their small size, enhanced tissue penetration, stability, and cost-effectiveness-make them a viable alternative to conventional antibodies for ADCs and reviews their current status in ADC development. Following PRISMA guidelines, this study focused on VHHs as components of ADCs, examining advancements and prospects from 1 January 2014 to 30 June 2024. Searches were conducted in PubMed, Cochrane Library, ScienceDirect and LILACS using specific terms related to ADCs and single-domain antibodies. Retrieved articles were rigorously evaluated, excluding duplicates and non-qualifying studies. The selected peer-reviewed articles were analyzed for quality and synthesized to highlight advancements, methods, payloads, and future directions in ADC research. VHHs offer significant advantages for drug conjugation over conventional antibodies due to their smaller size and structure, which enhance tissue penetration and enable access to previously inaccessible epitopes. Their superior stability, solubility, and manufacturability facilitate cost-effective production and expand the range of targetable antigens. Additionally, some VHHs can naturally cross the blood-brain barrier or be easily modified to favor their penetration, making them promising for targeting brain tumors and metastases. Although no VHH-drug conjugates (nADC or nanoADC) are currently in the clinical arena, preclinical studies have explored various conjugation methods and linkers. While ADCs are transforming cancer treatment, their unique mechanisms and associated toxicities challenge traditional views on bioavailability and vary with different tumor types. Severe toxicities, often linked to compound instability, off-target effects, and nonspecific blood cell interactions, highlight the need for better understanding. Conversely, the rapid distribution, tumor penetration, and clearance of VHHs could be advantageous, potentially reducing toxicity by minimizing prolonged exposure. These attributes make single-domain antibodies strong candidates for the next generation of ADCs, potentially enhancing both efficacy and safety.

An Overview of MR-Guided Laser Interstitial Thermal Therapy (MRg-LITT) in Disrupting the Blood-Brain Barrier: Efficacy and Duration.

The blood-brain barrier (BBB) is a selectively semi-permeable layer, crucial in shielding the brain from external pathogens and toxic substances while maintaining ionic homeostasis and sufficient nutrient supply. However, it poses a significant challenge for drugs to penetrate the BBB in order to effectively target brain tumors. Magnetic resonance-guided laser interstitial thermal therapy (MRg-LITT) is a minimally invasive technique that employs thermal energy to cauterize intracranial lesions with the potential to temporarily disrupt the BBB. This further opens a possible therapeutic window to enhance patient outcomes. Here, we review the impact of MRg-LITT on BBB and blood tumor barrier (BTB) and the duration of the BBB disruption. Studies have shown that MRg-LITT is effective due to its minimally invasive nature, precise tumor targeting, and low complication rates. Although the disruption duration varies across studies, the average peak disruption is within the initial two weeks post-ablation period and subsequently exhibits a gradual decline. However, further research involving larger groups with extended follow-up periods is required to determine disruption duration more accurately. In addition, evaluating toxicity and glymphatic system disruption is crucial to circumvent potential risks associated with this procedure.

Brain-targeting biomimetic disguised manganese dioxide nanoparticles via hybridization of tumor cell membrane and bacteria vesicles for synergistic chemotherapy/chemodynamic therapy of glioma

