280
A. S. Shinde et al.
drugs [128]. The in vivo studies have shown the accumulation of nanoparticles in
tumors at the hypoxia regions as differentiated to healthy cells.
The brain commands high amounts of oxygen supply. It is at risk of hypoxia,
causing irregularity in the flow of blood induced either by traumatic brain injury,
brain cancer, cardiac failure, or subcortical vascular disease. Hypoxia can also cause
neurodegenerative diseases due to neuronal dysfunction and cell death. HIF based
nanoparticles have the superiority of regulating the expressions of various genes,
thereby treating the disease [129]. Hypoxia targeting NPs have a potential advantage
to treat inaccessible brain tumors, which are difficult to achieve through conventional
surgeries.
22 Targeting Acidity
In the presence of oxygen, cancer cells undergo glycolysis, which is significantly vital
for survival and proliferation, resulting in the high production of lactic and carbonic
acids. These chemicals are intensively pumped out of the cells to keep the intracellular
pH nearly neutral. The acidification of the tumor microenvironment promotes cancer
aggressiveness and invasiveness. Thus, the acidic microenvironment around cancer
cells may provide a marker for detecting and targeting diseased tissues.
The pH-sensitive nanoparticles consist of lipids, polymers, or peptides such as
pHLIPs (pH Low Insertion Peptides). The fundamental principle of synthesizing pHsensitive fusogenic liposomes is to select such a lipid which is steady at physiological
pH and destabilized in acidic conditions ensuing cellular internalization thus, the
delivery of drugs within the nanoparticles into the cytosol [130]. The highly pHsensitive NPs are developed to target acidity, help for both treatment and diagnosis
of a wide array of cancers, and also many other pathological diseases.
Emmetiere et al. synthesized pHLIP using the dual-delivery method to tether
liposomes to cancer cells [131]. First, Tetrazine (Tz) was coupled to pHLIP, which
is a bioorthogonal reactive small molecule to form a pHLIP-Tz conjugate. This
conjugate was injected into mice that label the surface of the cancer cells. Then,
liposomes containing
18 F PET isotope was coated with bioorthogonal reactive transcyclooctenes and was given a second injection. After circulating for an extended
period, the radiolabelled liposomes due to the EPR effect accumulated at the tumor
site. This was then followed by a click reaction between trans-cyclooctenes and
pHLIP-Tz in liposome coat resulting in tethering and covalent conjugation of liposome to the cancer cell surface. This in vivo clicks reaction permits to attain higher
accumulation of radiolabelled liposomes in the tumor site, high signal/noise ratio,
low non-specific binding, and reduced toxicity to bone marrow and kidneys.
In another study, pHLIP-liposome construction is used to deliver nanopores and
induce apoptosis in cancer cells [132]. For the cell to function usually, the proper
balance of ion between extracellular and intracellular is crucial. Any slightest changes
in the conditions may lead to the death of the cell. A pore formation gramicidin A was
delivered to the membrane of the cell using pHLIP-coated DOPC liposome, which
A. S. Shinde et al.
drugs [128]. The in vivo studies have shown the accumulation of nanoparticles in
tumors at the hypoxia regions as differentiated to healthy cells.
The brain commands high amounts of oxygen supply. It is at risk of hypoxia,
causing irregularity in the flow of blood induced either by traumatic brain injury,
brain cancer, cardiac failure, or subcortical vascular disease. Hypoxia can also cause
neurodegenerative diseases due to neuronal dysfunction and cell death. HIF based
nanoparticles have the superiority of regulating the expressions of various genes,
thereby treating the disease [129]. Hypoxia targeting NPs have a potential advantage
to treat inaccessible brain tumors, which are difficult to achieve through conventional
surgeries.
22 Targeting Acidity
In the presence of oxygen, cancer cells undergo glycolysis, which is significantly vital
for survival and proliferation, resulting in the high production of lactic and carbonic
acids. These chemicals are intensively pumped out of the cells to keep the intracellular
pH nearly neutral. The acidification of the tumor microenvironment promotes cancer
aggressiveness and invasiveness. Thus, the acidic microenvironment around cancer
cells may provide a marker for detecting and targeting diseased tissues.
The pH-sensitive nanoparticles consist of lipids, polymers, or peptides such as
pHLIPs (pH Low Insertion Peptides). The fundamental principle of synthesizing pHsensitive fusogenic liposomes is to select such a lipid which is steady at physiological
pH and destabilized in acidic conditions ensuing cellular internalization thus, the
delivery of drugs within the nanoparticles into the cytosol [130]. The highly pHsensitive NPs are developed to target acidity, help for both treatment and diagnosis
of a wide array of cancers, and also many other pathological diseases.
Emmetiere et al. synthesized pHLIP using the dual-delivery method to tether
liposomes to cancer cells [131]. First, Tetrazine (Tz) was coupled to pHLIP, which
is a bioorthogonal reactive small molecule to form a pHLIP-Tz conjugate. This
conjugate was injected into mice that label the surface of the cancer cells. Then,
liposomes containing
18 F PET isotope was coated with bioorthogonal reactive transcyclooctenes and was given a second injection. After circulating for an extended
period, the radiolabelled liposomes due to the EPR effect accumulated at the tumor
site. This was then followed by a click reaction between trans-cyclooctenes and
pHLIP-Tz in liposome coat resulting in tethering and covalent conjugation of liposome to the cancer cell surface. This in vivo clicks reaction permits to attain higher
accumulation of radiolabelled liposomes in the tumor site, high signal/noise ratio,
low non-specific binding, and reduced toxicity to bone marrow and kidneys.
In another study, pHLIP-liposome construction is used to deliver nanopores and
induce apoptosis in cancer cells [132]. For the cell to function usually, the proper
balance of ion between extracellular and intracellular is crucial. Any slightest changes
in the conditions may lead to the death of the cell. A pore formation gramicidin A was
delivered to the membrane of the cell using pHLIP-coated DOPC liposome, which