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research is increasingly being diverted back to it. [103] Factors a surfactant, and histidine. In their patent Adair et al. [107]
that may encourage this resurgence of interest could include its described nonaggregating resorbable calcium phosphosilicate
ease of synthesis, high scale-up yield, ease of bench-to-bedside nanoparticles bioconjugated to targeting molecules that are
transformation, ease of formulation, and final formulation specific for brain cells. The targeting moieties used by Adair et
stability. [103] Bioconjugation reactions are generally categorized al. [107] included antibodies, peptides, ligands, and/or receptors
by the general reactivity or the functional group involved in the having sulfhydryl-group. Hutchison invented p97-antibody
conjugation process, such as amine reactions, thiol reactions, conjugates and related compositions that could be used in the
carboxylate reactions, hydroxyl reactions, aldehyde and ketone treatment of cancers such as Her2/neu-expressing and Her1/
reactions, active hydrogen reactions, photochemical reactions, EGFR-expressing cancers to inhibit, prevent, or delay the
and cyclo-addition reactions. [103] The design of a useful metastasis of an antibody-resistant cancer. [108]
bioconjugate will depend mainly on its use, purpose, and the
desired properties needed. [104] Thus, one could choose a suitable Kang et al. [109] hypothesized that modification of calreticulin
molecule and a proper cross-linker to form the bioconjugate. [104] (CRT) peptide to poly(ethylene glycol)-poly(l-lactic-co-glycolic
The key to forming a successful bioconjugate is choosing the acid) (PEG-PLGA) nanoparticles would mediate drug transport
suitable crosslinker between the molecules. [103] across the BBB and enable deep penetration to the interior of
the glioma by functionally mimicking iron. Their study proved
As in any delivery system, bioconjugates are usually tailor- that CRT-NP significantly improved the therapeutic efficacy of
designed to provide the function of interest. The active drug paclitaxel for the treatment of gliomas. [109]
entity can be linked to a diagnostic agent, targeting moiety,
pharmacokinetics-modifying agent such as PEG, bioresponsive Toxins: targeting agents and a potential treatment
or stimuli-sensitive agent, an aptamer, or an antibody. Disintegrins, a group of snake venom toxins, have the potential
Furthermore, the choice of the proper linker can impart new to block cancer cell migration and invasion by interaction
functions and smart characteristics to the bioconjugate system with integrins. [110] Contortrostatin, a snake venom disintegrin,
[Figure 3]. was proven to inhibit tumor growth and angiogenesis and
to prolong survival in a rodent glioma model by Pyrko et
A bioconjugate was patented by Bacha et al. [105] that may al. [111] Similarly, scorpion venoms has been used in targeting
compromise a chimeric peptide of the structure of Formula brain tumors, in tumor painting, and in cell sensitization to
(D-III): A-NH(CH ) S-S-B (cleavable linkage), avidin-biotin- chemotherapy. [112-114] Chlorotoxin (CTX) is a promising tool for
2 2
agent complex, PEG layer, and a fusion protein for targeting glioma management. [112,115-118]
the brain tumor. Another bioconjugate formulation, developed
by Jefferies et al. comprised a BBB-transport moiety linked Chlorotoxin binds to metallomatrix proteins-2 and a glioma-
[38]
to an antibody or therapeutic Fc-fusion polypeptide. Jefferies et specific chloride channel. [119] CTX is a highly diffusible peptide
al. modified Fc regions to facilitate the delivery of therapeutic that can cross the BBB or the BBTB with, to date, no evident
[38]
and/or diagnostic polypeptides across the BBB and thereby treat signs of toxicity for normal human cells. [110] Coated iron
and/or diagnose conditions associated with the CNS, including superoxide particles conjugated to CTX may be used as a MRI
cancer. contrast agent as well as for delivering therapeutic agents (e.g.
O6-benzylguanine and siRNA) to glioma cells. [120-122] Other
A patent entitled “Anti-EGFR antibody drug conjugate toxins such as BLZ-100 are being investigated. [123,124]
formulations” by Tschoepe et al. [106] discussed a staple
formulation including: an anti-EGFR antibody or antigen- Physically facilitated brain drug-delivery
binding portion thereof conjugated to an auristatin, a sugar, Advanced physically manipulated systems can be used to
treat diseases and allow controlled dosage of drugs. Physical
manipulation can be achieved via ultrasound, electric, magnetic,
or photonic-emission technologies. [125] Davalos et al. [126] applied
pulsed electric fields into brain tissue of an animal to cause
temporary disruption of the BBB. There are examples of using
electromagnetic field pulses to induce the permeability of the
BBB. Qiu et al. [127] showed that electromagnetic pulses alter
BBB permeability via regulating protein kinase C signaling and
translocation of tight junction’s protein ZO-1.

Kievit et al. [122] attached chlorotoxin to an iron oxide magnetic
nanoparticle (MNP) core using a short PEG linker. Similarly,
in vivo experiments by Braun et al. [128] have shown the effects
of MNPs within a magnetic field on glioma cells lasting up
Figure 3: Diagrammatic sketch for nanoparticulate and nanoconjugate to 100 min postexposure. A patent by Akhtari and Engel used
systems design strategies functionalized MNP that comprise a moiety that provides

Journal of Cancer Metastasis and Treatment ¦ Volume 2 ¦ March 15, 2016 ¦ 117