Nanoparticles Surmounting Blood–Brain Tumor Barrier Through Both Transcellular and Paracellular Pathways to Target Brain Metastases

Abstract

Brain metastases are one of the most difficult malignancies to treat owing to their location and mostly multifocal and infiltrative growth. Chemotherapy, which is often effective against tumors outside the brain, offers some hope for brain metastases. However, the efficacy of systemic drug delivery to brain metastases is extremely limited due largely to the blood–brain tumor barrier (BTB). Herein, it is reported that minoxidil‐loaded hyaluronic acid–tethered nanoparticles (M@H‐NPs) can efficiently and specially surmount the BTB through both transcellular and paracellular pathways and target brain metastases through coordination of hyaluronic acid with CD44 target. The transcellular endocytosis, paracellular claudin‐5 expression, and BTB crossing are evaluated to confirm that the developed M@H‐NPs can be endued with minoxidil's ability to boost transcytosis and downregulate tight junction protein in BTB endothelial cells at brain metastases for promoted BTB penetration. M@H‐NPs selectively deliver doxorubicin (DOX) to brain metastatic lesions, while sparing normal brain cells from harm. Treatment with M@H‐NPs/DOX significantly prolongs median survival of mice bearing brain metastases. Due to the fruitful BTB penetration and brain metastasis homing, and improved therapeutic outcome, the minoxidil‐based systemic drug delivery strategy may serve as a potential approach for clinical management of brain metastases.

Camouflaging Nanoparticles with Brain Metastatic Tumor Cell Membranes: A New Strategy to Traverse Blood–Brain Barrier for Imaging and Therapy of Brain Tumors

“…Some literatures reported that although the tight junctions of BBB are slightly disrupted in the early stage of glioma, most nanomaterials cannot traverse the BBB to accumulate in glioma for early diagnosis and therapy. [ 8,21,22 ] In order to explore whether the metastatic cancer cell membrane‐coated nanoparticles can cross the BBB to image glioma tumor cells in the early stage, an orthotopic mouse model bearing luciferase‐expressing human glioblastoma tumor (U87MG‐Luc) was used to perform the analysis. The glioma cell activity was measured by bioluminescence imaging.…”

“…Brain metastasis is a common complication of most tumors, including lung cancer, breast cancer, and melanoma. [ 22 ] About 20–30% of these malignant tumors can metastasize into the brain to form secondary brain tumors. [ 23 ] Obviously, these tumor cells are able to cross the blood–brain barrier into the brain.…”

Gold Nanoframeworks with Mesopores for Raman–Photoacoustic Imaging and Photo‐Chemo Tumor Therapy in the Second Near‐Infrared Biowindow

“…The large cavities of mesopores in AuNFs enabled encapsulation of small‐molecule cargos such as chemotherapeutics for local delivery. Doxorubicin (DOX), an ideal model drug for its broad anticancer activity and relatively stable fluorescence for in vitro and in vivo tracking, was chosen to evaluate the drug‐loading efficiency of AuNFs. Through thiol (SH) groups, a Raman reporter, 4‐aminothiophenol (4‐ATP), was linked onto the surface of AuNFs.…”

“…Through thiol (SH) groups, a Raman reporter, 4‐aminothiophenol (4‐ATP), was linked onto the surface of AuNFs. Hyaluronic acid (HA), a natural polysaccharide with high affinity for CD44, was further grafted onto the surface of AuNFs to obtain an HA‐4‐ATP‐AuNFs‐DOX nanosystem via the formation of amide bonds between carboxylic groups of HA and amino groups of 4‐ATP. In this nanosystem, the grafted HA not only acted as the cap for trapped DOX within mesopores but also endowed AuNFs with stability, biocompatibility, CD44‐overexpressing tumor target ability, and functional groups for Raman reporter‐linking.…”

Advancements in the Blood–Brain Barrier Penetrating Nanoplatforms for Brain Related Disease Diagnostics and Therapeutic Applications

“…These biomimetic nanocomposites can facilitate the mimicking of the tumor microenvironment that results in a wide range of favorable applications, such as specific targeting and prolonged circulation time. Although utilizing This strategy can treat cancer tumor models by using some cell membrane-coated nanostructures, [ 76 , 77 ] but, to use this strategy to treat brain tumors is rarely explored [ 78 ]. Over the years, there are numerous NPs that were successfully applied for brain tumors, which are summarized in Table 3 .…”