BIOMEDICAL APPLICATIONS OF “CLICK”-MODIFIED CYCLODEXTRINS - Click Chemistry in Glycoscience: New Developments and Strategies - page 281

Bone Soft tissues

Osteotropic molecular host Bone anabolic agent Guest/host molecular complex

FIGURE 11.1 The proposed bone anabolic mechanism of ALN- -CD as a molecular
sequestrant. (See color plate section.)

peptides) to CD rings. Because these targeting moieties are only soluble in water, the
final conjugation step has to be done in water, which restricts the use of many reac-
tions. “Click” HDC reaction was eventually selected by the team to conjugate alen-
dronate (ALN) to -CD, due to its high efficiency and most importantly its tolerance

of water. When tested in a simulated oral environment, ALN-

-CD/dexamethasone
(Dex) complex was shown to be able to bind to model tooth surface immediately
upon exposure and gradually release the complexed Dex. It was proposed that such
formulation could be used clinically as a mouthwash for the treatment of oral mucosi-
tis and vesiculo-erosive oral mucosal disease (V-EOMD) [45]. As another potential
application, the team proposed that ALN- -CD might act as a molecular seques-

trant. Once anchored on bone, the -CD annulus would sequester/enrich endoge-

nous bone anabolic agents such as prostaglandin E 2 , which would lead to a local
bone anabolic reaction (Figure 11.1). Indeed, when tested in a rat mandibular bone
model, the local injection of ALN- -CD to the mandibular bone caused substantial

localized bone formation. Such therapy is highly favored by periodontists for peri-
odontal bone repair via simple injection compared to the painful open gum surgery
repair.
Inspired by the successful synthesis and applications of ALN-

-CD and the exten-
sive development of polyrotaxane as a drug delivery carrier, the same team then
synthesized ALN- -CD and used it to develop a linear multifunctional “click” PEG-

based osteotropic polyrotaxane for diagnosis and treatment evaluation of cancer
bone metastasis. This system is designed to address a critical challenge in developing
osteotropic macromolecular prodrugs. It has been found in the past that the increase
of bone-targeting moiety in polymeric prodrug will enhance their osteotropicity [46].
Due to the fact that these targeting moieties are only soluble in water, their incorpora-
tion into the prodrug has always been difficult and nonconsistent from batch to batch.
By threading ALN- -CD onto PEG and followed by “click” copolymerization, one

could freely adjust the content of ALN-pendent functionality of the polyrotaxane
[47]. Indeed, by increasing the ALN-

-CD feed-in ratio, the team could gradually