Glioma is a prevalent brain malignancy associated with poor prognosis. Although chemotherapy serves as the primary treatment for brain tumors, its effectiveness is hindered by the limited ability of drugs to traverse the blood–brain barrier (BBB) and the development of drug resistance linked to tumor hypoxia. Herein, we report the creation of hybrid camouflaged multifunctional nanovesicles comprising membranes of tumor C6 cells (mT) and bacterial outer membrane vesicles (OMVs) and co-loaded with manganese dioxide nanoparticles (MnO2 NPs) and doxorubicin (DOX) to synergistically enhance the chemotherapy/chemodynamic therapy (CDT) of glioma. Owing to OMV-mediated BBB penetration and mT-inherited tumor-homing properties, MnO2-DOX@mT/OMVs can penetrate the BBB and enhance the tumor cell-specific uptake of DOX via “proton sponge effect”-mediated lysosomal escape. This enhances the apoptotic effect induced by DOX and minimizing DOX-associated cardiotoxicity by facilitating the accumulation of DOX at the tumor site. Furthermore, the MnO2 NPs in MnO2-DOX@mT/OMVs can generate potent CDT by accelerating the Fenton-like reaction with DOX-generated H2O2 and achieving glutathione (GSH)-depletion-induced glutathione peroxidase 4 (GPX4) inactivation. These results showed that MnO2-DOX@mT/OMVs, designed for brain tumor targeting, significantly inhibited tumor growth and exhibited favorable biological safety. This innovative approach offers the augmentation of anticancer treatment efficacy via a potential combination of chemotherapy and CDT.

Receptor Ligand-Free Mesoporous Silica Nanoparticles: A Streamlined Strategy for Targeted Drug Delivery across the Blood-Brain Barrier.

Mesoporous silica nanoparticles (MSNs) represent a promising avenue for targeted brain tumor therapy. However, the blood-brain barrier (BBB) often presents a formidable obstacle to efficient drug delivery. This study introduces a ligand-free PEGylated MSN variant (RMSN25-PEG-TA) with a 25 nm size and a slight positive charge, which exhibits superior BBB penetration. Utilizing two-photon imaging, RMSN25-PEG-TA particles remained in circulation for over 24 h, indicating significant traversal beyond the cerebrovascular realm. Importantly, DOX@RMSN25-PEG-TA, our MSN loaded with doxorubicin (DOX), harnessed the enhanced permeability and retention (EPR) effect to achieve a 6-fold increase in brain accumulation compared to free DOX. In vivo evaluations confirmed the potent inhibition of orthotopic glioma growth by DOX@RMSN25-PEG-TA, extending survival rates in spontaneous brain tumor models by over 28% and offering an improved biosafety profile. Advanced LC-MS/MS investigations unveiled a distinctive protein corona surrounding RMSN25-PEG-TA, suggesting proteins such as apolipoprotein E and albumin could play pivotal roles in enabling its BBB penetration. Our results underscore the potential of ligand-free MSNs in treating brain tumors, which supports the development of future drug-nanoparticle design paradigms.

Simultaneous targeting of peripheral and brain tumors with a therapeutic nanoparticle to disrupt metabolic adaptability at both sites

Brain metastasis of advanced breast cancer often results in deleterious consequences. Metastases to the brain lead to significant challenges in treatment options, as the blood-brain barrier (BBB) prevents conventional therapy. Thus, we hypothesized that creation of a nanoparticle (NP) that distributes to both primary tumor site and across the BBB for secondary brain tumor can be extremely beneficial. Here, we report a simple targeting strategy to attack both the primary breast and secondary brain tumors utilizing a single NP platform. The nature of these mitochondrion-targeted, BBB-penetrating NPs allow for simultaneous targeting and drug delivery to the hyperpolarized mitochondrial membrane of the extracranial primary tumor site in addition to tumors at the brain. By utilizing a combination of such dual anatomical distributing NPs loaded with therapeutics, we demonstrate a proof-of-concept idea to combat the increased metabolic plasticity of brain metastases by lowering two major energy sources, oxidative phosphorylation (OXPHOS) and glycolysis. By utilizing complementary studies and genomic analyses, we demonstrate the utility of a chemotherapeutic prodrug to decrease OXPHOS and glycolysis by pairing with a NP loaded with pyruvate dehydrogenase kinase 1 inhibitor. Decreasing glycolysis aims to combat the metabolic flexibility of both primary and secondary tumors for therapeutic outcome. We also address the in vivo safety parameters by addressing peripheral neuropathy and neurobehavior outcomes. Our results also demonstrate that this combination therapeutic approach utilizes mitochondrial genome targeting strategy to overcome DNA repair-based chemoresistance mechanisms.

