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Tour et al. devised poly(ethylene glycolated) Hydrophilic for the delivery of siRNA to inhibit c-Met expression, were able
[84]
Carbon Clusters Antibody Drug Enhancement System to suppress the tumor growth without evident signs of systemic
(HADES), in which nanovectors are coupled with an active toxicity in an orthotopic xenograft tumor mouse model of
agent and one of the agents that target glioma surface antigens, glioblastoma. [96]
such as Interleukin 13 receptor (IL-13R), epidermal growth
[97]
factor receptor (EGFR), and Gglial fibrillary acidic protein Singh et al. studied lactoferrin-bioconjugated solid lipid
(GFAP). nanoparticles as a new drug delivery system for potential brain
targeting. Lactoferrin was conjugated to the surface of SLN
Lipid-based nanoparticles using carbodimide coupling. SLN surface-conjugated with
Liposomes are the first generation of nanoparticulate drug lactoferrin-encapsulating docetaxel maintained its complete
delivery systems and consist of one or more vesicular bilayers activity and conserved its mechanism of action as characterized
(lamellae) composed of amphiphilic lipids, delimiting an by cell viability and apoptosis studies. [97]
internal aqueous compartment. The most advantageous
[85]
features of liposomes are their ability to incorporate and deliver PEGylated-liposomal formulation for enhanced
®
large amounts of drugs and the possibility of decorating their pharmacokinetics (Stealth technology)
®
surface with various ligands. [86] PEGylated liposomal doxorubicin (PLD; Caelyx , Doxil )
TM
represents the first commercial liposomal formulation for
Chlorotoxin-modified, doxorubicin-loaded liposomes were passive cancer management with enhanced efficacy and
described by Xiang et al. to target chloride channel-mediated reduced toxicity profile. PLD is superior to the conventional
[87]
[98]
brain gliomas. Also, Li et al. suggested that chemotherapy doxorubicin preparation, showing reduced cardiotoxicity and
[88]
using functional targeting of paclitaxel via artemether liposomes prolonged activity due to stealth properties imparted by its
could provide a novel strategy for treating invasive brain glioma. polyethylene glycol PEG layer. Despite PLD smart passive
Chen et al. studied lactoferrin-modified, doxorubicin-loaded properties in targeting cancer, its long circulation half-life and its
[89]
procationic liposomes and showed that the system offers ability to escape the reticuloendothelial system (RES) defense
effective therapeutic potential for gliomas. Cationic liposomes mechanism, it fails to manage brain tumors because of the BBB
were described in a patent by Migliore et al. to provide a novel, enhanced protective features. [50]
[90]
noninvasive strategy for nasal delivery of neuroactive proteins
to the brain for treatment of central nervous system disorders. For the PLD to cross BBB, glutathione-PEGylated liposomal
In another patent by Munson et al. PEGylated uni-lamellar doxorubicin (2B3-101) is being investigated. Based on the
[91]
vesicle liposomes were described that were appropriately patent owned by BBB Therapeutics BV (formerly, to-BBB
sized and formulated to cross the blood-brain barrier to deliver technologies), glutathione-based drug delivery system can target
[50]
imipramine. To overcome toxicity associated with high peak brain tissues by receptor-mediated transcytosis. According
drug concentration, Redelmeierand Luz used a non-PEGylated to the preclinical studies, 2B3-101 showed a 5-fold enhanced
liposomal composition comprising at least one saturated neutral doxorubicin brain delivery versus PLD (Doxil ). The
® [99]
phospholipid and at least one saturated anionic phospholipid company held a phase I/IIa clinical study in patients with solid
encapsulating a therapeutic or diagnostic agent. [92] tumors and brain metastases or recurrent malignant glioma. [100]

Solid lipid nanoparticles Nektar develops new drug candidates by utilizing its proprietary
Solid lipid nanoparticles (SLN) are stable lipid-based nanocarriers 3D 4-armed branched PEGylation and advanced polymer
with a solid hydrophobic lipid core in which the drug can be conjugate technologies to modify the chemical structure of
dissolved or dispersed. [93,94] They are made of biocompatible various active pharmaceutical ingredients. It is a PEGylation
lipids such as triglycerides, fatty acids, or waxes. [93,94] technology supplier to a number of pharmaceutical companies
including Affymax Inc., Amegen Inc., Merck and Co. Inc., Pfizer
Nanoparticles containing brain-derived lipids may be Inc., and UCB Pharma. [101] Nektar Therapeutics is currently
transported into the brain via specific receptors for these lipids. investigating the use of etirinotecan pegol (NKTR-102) for
Panyamand Chavanpatil designed nanoparticles composed of treating brain tumors. [101,102] Furthermore, Nektar Therapeutics is
a brain lipid (phospholipid), a supplemental lipid (long chain conducting a phase II pilot study of NKTR-102 in patients with
saturated or unsaturated fatty acids, stearic acid, palmitic acid, recurrence of high-grade glioma after bevacizumab therapy. [102]
linolic acid, or linoleic acid) and a PEG-conjugated lipid (dist
earoylphosphatidylethanolamine-polyethylene glycol). This Bioconjugates delivery systems
[95]
nanoparticle system can deliver a drug or therapeutic compound The main aim of bioconjugation is to form a stable, biologically
to the brain. [95] cleavable covalent link between two molecules, at least one
of which is a biomolecule [Figure 3B]. [103] Bioconjugation
Jin et al. used solid lipid nanoparticles made of lipids extracted is a form of functionalization of nanoparticles, which aims to
[96]
from deproteinated lipoproteins and enriched with cationic increase stability, protect a drug from proteolysis, or enhance
cholesteryl hydrochloride and phosphatidyl-ethanolamine. The the targeting properties of the delivery system. [77,103] In spite of
authors, after intravenous administration of such cationic NPs the historic fact that bioconjugates are older than nanoparticles,

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