Biomedical Engineering Reference
In-Depth Information
(1) Using new chemical processes to fabricate structured nanoparticles.
Polymeric micelles encapsulate drugs mostly via physical trapping based on
hydrophobic interactions. They are generally fabricated by coprecipitation of the
hydrophobic drugs with the hydrophobic blocks of amphiphilic copolymers by
dialysis or the solvent-evaporation method,
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assuming that the drugs and the
hydrophobic blocks precipitate simultaneously and thus the drugs are completely
embedded in the hydrophobic micelle core. However, in many cases this is not a
very realistic assumption, as either the drugs can precipitate first or the core can
form first, which prevents proper drug encapsulation in the core. For example,
when the core forms first, most drug molecules may precipitate around the core,
which are prone to burst release upon dispersion in an aqueous solution.
15
Building on this finding, we proposed that coating the core with an additional
hydrophobic layer would impose an extra diffusion barrier and thereby minimize
burst drug release. Using a stepwise pH-controlled process, three-layer onion-
structured nanoparticles (3LNPs) were synthesized that consisted of a poly(e-
caprolactone) (PCL) core, a pH-responsive poly[2-(N,N-diethylamino)ethyl
methacrylate] (PDEA) middle layer, and a polyethylene glycol (PEG) outer
coronal layer.
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Compared to the conventional core-corona micelles, such 3LNPs
were found to exhibit a significantly lower burst release of camptothecin (CPT) at
physiological pH due to the effective barrier of the hydrophobic PDEA barrier.
The conventional method for preparing polymeric micelles through liquid
solvent evaporation or dialysis offers little control of micellization versus drug
precipitation. However, this can be accomplished with a near-critical fluid
micellization (NCM) method to prepare drug-loaded polymeric micelles.
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The
solvating power of a near-critical fluid solvent is easily tunable with pressure.
Thus, more selective and flexible micellization can be controlled by adjusting
the pressure alone. At high pressures, drugs and polymers were molecularly
homogenous in a near-critical solvent, whereas at moderate pressures
micellization/drug encapsulation occurred (Figure 3.4A). With this process,
PEG-PCL micelles, formed in a near-critical dimethyl ether/trifluoromethane,
could be loaded with paclitaxel (PTX) as high as 12 wt% (Figure 3.4B). More
recently, we prepared three-layered micelles formed by a stepwise NCM
process that exhibited little, if any, burst release despite the high drug loading
content (Figure 3.4C, D).
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The biggest advantage of this NCM is that it uses
the conventional Food and Drug Administration (FDA) approved materials to
obtain high drug loading micelles with minimized burst or even burst-free.
Such products are also free of contamination from organic solvents.
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(2) Drug conjugation
The second approach to eliminate burst release is by conjugating drugs to the
carriers via covalent bonds. Because the drug must be released once at the target,
the covalent bonds or linkers must be cleavable in the tumor-cell environment.
For instance, doxorubicin (DOX) was conjugated to a poly(
L
-aspartic acid)
[P(Asp)] block in the block copolymer PEG-b-P(Asp) through amide
19,20
or
hydrazone linkers.
21,22
Drugs can also be conjugated to the ends of hydrophobic
blocks.
23,24
The resulting micelles formed from PEG-block-poly(
L
-amino acid)