Discovery of immunotherapy targets for pediatric solid and brain tumors by exon-level expression

Immunotherapy with chimeric antigen receptor T cells for pediatric solid and brain tumors is constrained by available targetable antigens. Cancer-specific exons present a promising reservoir of targets; however, these have not been explored and validated systematically in a pan-cancer fashion. To identify cancer specific exon targets, here we analyze 1532 RNA-seq datasets from 16 types of pediatric solid and brain tumors for comparison with normal tissues using a newly developed workflow. We find 2933 exons in 157 genes encoding proteins of the surfaceome or matrisome with high cancer specificity either at the gene (n = 148) or the alternatively spliced isoform (n = 9) level. Expression of selected alternatively spliced targets, including the EDB domain of fibronectin 1, and gene targets, such as COL11A1, are validated in pediatric patient derived xenograft tumors. We generate T cells expressing chimeric antigen receptors specific for the EDB domain or COL11A1 and demonstrate that these have antitumor activity. The full target list, explorable via an interactive web portal (https://cseminer.stjude.org/), provides a rich resource for developing immunotherapy of pediatric solid and brain tumors using gene or AS targets with high expression specificity in cancer.

Abstract 7182: Blood brain barrier masks effects of dosing strategy

Abstract The penetration of the blood brain barrier (BBB) presents a significant challenge in the design of drugs targeting brain tumors. The BBB desynchronizes drug concentrations between the body and brain, complicating the relationships between drug dose, effective concentration, and toxicity. In this work, we sought to understand the nature of these relationships in the context of dose schedule, in order to suggest minimally toxic and maximally effective strategies. We developed a two-compartment pharmacokinetic model to simulate the exchange of a drug between the body and the brain. Drug exchange was based on passive diffusion through the barrier and active transport into the brain as described by Michaelis-Menten kinetics. In the model, tumor cells exhibit binary resistance to the drug under a logistic growth model. The drug reduces the growth rate of the sensitive population while the resistant population suffers a small growth penalty because of the mutation conferring resistance. Strategy effectiveness was quantified in terms of survival time, the time until 95% of carrying capacity was reached, and toxicity was evaluated as the peak moving average over 18 days. Although the BBB complicates prediction of drug action, it simplifies drug impact by masking schedule effects. Our work suggests that drug concentrations in the brain increase with initial treatment until equilibrium between active transport, diffusion, and drug metabolism is reached. Fluctuations in drug concentration resulting from breaks between bolus dosing are greatly reduced in the brain relative to the body, and high frequency (daily) dosing results in a nearly constant equilibrium drug concentration. The rate at which equilibrium is reached and the drug concentration in the brain are unaffected by dosing period, as long as the average dose per day is constant. Our model suggests that the impact of dosing cycle length on survival time is negligible. Neutropenia is minimized by schedules with dosing cycle lengths that factor evenly into the 18-day neutrophil recovery period. These schedules have consistent toxicity throughout. Strategies with two, three, six, nine, and eighteen day cycles induce neutropenia least. As fluctuations in drug concentration are small at the equilibrium steady-state, effects of scheduling on drug interactions are predicted to be minimal. As drug concentration in the brain at equilibrium and latency to equilibrium are independent of dosing period, these parameters must be modulated through changes in the amount of drug dosed. The use of a loading dose may compensate for latency. Although this analysis is based on hypothetical drugs, it provides practical insights that are applicable across a wide range of systemically dosed small-molecule therapeutics. Further, the modeling framework derived here can be readily extended to guide the design of dosing schedules for real-world therapeutic interventions. Citation Format: Madison Stoddard, Andrew Chen, Lin Yuan, Debra Van Egeren, Arijit Chakravarty. Blood brain barrier masks effects of dosing strategy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7182.

