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Blood–brain/blood–tumor barriers (BBB and BTB) and interstitial transport may constitute major obstacles to the transport of therapeutics in brain tumors. In this study, we examined the impact of focused ultrasound (FUS) in combination with microbubbles on the transport of two relevant chemotherapy-based anticancer agents in breast cancer brain metastases at cellular resolution: doxorubicin, a nontargeted chemotherapeutic, and ado-trastuzumab emtansine (T-DM1), an antibody–drug conjugate. Using an orthotopic xenograft model of HER2-positive breast cancer brain metastasis and quantitative microscopy, we demonstrate significant increases in the extravasation of both agents (sevenfold and twofold for doxorubicin and T-DM1, respectively), and we provide evidence of increased drug penetration (>100 vs. <20 μm and 42 ± 7 vs. 12 ± 4 μm for doxorubicin and T-DM1, respectively) after the application of FUS compared with control (non-FUS). Integration of experimental data with physiologically based pharmacokinetic (PBPK) modeling of drug transport reveals that FUS in combination with microbubbles alleviates vascular barriers and enhances interstitial convective transport via an increase in hydraulic conductivity. Experimental data demonstrate that FUS in combination with microbubbles enhances significantly the endothelial cell uptake of the small chemotherapeutic agent. Quantification with PBPK modeling reveals an increase in transmembrane transport by more than two orders of magnitude. PBPK modeling indicates a selective increase in transvascular transport of doxorubicin through small vessel wall pores with a narrow range of sizes (diameter, 10–50 nm). Our work provides a quantitative framework for the optimization of FUS–drug combinations to maximize intratumoral drug delivery and facilitate the development of strategies to treat brain metastases.

The blood-brain barrier (BBB) and blood-tumor barrier (BTB) pose substantial challenges to efficacious drug delivery for glioblastoma multiforme (GBM), a primary brain tumor with poor prognosis. Nanoparticle-based combinational strategies have emerged as promising modalities to overcome these barriers and enhance drug penetration into the brain parenchyma. This review discusses various nanoparticle-based combinatorial approaches that combine nanoparticles with cell-based drug delivery, viral drug delivery, focused ultrasound, magnetic field, and intranasal drug delivery to enhance drug permeability across the BBB and BTB. Cell-based drug delivery involves using engineered cells as carriers for nanoparticles, taking advantage of their intrinsic migratory and homing capabilities to facilitate the transport of therapeutic payloads across BBB and BTB. Viral drug delivery uses engineered viral vectors to deliver therapeutic genes or payloads to specific cells within the GBM microenvironment. Focused ultrasound, coupled with microbubbles or nanoparticles, can temporarily disrupt the BBB to increase drug permeability. Magnetic field-guided drug delivery exploits magnetic nanoparticles to facilitate targeted drug delivery under an external magnetic field. Intranasal drug delivery offers a minimally invasive avenue to bypass the BBB and deliver therapeutic agents directly to the brain via olfactory and trigeminal pathways. By combining these strategies, synergistic effects can enhance drug delivery efficiency, improve therapeutic efficacy, and reduce off-target effects. Future research should focus on optimizing nanoparticle design, exploring new combination strategies, and advancing preclinical and clinical investigations to promote the translation of nanoparticle-based combination therapies for GBM.

Purpose Breast cancer brain metastases (BCBM) are becoming an increasingly common diagnosis due to improved systemic control and more routine surveillance imaging. Treatment continues to require a multidisciplinary approach managing systemic and intracranial disease burden. Although, improvements have been made in the diagnosis and management of BCBM, brain metastasis patients continue to pose a challenge for practitioners. Methods In this review, a group of medical oncologists, radiation oncologists, radiologists, breast surgeons, and neurosurgeons specializing in the treatment of breast cancer reviewed the available published literature and compiled a comprehensive review on the current state of BCBM. Results We discuss the pathogenesis, epidemiology, diagnosis, treatment options (including systemic, surgical, and radiotherapy treatment modalities), and treatment response evaluation for BCBM. Furthermore, we discuss the ongoing prospective trials enrolling BCBM patients and their biologic rationale. Conclusions BCBM management is an increasing clinical concern. Multidisciplinary management combining the strengths of surgical, systemic, and radiation treatment modalities with prospective trials incorporating knowledge from the basic and translational sciences will ultimately lead to improved clinical outcomes for BCBM patients.

