Targeted Drug Delivery - Nanomaterials for Medical Applications - page 182

coat the NPs with hydrophilic polymers/surfactants or by formulating NPs with
biodegradable copolymers with hydrophilic characteristics such as polyethyl-
ene glycol (PEG), polyethylene oxide, polyoxamer, poloxamine, and polysor-
bate 80 (Tween 80). 1 Studies have shown that PEG on NP surfaces prevents
opsonization by complement and other serum factors. PEG molecules reduced
phagocytosis. 22
Superparamagnetic iron oxide (SPIO) NPs that are coated with dextran are
widely used as magnetic resonance imaging (MRI) contrast agents in the clinic
(e.g. Ferridex™). Some SPIO NPs have been shown to exhibit prolonged cir-
culation times that is attributed to their ultrasmall size (less than 20 nm) 23 or
extensive surface cross-linking and PEGylation. 24 Larger SPIO (50-150 nm:
Ferridex, Micromod SPIO, Ferumoxides) that are not dextran coated are rapidly
eliminated from circulation by the liver and spleen and serve to enhance the MR
contrast in these organs. 25 The mechanism of the rapid clearance of NP drug
carriers must be understood in order to design long-circulating (stealth) SPIO.
In spite of the unknowns to date, NMs for drug delivery systems offer advan-
tages that are desirable for therapeutics. 26 First, drugs and imaging agents that
are associated with nanoscale carriers are distributed over smaller volumes. 27
Second, drug nanocarriers also have the ability to improve the pharmacokinetics
and increase biodistribution of therapeutic agents at the target organs that result
in improved efficacy. 11,28,29,30 Third, the toxicity of the drug is minimized as a
result of the preferential accumulation at target diseased sites and minimized con-
centration in healthy tissues. 31 The nanocarriers have been engineered to target
tumors and disease sites that have permeable vasculature allowing easy delivery
of payload. Specific targeting and reduced clearance increases the therapeutic
index that consequently lowers the dose required for efficacy. 31 Fourth, nano-
carriers improve the solubility of hydrophobic therapeutics in aqueous medium
allowing parenteral administration. Fifth, reports have shown that nanocarriers
increase the stability of a variety of therapeutic agents such as small hydropho-
bic molecules, peptides, and oligonucleotides. 32,33,34 Additionally, biocompat-
ible nanocarriers that are safe alternatives to existing drug vehicles that may
cause hypersensitivity reactions and peripheral neuropathy are currently being
strictly investigated. 31 Finally, nanocarriers composed of biocompatible materi-
als 31,35,36,37,38 are investigated as safe alternatives to existing vehicles, such as
Cremophor® EL (BASF, Mount Olive, NJ), that may cause hypersensitivity
reactions and peripheral neuropathy. 39,40 Majority of the drugs are polycyclic
making them insoluble in water. 41 Paclitaxel (TAX) and dexamethasone, for
example, have low water solubility values of 0.0015 42 and 0.1 mg/mL, 43 respec-
tively, making them unacceptable for aqueous i.v. injection. 44 A major obstacle
which prevents the drug from reaching its target is its highly unspecific distribu-
tion with only 1 in 10,000 to 1 in 100,000 molecules reaching their intended site
of action. 45 As a result, a much higher dose needs to be administered to obtain
the desired therapeutic effect which in turn could lead closer to the toxic dose 46
as exemplified by doxorubicin (dox) which exhibits prominent cardiotoxicity. 47