Targeting brain tumors with innovative nanocarriers: bridging the gap through the blood-brain barrier.

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. 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. 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. 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.

Stem Cells and Tumor-Killing Virus to Target Brain Tumor: In Pursuit to Bring a Potential Delivery Vehicle for the Central Nervous System Tumors.

To target brain cancer, various therapeutic options are present to fight against cancer cells. But the existing therapies are not showing a proper curation of cancer patients. Henceforth, activating the immune cells and targeting oncogenes/proteins might be an emerging therapeutic approach to target and destroy malignant brain tumor. Stem cells (SCs) are considered potential immunomodulators that trigger the highly suppressed immune system in the tumor microenvironment. Also, engineered SCs can repress the aberrantly expressed oncoproteins that cause tumor cell proliferation and growth. SCs have an excellent migration capability to reach the infected site and support the regeneration of damaged blood vessels and tissues. Likewise, oncolytic virotherapy (OVT) is a promising novel therapeutic molecule in which genetically modified viruses can selectively replicate and destroy cancer cells without harming healthy cells. Same as SCs, oncolytic viruses (OVs) tend to stimulate the host's innate and adaptive immune response to battle against the advanced brain tumor. In clinical studies, various OVs have shown good immunogenic responses with a high safety profile and tolerability against cancer patients with reduced morbidity and mortality rate. SCs act as an attractive cargo for OVs which helps to influence the tumor site and destroy the tumor volume. SCs protect the OVs from systemic degradation and promote therapeutic efficacy against cancer cells. SCs carried OVs might be a potential therapeutic way to bring an effective treatment option for brain tumors.

Immune Checkpoint-Blocking Nanocages Cross the Blood-Brain Barrier and Impede Brain Tumor Growth.

Glioblastoma (GBM) is the deadliest tumor of the central nervous system, with a median survival of less than 15 months. Despite many trials, immune checkpoint-blocking (ICB) therapies using monoclonal antibodies against the PD-1/PD-L1 axis have demonstrated only limited benefits for GBM patients. Currently, the main hurdles in brain tumor therapy include limited drug delivery across the blood-brain barrier (BBB) and the profoundly immune-suppressive microenvironment of GBM. Thus, there is an urgent need for new therapeutics that can cross the BBB and target brain tumors to modulate the immune microenvironment. To this end, we developed an ICB strategy based on the BBB-permeable, 24-subunit human ferritin heavy chain, modifying the ferritin surface with 24 copies of PD-L1-blocking peptides to create ferritin-based ICB nanocages. The PD-L1pep ferritin nanocages first demonstrated their tumor-targeting and antitumor activities in an allograft colon cancer model. Next, we found that these PD-L1pep ferritin nanocages efficiently penetrated the BBB and targeted brain tumors through specific interactions with PD-L1, significantly inhibiting tumor growth in an orthotopic intracranial tumor model. The addition of PD-L1pep ferritin nanocages to triple in vitro cocultures of T cells, GBM cells, and glial cells significantly inhibited PD-1/PD-L1 interactions and restored T-cell activity. Collectively, these findings indicate that ferritin nanocages displaying PD-L1-blocking peptides can overcome the primary hurdle of brain tumor therapy and are, therefore, promising candidates for treating GBM.

Spatiotemporally sequential delivery of biomimetic liposomes potentiates glioma chemotherapy

As one of the most challenging cancers, glioma still lacks efficient therapeutic treatment in clinics. The dilemmas of nanodrug-based therapies for glioma are due not only the limited permeability of the blood–brain barrier (BBB) but also the deficiency of targeting tumor lesions. Thus, spatiotemporally sequential delivery of therapeutics from BBB-crossing to glioma accumulation is considered a strategy to obtain better outcomes. Here, we developed a biomimetic chemotherapy nanodrug composed of the hybrid membrane envelope of U87 cell membranes and RAW264.7 cell membranes, and the core of paclitaxel (PTX)-loaded liposome (PTX@C-MMCL). In the research, PTX@C-MMCL showed superior ability to cross the BBB via RAW264.7 cell membranes and accurate targeting to the brain tumor lesions relying on the homotypic targeting capacity of U87 cell membranes. Furthermore, PTX@C-MMCL can maintain a prolonged circulation in vivo. Importantly, PTX@C-MMCL effectively inhibited the development of glioma. Conclusively, our biomimetic nanodrug holds great potential for brain tumor targeting therapy.