The incidence of brain metastases has increased in the last 10 years. However, the survival of patients with brain metastases remains poor and challenging in daily practice in medical oncology. One of the mechanisms suggested for the persistence of a high incidence of brain metastases is the failure to cross the blood–brain barrier of most chemotherapeutic agents, including the more recent targeted therapies. Therefore, new pharmacological approaches are needed to optimize the efficacy of anticancer drug protocols. In this article, we present recent findings in molecular data on brain metastases. We then discuss published data from pharmacological studies on the crossing of the blood–brain barrier by anticancer agents. We go on to discuss future developments to facilitate drug penetration across the blood–brain barrier for the treatment of brain metastases among cancer patients, using physical methods or physiological transporters.

Purpose Glioblastoma (GBM) is the most prevalent, malignant, primary brain tumor in adults, characterized by limited treatment options, frequent relapse, and short survival after diagnosis. Until now, none of the existing therapy and treatment approaches have proven to be an effective cure. The availability of predictive human blood-tumor barrier (BTB) test systems that can mimic in-vivo pathophysiology of GBM would be of great interest in preclinical research. Here, we present the establishment of a new BTB in-vitro test system combining GBM spheroids and BBB models derived from human induced pluripotent stem cells (hiPSCs). Methods We co-cultured hiPSC-derived brain capillary endothelial-like cells (iBCECs) with GBM spheroids derived from U87-MG and U373-MG cell lines in a cell culture insert-based format. Spheroids were monitored over 168 hours (h) of culture, characterized for GBM-specific marker expression and treated with standard chemotherapeutics to distinguish inhibitory effects between 2D mono-culture and 3D spheroids. GBM-induced changes on iBCECs barrier integrity were verified via measurement of transendothelial electrical resistance (TEER), immunocytochemical staining of tight junction (TJ) proteins claudin-5 and occludin as well as the glucose transporter-1 (Glut-1). GBM-induced secretion of vascular endothelial growth factor (VEGF) was additionally quantified. Results Our hypothesis was validated by reduced expression of TJ proteins, occludin and claudin-5 together with significant barrier breakdown in iBCECs after only 24 h of co-culture, demonstrated by reduction in TEER from 1313 ± 265 Ω*cm 2 to 712 ± 299 Ω*cm 2 (iBCECs + U87-MG) and 762 ± 316 Ω*cm 2 (iBCECs + U373-MG). Furthermore, 3D spheroids show more resistance to standard GBM chemotherapeutics in-vitro compared to 2D cultures. Conclusions We demonstrate the establishment of a simplified, robust in-vitro BTB test system, with potential application in preclinical therapeutic screening and in studying GBM-induced pathological changes at the BBB.

Triple-negative breast cancer (TNBC) is a highly malignant subtype of breast cancer. High invasiveness and heterogeneity, as well as a lack of drug targets, are the main factors leading to poor prognosis. Brain metastasis (BM) is a serious event threatening the life of breast cancer patients, especially those with TNBC. Compared with that for hormone receptor-positive and HER2-positive breast cancers, TNBC-derived BM (TNBCBM) occurs earlier and more frequently, and has a worse prognosis. There is no standard treatment for BM to date, and one is urgently required. In this review, we discuss the current knowledge regarding the developmental patterns of TNBCBM, focusing on the key events in BM formation. Specifically, we consider (i) the nature and function of TNBC cells; (ii) how TNBC cells cross the blood-brain barrier and form a fenestrated, more permeable blood-tumor barrier; (iii) the biological characteristics of TNBCBM; and (iv) the infiltration and colonization of the central nervous system (CNS) by TNBC cells, including the establishment of premetastatic niches, immunosurveillance escape, and metabolic adaptations. We also discuss putative therapeutic targets and precision therapy with the greatest potential to treat TNBCBM, and summarize the relevant completed and ongoing clinical trials. These findings may provide new insights into the prevention and treatment of BM in TNBC patients.

The delivery of cancer chemotherapy to treat brain tumors remains a challenge, in part, because of the inherent biological barrier, the blood–brain barrier. While its presence and role as a protector of the normal brain parenchyma has been acknowledged for decades, it is only recently that the important transporter components, expressed in the tightly knit capillary endothelial cells, have been deciphered. These transporters are ATP-binding cassette (ABC) transporters and, so far, the major clinically important ones that functionally contribute to the blood–brain barrier are ABCG2 and ABCB1. A further limitation to cancer therapy of brain tumors or brain metastases is the blood–tumor barrier, where tumors erect a barrier of transporters that further impede drug entry. The expression and regulation of these two transporters at these barriers, as well as tumor derived alteration in expression and/or mutation, are likely obstacles to effective therapy.

