Primary brain and central nervous system (CNS) tumors are a diverse group of neoplasms that occur within the brain and spinal cord. Although significant advances in our understanding of the intricate biological underpinnings of CNS neoplasm tumorigenesis and progression have been made, the translation of these discoveries into effective therapies has been stymied by the unique challenges presented by these tumors’ exquisitely sensitive location and the body’s own defense mechanisms (e.g., the brain–CSF barrier and blood–brain barrier), which normally protect the CNS from toxic insult. These barriers effectively prevent the delivery of therapeutics to the site of disease. To overcome these obstacles, new methods for therapeutic delivery are being developed, with one such approach being the utilization of nanoparticles. Mayo Clinic researchers discuss the current state of the field with a particular focus on the challenges posed by the BBB, the different nanoparticle classes which are under development for targeted CNS tumor therapeutics delivery, and strategies which have been developed to bypass the BBB and enable effective therapeutics delivery to the site of disease.
Biogenesis, production and general structure of biological NPs
(1–3) Extracellular vesicles (EVs) are differentiated into three groups based on their biogenesis (1) Microvesicles are small to medium sized vesicles (100–1000 nm) that originate from outward budding of the plasma membrane (PM), incorporating cytosolic proteins. (2) Exosomes are small, homogenous vesicles (30–150 nm), formed by inward budding of the endosomal membrane, forming intraluminal vesicles (ILVs) in an MVB and subsequently transported to either the PM, where they are released as exosomes, or to the lysosome for degradation. (3) Apoptotic bodies are usually large (50–5000 nm), heterogeneously shaped vesicles, shed by cells undergoing apoptosis. (4) Cell-derived nanovesicles (CDNs) are generated through mechanical extrusion, ultrasonication or freeze–thawing of parent cells. (5) EVs and CDN are both constructed from a phospholipid bilayer, inherently functionalized with various groups of membrane proteins. While some proteins are more common in certain vesicle types, there is considerable overlap. In the lumen, a diverse range of cargo proteins and nucleic acids can be identified. Abbreviations: MVB = multivesicular body, ER = endoplasmic reticulum, HSP = heat shock protein, ESCRT = endosomal sorting complexes required for transport.