Table 3.

Major structures of nanodrugs: advantages and disadvantages for brain delivery

Nanostructure	Advantages for Brain	Disadvantages for Brain
		Comparison with nano covalent conjugates
Liposome ➢Vesicles on one or more phospholipid bilayer with aqueous core ➢50 nm – 5 μm	➢Can cross BBTB through interendothelial gaps ➢Can be functionalized for active transport across BBB ➢Targeted liposomes are shown to accumulate in tumor tissue over normal brain (reduced non-specific toxicity) ➢Can carry both hydrophilic and hydrophobic drugs ➢Inherently non-toxic structure ➢Simple to manufacture [5] ➢Can control physiochemical properties of size, surface charge, and functionalization [6]	➢Low stability ➢Poor reproducibility ➢Low drug loading capacity for insoluble drugs ➢Limited control over drug release ➢Difficult to sterilize ➢Immunogenicity [6] ➢Low circulation time [7]
Dendrimers ➢Highly branched structure, extending from central core ➢Branches are synthetic polymeric macromolecules ➢10-100 nm [6]	➢Uniform size and shape for BBB crossing [6, 7] ➢Many locations for drug/ligand attachment ➢High drug loading ➢High stability [6] ➢Carry both hydrophilic and hydrophobic drugs	➢Complicated synthesis and formulation development ➢Toxicity with amino functional groups [6] ➢Core is difficult to access ➢Some rely on limited diffusion mechanisms, not ideal for BBB crossing [7]
Polymer-conjugates ➢Macromolecular structure, often linear ➢2-25 nm [8]	➢Inherently water soluble ➢Versatility with many regions for moiety attachment ➢Great potential for combinatorial therapeutics ➢Easily functionalized and high drug loading capacity [9] ➢Interactions with self form stable structure [7] ➢Covalent bonds might be present for 100%	➢Conjugate complexity requires careful physical-chemical characterization [9] ➢Potential uncertainty with composition
Micelles ➢Consist of biodegradable and biocompatible amphiphilic block polymers ➢10-100 nm [6]	➢Can carry both hydrophilic and hydrophobic drugs ➢Hydrophilic shell provides stability and long circulation time ➢Small size allows for escape of RES ➢Easy sterilization ➢Popular in siRNA delivery, useful in brain tumor treatment ➢Versatile by polymer block selection	➢Low stability and tend to dissociate ➢Potential premature drug release (particularly bad for brain delivery) ➢Immunogenicity ➢Formulation scale up methods not yet available [6]
Carbon Nanotubes ➢Tube formed of graphene sheet, either open or capped ➢Diameter: 1 nm, length: several micrometers	➢Can penetrate BBB like needle ➢Can be functionalized with moieties covalently or non-covalently [6]	➢Not inherently soluble ➢Generate toxicity and biosafety issues ➢Difficult for targetable moieties to be attached ➢Low reproducibility [6]
Gold Nanoparticles ➢Silica core coated with thin gold layer [10] ➢1-200 nm [8]	➢Small enough to pass through brain microvasculature ➢Neutral surface charge, low toxicity, and tissue reactivity for BBB crossing ➢Can uniquely produce heat for therapeutic effect ➢Large surface for functionalization	➢Potential toxicity and immunogenicity ➢Unknown effect of functionalization on biodistribution
Magnetic Nanoparticles ➢Iron oxide core coated with material such as polysaccharide, polymer, lipid, or protein ➢1-200 nm [8]	➢Applications in both brain tumor treatment and imaging ➢Can cross BBB favorably ➢Can be administered systemically and targeted by external magnetic field ➢Demonstrated uptake by malignant brain tumor cells	➢Aggregation and instability ➢Non-specific uptake by RES ➢Potential toxicity and immunogenicity