Chemistry Reference
In-Depth Information
monoclonal antibodies were recognized by specific transfer receptors at the barrier,
marking the drug-containing liposomes for transport into the brain. Other active
targeting schemes rely on in situ stimulus to release liposome payloads. Irradiation
with light (Pidgeon and Hunt 1983) and changes in temperature (Weinstein et al.
1979) or pH (Yatvin et al. 1980), for example, can cause modified liposomes to
release pharmaceutical payloads. Similar targeting schemes have been adapted by
others in creating synthetic copolymer micelles for drug delivery, as we will
discuss in the next section.
Block Copolymer Micelles.
Researchers have borrowed Nature's design of lipo-
somes made from self-assembling amphiphilic molecules to create synthetic poly-
mers that mimic this behavior. Although liposomes are immensely useful and
researchers have learned many guiding principles from studying them, synthetic
copolymer amphiphiles offer the potential of more control over the physical and
chemical characteristics of nanocapsules, as well as more diverse functionality.
Self-assembling polymers are usually diblock copolymers that contain components
with significantly different hydrophilicity. Thus, the polymers self-assemble into
hydrophobic-core and hydrophilic-shell nanoassemblies in aqueous environments.
In this case, hydrophobic guest molecules, such as drugs, can be entrapped in the
greasy core of the artificial vesicles.
One of the most widely used amphiphilic block copolymer architectures is the
family of triblock copolymers with the trade name Pluronic
w
. These polymers,
also called poloxamers, consist of two terminal PEG blocks with a middle poly(pro-
pylene glycol) (PPG) block. In aqueous solution, the chains aggregate so that the
PPG blocks form a hydrophobic core and the PEG blocks point outward, remaining
hydrated. Pharmaceutical agents trapped in the hydrophobic core and dispersed in the
body enjoy the same benefits provided to PEGylated liposomes already discussed,
such as increased circulation time and improved biodistribution. Research by
Batrakova et al. (1996) showed that Pluronic copolymer micelles can deliver anthra-
cycline drugs, which are noncovalently bound in the cores of the micelles, to tumors.
Studies with mice showed complete disappearance of tumors in nearly 50% of sub-
jects. Subsequent work showed that the composition of the triblock copolymers, such
as the total molecular weight and relative block lengths between hydrophilic and
hydrophobic units, strongly affects the cytotoxicity of encapsulated doxorubicin
and the accumulation of micelles in cancerous cells (Batrakova et al. 1999).
Hydrophobic chains of intermediate length and short hydrophilic chains are the
most effective, and the use of Pluronic micelles for the delivery of doxorubicin has
reached phase II clinical trials (Alakhov et al. 1999).
Another synthetic polymer that has shown promise in recent clinical trials for the
micellar encapsulation of anticancer drugs is a block copolymer of PEG and poly
(aspartic acid) [PEG-b-P(Asp)]. Doxorubicin can be covalently attached to PEG-b-
P(Asp) through the free carboxylic acid groups on aspartic acid, and the block
copolymer then forms micelles in solution with the hydrophobic aspartic acid and
drug block forming the core (Yokoyama et al. 1991; Kataoka et al. 1993). As typi-
cally occurs,
the hydrated PEG chains significantly increased blood circulation
