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Medical Center owned two patents on using anti-TfR antibodies However, mostly amphiphilic molecule-formed liposomes and
conjugated to polycefin-LLL to cross BBB. In the second polymeric nanoparticles (chemical species having a “polar” head
[54]
patent, Patil et al. prepared polycefin-LLL nanonjugates that group and “hydrophobic” tails) have been extensively exploited
[55]
could be loaded with temozolomide (TMZ) in its hydrazide for brain drug delivery. [73,75] Long circulation time of the delivery
form and modified with PEG. system can be achieved by conjugating the nanoparticles with
polyethylene glycol (PEG) (“PEGylation”). [66,67] The PEG-
A promising approach to enhance brain delivery is to inhibit coated nanoparticles can escape the mononuclear phagocytic
efflux transporters by modulating their expression and/or system and circulate in the body for a longer time, increasing the
activity. [56,57] Clinical trial data of third-generation inhibitors chance of reaching the target and thereby enhancing the effect of
(ariquidar, zosuquidar and elacridar) are awaited for possible the loaded drug. [66,67] The effect and benefits of PEGylation are
clinical application of this treatment approach. Other naturally discussed later.
[58]
occurring compounds such as curcumin, quercetin, [60,61] and
[59]
kaempferol are being studied and modified for use in brain Unfortunately, nanoparticles can carry some serious adverse
cancer therapy to overcome the problem of multidrug resistance effects. Adverse effects of nanoparticles depend on individual
[76]
(MDR). Barthomeuf et al. studied the use of curcuminoid factors such as genetics, existing disease conditions, exposure,
[62]
[22]
compounds to enhance the clinical efficacy of docetaxel for the nanoparticle chemistry, size, shape, agglomeration state, and
treatment of cancers including GBM. The group proposes that, in electromagnetic properties. The key to understanding the
[76]
addition to reducing Pgp transport, curcumin may reduce HIF-1- toxicity of nanoparticles is their size. Nanoparticles are
[76]
dependent and HIF-1-independent angiogenesis, which in turn smaller than mammalian cells and cellular organelles, which
would inhibit tumor progression, angiogenesis, and induction allows them to penetrate these biological structures and disrupt
of resistance. Banks et al. provided a method to inhibit the their normal function. Examples of toxic effects include
[63]
[22]
[76]
function of RNA- and DNA-encoding efflux transporters among tissue inflammation and altered cellular redox balance toward
other blood-brain barrier proteins using antisense compounds. oxidation, causing abnormal function or cell death. [76]
The patent suggests that inhibition of Pgp expression would
allow increased accumulation of chemotherapeutic drugs in the Polymeric nanoparticles
CNS and thus improve therapeutic clinical outcomes.In another Polymeric micelles are formed from amphiphilic block
patent, McChesney et al. used a group of taxane analogues that copolymers forming a core/shell nanostructure. In aqueous
stabilize tubulin dimers or microtubules at G2-M during mitosis media, the hydrophilic heads are arranged to the outside and the
but are not substrates for MDR proteins. [64] hydrophobic tails to the inside to stabilize the structure, which
[77]
The physiologic approach to target brain tumors takes advantage is suitable for IV injections . Delivery of docetaxel for the
treatment of brain tumors by cyclic arginine-glycine-aspartic
of endogenous receptors that are highly expressed at the
BBB. [30,31] Unfortunately, almost all the receptors are nearly acid (RGD)-tagged polymeric micelles was developed by Li et
[78]
nonspecific as indicated by percentage dose reaching the brain al. The authors found that RGD has affinity to bind to integrin
[78]
following administration compared to percentage reaching receptor, which is overexpressed in glioblastoma tissues.
other organs such as the liver, spleen or lung. To avoid such
[30]
nonselective patterns, Tosi et al. used double-targeting ligands Krebs invented a novel biodegradable hydrogel polymer
[65]
to provide added targeting benefit and minimize nonselectivity. comprising chitin and poly(lactic-co-glycolic acid) for delivery
[79]
The targeting ligands used by Tosi et al. were sialic acid and of therapeutic agents to brain tumors. The biodegradable
[65]
glycopeptides. The targeting ligands were covalently conjugated hydrogel detailed in Krebs’ patent would allow release of anti-
to PLGA nanoparticles (SA-g7-Np). [65] VEGF to the periphery of the resected tumor site in a localized
manner, with stable release rate over a sustained period. The
Nanocarriers for brain drug delivery pH-sensitive polymers which release the drug in an acidic
Nano-based delivery systems have seized increased attention microenvironment of solid tumors and endosomes, were the
[80]
from formulators, as indicated by recent patents and studies[ focus of a patent by Bae et al. Targeting ligands, such as
supplement material Table 1]. This can be attributed to folate, can also be attached to the mixed micelles for enhancing
their unique ability to deliver to therapeutic and diagnostic drug delivery into brain cells. [56]
moieties. [66-72] Nanocarriers are unique because of their small
[81]
size (typically sub 200 nm). Nanoparticles are easily Zhou et al. in a recent patent, developed small, less aggregable
[73]
tailored in their structure and properties. They also can carry brain-penetrating polymeric nanoparticles that can be loaded
[73]
[82]
active therapeutic or diagnostic moieties of heterogeneous with drugs. In another patent, Wu et al. used polymethacrylic
physicochemical properties, and their release pattern can be acid grafted starch (PMAA-g-St) nanoparticles containing
controlled. [73] polysorbate moieties that can target the polymer to brain tissues.
Hyper-branched polymer of polyglycerol-amine (PG-NH2) was
A representation of possible NP structure(s) is shown in Figure demonstrated to accumulate in the tumor environment due to the
3A. NPs can be formulated from different materials including enhanced permeability and retention effect (EPR), as described
polymers, lipids, organometallic compounds, and viruses. in a patent by Yerushalmi et al. [83]
[74]

Journal of Cancer Metastasis and Treatment ¦ Volume 2 ¦ March 15, 2016 ¦ 115