Biomedical Engineering Reference
In-Depth Information
antigens from endosomes to the cytoplasm is an important subject relating to
control of the antigen processing/presentation pathways.
The release of biomolecules from acidic endosomes requires a membrane-
disruptive agent, which can release the internalized compounds into the cyto-
plasm. Approaches include the use of membrane-penetrating peptides, pathogen-
derived pore-forming proteins, and “endosome escaping” polymers or lipids that
disrupt the endosomal membrane in response to the pH reduction that occurs in
these compartments. Thus, in recent years, there has been significant interest in
developing pH-sensitive nanoparticles that can enhance the cytoplasmic delivery
of various biomolecules [
133
-
136
]. Standley et al. reported an acid-degradable
particle composed of acrylamide and acid-degradable crosslinker for protein-
based vaccines. These particles released encapsulated protein in a pH-dependent
manner. They were stable at the physiological pH of 7.4 but degraded quickly in
the pH 5.0 environment of endosomes. The degradation of particles led to the
endosome escape of encapsulated proteins. The colloid osmotic mechanism
generates a quick degradation of the particles into many molecules, thus increas-
ing the osmotic pressure within the endosomes, leading to a rapid influx of water
across the membrane, resulting in its disruption. In fact, the MHC class I presen-
tation levels achieved with these particles were vastly enhanced as a result of their
ability to deliver more protein into the cytoplasm of APCs. In a mouse immuni-
zation study, these acid-sensitive particles could induce antigen-specific CTL
responses and showed antitumor activity [
137
,
138
]. Hu et al. also reported the
endosome escape of pH-responsive core-shell nanoparticles. pH-sensitive poly
(diethylamino ethyl methacrylate) (PDEAEMA)- core/poly(ethylene glycol)
dimethacrylate (PAEMA)-shell nanoparticles were capable of efficient cytosolic
delivery of membrane-impermeable molecules such as calcein and OVA to DCs.
These particles effectively disrupted endosomes and delivered molecules to the
cytosol of cells without cytotoxicity, and enhanced priming of CD8
+
Tcellsby
DCs pulsed with OVA/PDEAEMA-core nanoparticles [
139
]. Polycations that
absorb protons in response to the acidification of endosomes can disrupt these
vesicles via the proton sponge effect. The proton sponge effect arises from a large
number of weak conjugate bases with buffering capacities between 7.2 and 5.0,
suchasPEI,leadingtoprotonabsorptioninacidorganellesandanosmotic
pressure buildup across the organelle membrane. This osmotic pressure causes
swelling and/or rupture of the acidic endosomes and a release of the internalized
molecules into the cytoplasm [
140
].
4.2 Amphiphilic Polymers for Cytosolic Delivery
Synthetic poly(alkylacrylic acid) [
141
,
142
] and poly(alkylacrylic acid-
co
-alkyl
acrylate) [
143
,
144
] also have pH-dependent, membrane-disruptive properties.
