14.1 Introduction
The history of cyclodextrins (CDs) began in France in the late nineteenth century,
with the work of a pharmacist and chemist, Antoine Villiers, on the action of
enzymes on various carbohydrates, which he particularly studied using the butyric
ferment Bacillus amylobacter (Clostridium butyricum) on potato starch. After the
starch was treated with the butyric ferment method, a lot of chemicals were obtained,
of course, and some of the by-products attracted Villiers’s attention. By manipulating
the experimental conditions, Villiers obtained two distinct crystallized “cellulosines”
(as named by Villiers)—most probably, α-dextrin (α-cyclodextrin) and β-dextrin
(β-cyclodextrin). It was only in 1972 that Manor and Saenger demonstrated that the
formula of one of these cyclodextrins was ((C 6 H 10 O 5 ) 6 -H 2 O) [1].
Once the structures of CDs were confirmed, chemists started to modify the hydroxyl
groups of CDs to yield plentiful applications. The hydroxyl groups of each sugar unit at
the 2-, 3-, and 6-positions compete for nucleophilic reagents in most conditions, making
selective modification extremely difficult. In fact, there are minor differences among
them—for example, the hydroxyl groups at position 2 (OH-2) are the most acidic (acid
dissociation constant (pKa) 12.2) [2], those at position 6 (OH-6) are the most nucleophilic, and those at position 3 (OH-3) have the lowest reactivity. These features give
CDs considerable potential for functionalization via modification of specific hydroxyl
groups. On the basis of this, pioneering chemists have developed various different
selective functionalization strategies, including site-selective functionalization [3],
which has been a boon to those who need special functionalized molecules to fulfill
new purposes they have devised. According to the chemical and physical properties of
CDs, the water solubility of enhanced hydrophobic molecules is one of the special
properties of CDs. In one remarkable example, Zhang and coworkers used conjugation
of functionalized CDs with C 60 to improve the water solubility of C 60 by 10
10 times
[4]. Also, there has been some interesting work on cytotoxic anticancer drugs, most of
which have very low solubility in aqueous media and low apparent permeability as well
[5]. To overcome these problems, scientists have designed and prepared various delivery
systems based on CDs, which have demonstrated good results. Some scientists have
even synthesized stimuli-responsive delivery systems that release drugs in an acidic
environment (pH 6.8), such as the tumor microenvironment [6, 74]. Functionalized CDs
can also be employed as platform molecules—for example, their hydrophobic cavities
interact with some hydrophobic molecules, such as some drugs, to improve their water
solubility and optimize their bioavailability. Hydroxyl groups modified for such purposes can be used in specific preferred applications such as multivalent carriers and
targeted drug delivery systems. In this review we first discuss CD functionalization
methods and then discuss their delivery applications.
14.2 Selectively Functionalized Cyclodextrins
Selectivity is an essential meaning in chemistry, which attracts all chemists’ attention, and the same situation also occurs in cyclodextrin chemistry. Although use of
regioselectivity as an effective method to access a specific hydroxyl group at a
386
J. Liu et al.
The history of cyclodextrins (CDs) began in France in the late nineteenth century,
with the work of a pharmacist and chemist, Antoine Villiers, on the action of
enzymes on various carbohydrates, which he particularly studied using the butyric
ferment Bacillus amylobacter (Clostridium butyricum) on potato starch. After the
starch was treated with the butyric ferment method, a lot of chemicals were obtained,
of course, and some of the by-products attracted Villiers’s attention. By manipulating
the experimental conditions, Villiers obtained two distinct crystallized “cellulosines”
(as named by Villiers)—most probably, α-dextrin (α-cyclodextrin) and β-dextrin
(β-cyclodextrin). It was only in 1972 that Manor and Saenger demonstrated that the
formula of one of these cyclodextrins was ((C 6 H 10 O 5 ) 6 -H 2 O) [1].
Once the structures of CDs were confirmed, chemists started to modify the hydroxyl
groups of CDs to yield plentiful applications. The hydroxyl groups of each sugar unit at
the 2-, 3-, and 6-positions compete for nucleophilic reagents in most conditions, making
selective modification extremely difficult. In fact, there are minor differences among
them—for example, the hydroxyl groups at position 2 (OH-2) are the most acidic (acid
dissociation constant (pKa) 12.2) [2], those at position 6 (OH-6) are the most nucleophilic, and those at position 3 (OH-3) have the lowest reactivity. These features give
CDs considerable potential for functionalization via modification of specific hydroxyl
groups. On the basis of this, pioneering chemists have developed various different
selective functionalization strategies, including site-selective functionalization [3],
which has been a boon to those who need special functionalized molecules to fulfill
new purposes they have devised. According to the chemical and physical properties of
CDs, the water solubility of enhanced hydrophobic molecules is one of the special
properties of CDs. In one remarkable example, Zhang and coworkers used conjugation
of functionalized CDs with C 60 to improve the water solubility of C 60 by 10
10 times
[4]. Also, there has been some interesting work on cytotoxic anticancer drugs, most of
which have very low solubility in aqueous media and low apparent permeability as well
[5]. To overcome these problems, scientists have designed and prepared various delivery
systems based on CDs, which have demonstrated good results. Some scientists have
even synthesized stimuli-responsive delivery systems that release drugs in an acidic
environment (pH 6.8), such as the tumor microenvironment [6, 74]. Functionalized CDs
can also be employed as platform molecules—for example, their hydrophobic cavities
interact with some hydrophobic molecules, such as some drugs, to improve their water
solubility and optimize their bioavailability. Hydroxyl groups modified for such purposes can be used in specific preferred applications such as multivalent carriers and
targeted drug delivery systems. In this review we first discuss CD functionalization
methods and then discuss their delivery applications.
14.2 Selectively Functionalized Cyclodextrins
Selectivity is an essential meaning in chemistry, which attracts all chemists’ attention, and the same situation also occurs in cyclodextrin chemistry. Although use of
regioselectivity as an effective method to access a specific hydroxyl group at a
386
J. Liu et al.