Biomaterials and the Central Nervous System: Neurosurgical Applications of Materials Science - Biomaterials Science: An Integrated Clinical and Engineering Approach - page 139

Drug Delivery Systems
One of the significant challenges in the pharmacologic treatment of CNS con-
ditions is the necessity of crossing the BBB. Because of the selective perme-
ability of the endothelial cells in brain capillaries, many drugs do not cross
the BBB with high efficiency [24, 25]. As a result, CNS drugs may require
administration at high systemic doses to achieve appropriate intracranial
concentrations. These high doses may result in a worsening of systemic side
effects. Efforts in neuropharmacology have focused largely on improving a
drug's ability to hone in on the brain and cross the BBB more efficiently, or
on strategies to circumvent the BBB, such as through intracranial delivery.
Systemic administration of drugs intended for the CNS may be ameliorated
by the use of certain drug carriers that target the CNS tissue and/or facilitate
crossing of the BBB [1]. There are many examples of drug carriers, including
nanoparticles, polymeric micelles, liposomes, and dendrimers [26]. Liposomes
are small vesicles whose cores are enclosed by phospholipid bilayer mem-
branes, which are fully biocompatible [1]. Liposomes have shown the most
clinical promise, though traditional liposomes do little to improve crossing of
the BBB without vector-mediated delivery [1, 25]. Without surface modifica-
tion, these liposomes are rapidly cleared by the reticuloendothelial system
(RES); coating their surface with hydrophilic polymers greatly reduces this
problem and prolongs their circulation time [27]. Further surface modifica-
tion with targeting vectors improves the tissue-specificity of liposomal drug
formulations [27]. Doxil ® is a pegylated (polyethylene glycol) liposomal for-
mulation of doxorubicin, an anthracycline antibiotic cum chemotherapy used
to treat cutaneous tumors. The pegylated surface modification allows better
skin targeting and reduces the cardiotoxicity usually seen with its adminis-
tration [28]. Intracranial drug targeting is largely in experimental stages but
hinges on the understanding that intracranial tumors (both intrinsic and met-
astatic) demonstrate a breakdown in the BBB, thereby facilitating the crossing
of liposomal drugs across the BBB [1, 29].
Other drug carriers that have shown promise include polymeric nanopar-
ticles, which are particles less than 100 nm in size attached to natural or syn-
thetic polymers that encapsulate or are attached to pharmacologic agents [30].
The polymers most commonly used are polyalkylcyanoacrylates (PACAs),
polyacetates, polysaccharides, and copolymers [1, 31]. These polymeric NPs are
thought to cross the BBB through receptor-mediated endocytosis or by the pro-
cess of diffusion [25]. Release of drug from the polymer is carried out through
a process of hydrolytic degradation of the polymer [32]; this method of deg-
radation allows for sustained and controlled release of pharmacologic agents.
Two opiod agonists, loperamide and dalargin, have profound CNS pharma-
cologic effects, but do not readily cross the BBB. Using polybutylcyanoacry-
late (PBCA) nanoparticles overcoated with surfactant and loaded with each
of these agents, investigators were able to demonstrate good pharmacologic