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interaction, the hydrophilic and hydrophobic segments were joined together nonco-
valently to allow the self-assembly and micellization of chemotherapeutic agents in
aqueous solution [42].
11.3.4.4 Development of Osteotropic CDs for Musculoskeletal Disease
The
skeletal system is the only tissue
in vivo
that contains calcium phosphate in the form of
hydroxyapatite (HA). The nanosized HA needle crystals embeds in an organic matrix,
mainly type-I collagen to form a hard and tough composite material, the bone. The
skeletal system's first function is to provide a mechanical support and protection
for our body. It also provides a rich source of inorganic ions, which helps to main-
tain the homeostasis of calcium and phosphate. Together with tendons, ligaments,
and muscles, the skeletal system provides mobility, which is critical for the life of
mammals. Three types of cells populate the skeletal system: osteoclasts, osteoblasts,
and osteocytes. The abnormity of their biological functions leads to a wide array of
musculoskeletal diseases [43].
One major issue of drug development for musculoskeletal diseases is the fact that
most of the bone drugs are not osteotropic, which often lead to limited efficacy and
severe safety concerns due to the drugs' ubiquitous distribution in the soft tissue.
To address this issue, several groups have focused on the development of bone-
targeted prodrugs [44]. As an example, Liu et al. proposed the development of the
osteotropic CDs (Scheme 11.17). The general idea is to synthesize CD derivatives
that have strong bone/tooth-binding capability. As part of the critical element of the
derivatives, the CD annuli will interact with hydrophobic drugs to form molecular
complexes. Upon exposure of the osteotropic CD/drug complex to the hard tissues,
they will be immediately immobilized on the hard tissue surface. The complexed drug
will be gradually released from the complex via extracellular fluid exchange/dilution.
One issue surfaced during the synthesis of the osteotropic CDs is the diffi-
culty of conjugating osteotropic moieties (e.g., bisphosphonates, oligo glutamic acid
OH
O
O
O
HO
O
N
N
OH HO
P
HO
OH
OH
H
N
O
N
HO
HO
O
OH
OH
O
O
O
HO
P
OH
OH
HO
O
OH
O
OH
O
OH
OH
OH
O
O
OH
OHO
O
OH
HO
O
OH
SCHEME 11.17
The structure of ALN-
-CD. (Adapted from ref. 45.)
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