Hyaluronic acid (HA), a copolymer of N-acetyl-D-glucosamine and D-glucuronic
acid, is a widely used targeting macromolecule that can bind to CD44, which is
overexpressed in various tumors [45]. Wu et al. used HA as a targeting ligand to
develop a thermo-responsive hybrid nanogel for simultaneous temperature sensing,
cancer cell targeting, fluorescence imaging, and combined chemo-photothermal
treatment [46]. Recently, Hwang et al. constructed a fluorescence-switchable
theranostic nano-platform using HA-conjugated graphene oxide (GO), which is
capable of both sensing oncogenic miR-21 and inhibiting its tumorigenicity
simultaneously [47].
12.3.3 Conjugation Methods
The possible conjugation method can be categorized as conventional method, click
chemistry, and physicochemical interaction. Because there are several merits or
demerits on each method, we should thoroughly review and select the conjugation
method for each nano-system.
The major portion of conventional method is the peptide bond formation
between nanoparticle and targeting molecule. Amine and acid functionalized
moieties are linked as a peptide bond and in most cases the acid-group is activated
with active ester derivatives, such as N-hydroxysuccinimide (NHS) ester, to
improve the conjugation efficiency. Amino-group also can react with aldehyde or
isothiocyanate (–SCN) to form imine or thiourea bond. Thiol-group can react with
maleimide derivatives to form thio-ether bond. Several types of chemical linker
between nanoparticles and targeting molecules can be used for the conjugation.
Sulfosuccinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC) can
be used between amino-group and thiol-group.
Click chemistry can be done on click chemical combinations, such as azide and
diarylcyclooctyne (DBCO) or tetrazine and trans-cyclooctene (TCO) combinations.
Physicochemical interactions, which is non-covalent bond formation, come from
electrostatic, hydrophobic, and affinity interactions between nanoparticles and targeting molecules. Physicochemical conjugation strategies are particularly useful for
the assembly of therapeutic agents onto nanoparticles. Typical example of
physicochemical interactions is the positively charged nanomaterials and negatively
charged siRNA can form a very stable nanocomposite even in in vivo condition.
Each chemical reaction should need chemicals such as base/acid or reducing/
oxidation agent, therefore, we should consider and check the chemical instability of
each nanomaterials or targeting molecules for each reaction condition, and finally
we can select the optimal conjugation method for each conjugation.
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Y.-S. Lee et al.
acid, is a widely used targeting macromolecule that can bind to CD44, which is
overexpressed in various tumors [45]. Wu et al. used HA as a targeting ligand to
develop a thermo-responsive hybrid nanogel for simultaneous temperature sensing,
cancer cell targeting, fluorescence imaging, and combined chemo-photothermal
treatment [46]. Recently, Hwang et al. constructed a fluorescence-switchable
theranostic nano-platform using HA-conjugated graphene oxide (GO), which is
capable of both sensing oncogenic miR-21 and inhibiting its tumorigenicity
simultaneously [47].
12.3.3 Conjugation Methods
The possible conjugation method can be categorized as conventional method, click
chemistry, and physicochemical interaction. Because there are several merits or
demerits on each method, we should thoroughly review and select the conjugation
method for each nano-system.
The major portion of conventional method is the peptide bond formation
between nanoparticle and targeting molecule. Amine and acid functionalized
moieties are linked as a peptide bond and in most cases the acid-group is activated
with active ester derivatives, such as N-hydroxysuccinimide (NHS) ester, to
improve the conjugation efficiency. Amino-group also can react with aldehyde or
isothiocyanate (–SCN) to form imine or thiourea bond. Thiol-group can react with
maleimide derivatives to form thio-ether bond. Several types of chemical linker
between nanoparticles and targeting molecules can be used for the conjugation.
Sulfosuccinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC) can
be used between amino-group and thiol-group.
Click chemistry can be done on click chemical combinations, such as azide and
diarylcyclooctyne (DBCO) or tetrazine and trans-cyclooctene (TCO) combinations.
Physicochemical interactions, which is non-covalent bond formation, come from
electrostatic, hydrophobic, and affinity interactions between nanoparticles and targeting molecules. Physicochemical conjugation strategies are particularly useful for
the assembly of therapeutic agents onto nanoparticles. Typical example of
physicochemical interactions is the positively charged nanomaterials and negatively
charged siRNA can form a very stable nanocomposite even in in vivo condition.
Each chemical reaction should need chemicals such as base/acid or reducing/
oxidation agent, therefore, we should consider and check the chemical instability of
each nanomaterials or targeting molecules for each reaction condition, and finally
we can select the optimal conjugation method for each conjugation.
238
Y.-S. Lee et al.