Microfluidics-Prepared Ultra-small Biomimetic Nanovesicles for Brain Tumor Targeting.

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-100nm macrophage plasma membrane-derived vesicles as small as 51nm (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-100nm macrophage cell membrane vesicles (general macrophage vesicles, GMVs) prepared via the traditional methods, the new NMVs exhibits rapid (within 1h 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.

Porphyrin-Based Brain Tumor-Targeting Agents: [64Cu]Cu-porphyrin and [64Cu]Cu-TDAP.

The aim of this study is to evaluate a radioactive metal complex platform for brain tumor targeting. Herein, we introduce a new porphyrin derivative, 5,10,15,20-(tetra-N,N-dimethyl-4-aminophenyl)porphyrin (TDAP), in which four N,N-dimethyl-4-p-phenylenediamine (DMPD) moieties are conjugated to the porphyrin labeled with the radiometal 64Cu. DMPD affected the pharmacokinetics of porphyrin in terms of retention time in vivo and tumor-targeting ability relative to those of unmodified porphyrin. [64Cu]Cu-TDAP showed stronger enhancement than [64Cu]Cu-porphyrin in U87MG glioblastoma cells, especially in the cytoplasm and nucleus, indicating its tumor-targeting properties and potential use as a therapeutic agent. In the subcutaneous and orthotopic models of brain-tumor-bearing mice, [64Cu]Cu-TDAP was clearly visualized in the tumor site via positron emission tomography imaging and showed a tumor-to-brain ratio as high as 13. [64Cu]Cu-TDAP deserves attention as a new diagnostic agent that is suitable for the early diagnosis and treatment of brain tumors.

Recent Advancements and Strategies for Overcoming the Blood-Brain Barrier Using Albumin-Based Drug Delivery Systems to Treat Brain Cancer, with a Focus on Glioblastoma.

Glioblastoma multiforme (GBM) is a highly aggressive malignant tumor, and the most prevalent primary malignant tumor affecting the brain and central nervous system. Recent research indicates that the genetic profile of GBM makes it resistant to drugs and radiation. However, the main obstacle in treating GBM is transporting drugs through the blood-brain barrier (BBB). Albumin is a versatile biomaterial for the synthesis of nanoparticles. The efficiency of albumin-based delivery systems is determined by their ability to improve tumor targeting and accumulation. In this review, we will discuss the prevalence of human glioblastoma and the currently adopted treatment, as well as the structure and some essential functions of the BBB, to transport drugs through this barrier. We will also mention some aspects related to the blood-tumor brain barrier (BTBB) that lead to poor treatment efficacy. The properties and structure of serum albumin were highlighted, such as its role in targeting brain tumors, as well as the progress made until now regarding the techniques for obtaining albumin nanoparticles and their functionalization, in order to overcome the BBB and treat cancer, especially human glioblastoma. The albumin drug delivery nanosystems mentioned in this paper have improved properties and can overcome the BBB to target brain tumors.

