physiological conditions are mildly acidic, usually in the range of pH 6.5–5.5. pH
responsiveness is used to trigger the controlled release in pathological tissue or after
internalized by endocytosis. Therefore, it is often used for targeted delivery of
pharmaceutical drugs to pathological tissues.
pH responsiveness is generally based on two mechanisms: (1) protonation of
carboxylic acid or amino groups at acidic pH, which triggers the release of cargo,
and (2) acid-degradable linkers, which release drug under acidic environment.
Compared to carboxylic acid group, there are primary, secondary, and tertiary
amino groups with variable pK a value, which could be fine-tuned for desired
controlled release characteristics. As for acid-degradable linkers, there are multiple
choices, including acetal, hydrazine, silyl ether, and so on. By introducing different
substitutes to acid-degradable linkers, the degradation and release rate could be
adjusted accordingly.
23.3.2 Reducing Agent Responsiveness
Reducing agents are widely existing in physiological or pathological environment
[19]. For instance, there is reducing agent glutathione (GSH, 5–10 mM) inside
animal cells. By comparison, extracellular environment has negligent level of
GSH. This significant difference in GSH level could be used to trigger controlled
release.
Disulfide bond is the most widely used reducing agent-responsive linker, which
may rapidly degrade in the presence of GSH and other reducing agents. Another
important reducing agent-responsive linker is thioester. Stimuli-responsive DDSs
could respond to GSH and release cargo by carrier degradation or prodrug
conversion.
23.3.3 Reactive Oxygen Species Responsiveness
During vital biological processes, a number of species are produced by the body
derived from molecular oxygen. One class of these species is referred to as “reactive
oxygen species (ROS),” including the superoxide, hydroxyl and peroxyl radical,
hydrogen peroxide, singlet oxygen, and hypochlorous acid/hypochlorite. The major
ROS production route is the mitochondrial respiration process. ROS are involved in
a wide range of physiological and pathological processes, including signal transduction, inflammation, carcinogenesis, and neurodegenerative injury [20].
It is an interesting topic to design probes for the detection of ROS. Preferably,
category of ROS is to be determined. Drug delivery systems (DDSs) targeting
pathological ROS is of great importance. Tumor and inflammatory tissues are
often overexpressed with ROS. Therefore, ROS-responsive probes or DDSs are
important for bioimaging or targeted drug delivery to tumor or inflammatory tissues.
A variety of chemical linkers responsive to ROS are used in biosensor or DDS
design.
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responsiveness is used to trigger the controlled release in pathological tissue or after
internalized by endocytosis. Therefore, it is often used for targeted delivery of
pharmaceutical drugs to pathological tissues.
pH responsiveness is generally based on two mechanisms: (1) protonation of
carboxylic acid or amino groups at acidic pH, which triggers the release of cargo,
and (2) acid-degradable linkers, which release drug under acidic environment.
Compared to carboxylic acid group, there are primary, secondary, and tertiary
amino groups with variable pK a value, which could be fine-tuned for desired
controlled release characteristics. As for acid-degradable linkers, there are multiple
choices, including acetal, hydrazine, silyl ether, and so on. By introducing different
substitutes to acid-degradable linkers, the degradation and release rate could be
adjusted accordingly.
23.3.2 Reducing Agent Responsiveness
Reducing agents are widely existing in physiological or pathological environment
[19]. For instance, there is reducing agent glutathione (GSH, 5–10 mM) inside
animal cells. By comparison, extracellular environment has negligent level of
GSH. This significant difference in GSH level could be used to trigger controlled
release.
Disulfide bond is the most widely used reducing agent-responsive linker, which
may rapidly degrade in the presence of GSH and other reducing agents. Another
important reducing agent-responsive linker is thioester. Stimuli-responsive DDSs
could respond to GSH and release cargo by carrier degradation or prodrug
conversion.
23.3.3 Reactive Oxygen Species Responsiveness
During vital biological processes, a number of species are produced by the body
derived from molecular oxygen. One class of these species is referred to as “reactive
oxygen species (ROS),” including the superoxide, hydroxyl and peroxyl radical,
hydrogen peroxide, singlet oxygen, and hypochlorous acid/hypochlorite. The major
ROS production route is the mitochondrial respiration process. ROS are involved in
a wide range of physiological and pathological processes, including signal transduction, inflammation, carcinogenesis, and neurodegenerative injury [20].
It is an interesting topic to design probes for the detection of ROS. Preferably,
category of ROS is to be determined. Drug delivery systems (DDSs) targeting
pathological ROS is of great importance. Tumor and inflammatory tissues are
often overexpressed with ROS. Therefore, ROS-responsive probes or DDSs are
important for bioimaging or targeted drug delivery to tumor or inflammatory tissues.
A variety of chemical linkers responsive to ROS are used in biosensor or DDS
design.
612
W. Mao and D. Ma