Biomedical Engineering Reference
In-Depth Information
amphiphilic polymer brushes. 59 The key point is that the backbones of the
polymer brushes acted as crosslinkages on the hydrophobic core surface,
instead of chemical crosslinking, which substantially enhanced the micelle
stability. Specifically, the resulting micelles had much lower CMCs than
corresponding PEG-PCL block copolymers.
For the excretion of the nanocarriers from the body, crosslinked micelles must
be able to break into small polymer chains. Toward this end, reversible
crosslinking triggered by different stimuli like pH, 60 UV light, 61 or others 62 was
later developed. Historically, pH-sensitivity was the first one used to trigger a
desired carrier change because cancer or inflammation makes the extracellular
pH at the disease site acidic. 63 For instance, micelles formed from the triblock
copolymer PEG-b-poly[N-(3-aminopropyl)methacrylamide]-b-poly(N-isopro-
pylacrylamide) (PEG-PAPMA-PNIPAM) were shell-crosslinked with ter-
ephthaldicarbaldehyde (TDA) at pH 9 via cleavable imine linkages. 60
However, at pH , 6 the hydrolytic cleavage of the imine crosslinkages occurred.
Other examples 64,65 were inspired by crosslinking, using disulfide linkages that
are sensitive to intracellular GSH (y0.5-10 mM as opposed to y20-40 mMin
the bloodstream 66 ). For example, micelles made of a PCL-b-poly[(2,4-
dinitrophenyl)thioethyl ethylene phosphate]-b-PEG (PCL-b-PPE DNPT -b-PEG)
triblock copolymer, crosslinked with disulfide bonds, were found to be stable in
circulation but quickly decomposed in intracellular fluid. 65
Even if the micelle happens to be unstable, its decomposition rate can be reduced
by choosing a stiff or bulky core. Toward this end, benzyl groups were introduced
to increase the rigidity of hydrophobic cores. 67 Lavasanifar et al. synthesized benzyl
carboxylate-substituted e-CL monomers and prepared PEG-b-poly(a-benzyl
carboxylate e-caprolactone) (PEG-b-PBCL) copolymers. 67 For comparison, they
also prepared PEG-b-poly(a-carboxyl-e-caprolactone) (PEG-b-PCCL) by further
catalytic debenzylation. Their results demonstrated that the stability of micelles
with core structures containing aromatic groups (PEG-b-PBCL) was higher than
that of the parent PEG-PCL micelles and of the PEG-b-PCCL micelles. The
micelle decomposition rate can also be reduced by crystallizable hydrophobic
blocks. 45,68 Another approach is to enhance ionic or hydrogen bonding interactions
in the micelle core. For example, polyion complex (PIC) micelles with oppositely
charged macromolecules, such as DNA or peptides, are resistant to enzymes in the
bloodstream, 69 but they disassemble once the salt concentration rises above a
certain threshold. 70 Hedrick et al. introduced urea functional groups, 71 while Zhu
et al. introduced DNA base pairs 72 into block copolymers to show that hydrogen
bonding can reduce micelle decomposition rates.
d n 4 y 3 n g | 2
3.2.1.3 Approaches to Achieve Robust Intracellular Release
The chemical forces discussed above that make carriers retain drugs can conflict
with the need for a rapid and complete release at the target site. Drugs become
active only after liberation from their carriers. 73,74 DOX that was stably bonded
to the nanoparticle core of poly(lactic-co-glycolic acid) (PLGA) 75
or P(Asp) 76
 
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