Focused ultrasound (FUS) has emerged as a promising technique for temporarily disrupting the blood-brain barrier (BBB) and blood-tumor barrier (BTB) to enhance the delivery of therapeutic agents. Despite its potential, optimizing FUS to maximize drug delivery while minimizing adverse effects remains a significant challenge. In this study, we evaluated a novel FUS protocol that incorporates additional FUS stimulation without microbubbles (MBs) (“FUS protocol”) prior to conventional BBB disruption with MBs (“BBBD protocol”) in a rat brain tumor model (n = 35). This approach aimed to validate its effectiveness in enhancing BBB/BTB disruption and facilitating doxorubicin delivery. T1-weighted contrast-enhanced and dynamic contrast-enhanced (DCE) MRI demonstrated significant increases in signal intensity and permeability (K trans ) in the tumor region under the “FUS + BBBD protocol”, with 2.65-fold and 2.08-fold increases, respectively, compared to the non-sonicated contralateral region. These values were also elevated compared to the conventional “BBBD protocol” by 1.45-fold and 1.25-fold, respectively. Furthermore, doxorubicin delivery in the targeted region increased by 1.91-fold under the “FUS + BBBD protocol”, compared to a 1.44-fold increase using the conventional “BBBD protocol”. This novel FUS approach offers a promising, cost-effective strategy for enhancing drug delivery to brain tumors. While further studies are required to assess its applicability with different chemotherapeutics and tumor types, it holds significant potential for improving brain tumor treatment in both preclinical and clinical settings.

The blood–brain barrier (BBB) is a highly selective interface between the bloodstream and the brain that prevents systemically administered therapeutics from effectively reaching tumor cells. As tumors progress, this barrier undergoes structural and functional alterations, giving rise to the blood–tumor barrier (BTB)—a pathologically modified structure that, despite increased permeability, often exhibits heterogeneous and clinically insufficient drug transport. Although a new generation of therapies is promising, their therapeutic potential cannot be realized unless the challenges posed by these barriers are effectively addressed. Various pharmacological strategies were explored to enhance brain tumor drug delivery. These include receptor-mediated disruption, inhibition of efflux transporters, and the engineering of delivery platforms that leverage endogenous transport pathways—such as carrier-mediated, adsorptive-mediated, and receptor-mediated mechanisms—as well as cell-mediated drug delivery. This review synthesizes (1) the BBB and BTB’s structural characteristics; (2) the influence of the tumor microenvironment (TME) on drug delivery; (3) pharmacological strategies to enhance drug accumulation within brain tumors; (4) the integration of pharmacological methods with neurosurgical techniques to enhance drug delivery. As efforts to improve drug delivery across the BBB and BTB accelerate, this review aims to map the current landscape of pharmacological approaches for enhancing drug penetration into brain tumors.

Breast cancer (BC) is the most common cancer in women, with metastatic BC being responsible for the highest number of deaths. A frequent site for BC metastasis is the brain. Brain metastasis derived from BC involves the cooperation of multiple genetic, epigenetic, angiogenic, and tumor–stroma interactions. Most of these interactions provide a unique opportunity for development of new therapeutic targets. Potentially targetable signaling pathways are Notch, Wnt, and the epidermal growth factor receptors signaling pathways, all of which are linked to driving BC brain metastasis (BCBM). However, a major challenge in treating brain metastasis remains the blood–brain barrier (BBB). This barrier restricts the access of unwanted molecules, cells, and targeted therapies to the brain parenchyma. Moreover, current therapies to treat brain metastases, such as stereotactic radiosurgery and whole-brain radiotherapy, have limited efficacy. Promising new drugs like phosphatase and kinase modulators, as well as BBB disruptors and immunotherapeutic strategies, have shown the potential to ease the disease in preclinical studies, but remain limited by multiple resistance mechanisms. This review summarizes some of the current understanding of the mechanisms involved in BC brain metastasis and highlights current challenges as well as opportunities in strategic designs of potentially successful future therapies.