P02.24.B A DRUG DISCOVERY PLATFORM FOR COMBINATORIAL TARGETING OF CELL STATES AND ENTITIES

Abstract Glioblastoma (GBM) is a lethal brain tumor with limited therapeutic options. Therapeutic resistance arises from the collaboration among heterogeneous and highly plastic cellular entities and states conserved across GBM patients and the tumor microenvironment.Tumor cells adapt in response to the current standard of care and infiltration of innate immune cells, recurrently acquiring a mesenchymal state that drives therapeutic resistance.Moreover, the blood-brain barrier (BBB) poses challenges to the effectiveness and bioavailability of approved therapeutics, as well as the discovery of new ones.Our lab has developed synthetic locus control regions (sLCRs) as transcriptional reporters for glioblastoma subtypes, enabling the study of cell identity and state transitions in vitro and in vivo. We have combined this tool with validated cellular models for glioblastoma mesenchymal transition and therapeutic resistance to establish an in vitro phenotypic screening platform. Currently, we are utilizing this platform to identify treatment combinations and dosing schemes that aim to overcome innate immunity-driven resistance and synergize with the standard of care. As a proof-of-concept for a new generation of brain tumor target discovery platforms, we will present the setup of our platform and preliminary results for a class of BBB-penetrant drugs.

Insight into lipid-based nanoplatform-mediated drug and gene delivery in neuro-oncology and their clinical prospects.

Tumors of the Central nervous System (CNS) are a spectrum of neoplasms that range from benign lesions to highly malignant and aggressive lesions. Despite aggressive multimodal treatment approaches, the morbidity and mortality are high with dismal survival outcomes in these malignant tumors. Moreover, the non-specificity of conventional treatments substantiates the rationale for precise therapeutic strategies that selectively target infiltrating tumor cells within the brain, and minimize systemic and collateral damage. With the recent advancement of nanoplatforms for biomaterials applications, lipid-based nanoparticulate systems present an attractive and breakthrough impact on CNS tumor management. Lipid nanoparticles centered immunotherapeutic agents treating malignant CNS tumors could convene the clear need for precise treatment strategies. Immunotherapeutic agents can selectively induce specific immune responses by active or innate immune responses at the local site within the brain. In this review, we discuss the therapeutic applications of lipid-based nanoplatforms for CNS tumors with an emphasis on revolutionary approaches in brain targeting, imaging, and drug and gene delivery with immunotherapy. Lipid-based nanoparticle platforms represent one of the most promising colloidal carriers for chemotherapeutic, and immunotherapeutic drugs. Their current application in oncology especially in brain tumors has brought about a paradigm shift in cancer treatment by improving the antitumor activity of several agents that could be used to selectively target brain tumors. Subsequently, the lab-to-clinic transformation and challenges towards translational feasibility of lipid-based nanoplatforms for drug and gene/immunotherapy delivery in the context of CNS tumor management is addressed.

Macrophage-Cancer Hybrid Membrane-Camouflaged Nanoplatforms for HIF-1α Gene Silencing-Enhanced Sonodynamic Therapy of Glioblastoma.

Fabrication of ingenious nanomedicines to penetrate the blood-brain barrier (BBB) and blood-brain-tumor barrier (BBTB) for efficient glioblastoma (GBM) therapy remains a big challenge. In this work, macrophage-cancer hybrid membrane-camouflaged nanoplatforms were fabricated for target gene silencing-enhanced sonodynamic therapy (SDT) of GBM. The J774.A.1 macrophage cell membrane and the U87 glioblastoma cell membrane were fused to create a hybrid biomembrane (JUM) with good BBB penetration and glioblastoma targeting capability for camouflaging. The ZIF-8 nanoparticles were synthesized for indocyanine green (ICG) and HIF-1α siRNA encapsulation (ICG-siRNA@ZIF-8, ISZ) with a high loading efficiency. After accumulation in the tumor sites, the pH sensitivity of the nanoplatform enabled release of ICG and HIF-1α siRNA in the tumor cells. Then, the expression of HIF-1α could be efficiently inhibited by the released HIF-1α siRNA to increase the SDT efficiency under hypoxic conditions. In vitro and in vivo experiments revealed that ISZ@JUM showed good BBB penetration and brain tumor-targeting capability and could achieve effective gene silencing-enhanced SDT, demonstrating great promise for clinical applications.