Osteotropic Peptide That Differentiates Functional Domains of the Skeleton

Abstract

HPMA copolymer-d-aspartic acid octapeptide (D-Asp8) conjugates have been found to target the entire skeleton after systemic administration. In a recent study using the ovariectomized rat model of osteoporosis, we surprisingly discovered that D-Asp8 would favorably recognize resorption sites in skeletal tissues, while another bone-targeting moiety, alendronate (ALN), directs the delivery system to both formation and resorption sites. Atomic force microscopy (AFM) analyses reveal that ALN has a stronger binding force to hydroxyapatite (HA) than D-Asp8. In vitro HA binding studies indicate that D-Asp8 is more sensitive to change of HA crystallinity than ALN. Because the bone apatite in the newly formed bone (formation sites) usually has lower crystallinity than the resorption sites (mainly mature bone), we believe that the favorable recognition of D-Asp8 to the bone resorption sites could be attributed to its relatively weak binding to apatite, when compared to bisphosphonates, and the different levels of crystallinity of bone apatite at different functional domains of the skeleton.

A delivery system specifically approaching bone resorption surfaces to facilitate therapeutic modulation of microRNAs in osteoclasts

“…Moreover, the serum stability data suggested that (D-Asp 8 )-liposome could protect antagomir-148a from degradation by endogenous nucleases in serum, as indicated by the agarose gel electrophoresis analysis showing significantly longer period for the detectable antagomir-148a in (D-Asp 8 )-liposome-antagomir148a group when compared to that in free antagomir-148a group. In addition, no difference was found in serum stability data between (DAsp 8 Previously published studies have shown that D-Asp 8 could preferentially bind to highly crystallized hydroxyapatite [12e14], which is the physicochemical characterization of bone resorption surfaces [12,15], implying its potential as targeting moiety to approach the bone resorption surfaces. Our current data from TRAP staining following bone histomorphometry analysis further validated our published findings that D-Asp 8 moiety could bind to bone resorption surfaces [15], as evidenced by the rhodamine B labeling at the bone resorption surface after the mice were treated with rhodamine B-conjugated D-Asp 8 .…”

“…However, there is still lack of drug delivery system to facilitate miRNA modulators specifically targeting osteoclasts at the cellular level. It has been known that bone resorption surfaces characterized by highly crystallized hydroxyapatite are dominantly occupied by osteoclasts and osteoclast precursors [12]. It is documented that eight repeating sequences of aspartate (D-Asp 8 ) preferably bind to highly crystallized hydroxyapatite [12e14].…”

Design of polyaspartic acid peptide-poly (ethylene glycol)-poly (ε-caprolactone) nanoparticles as a carrier of hydrophobic drugs targeting cancer metastasized to bone

“…18 A short peptide sequence of repetitive aspartic acid (4-10 amino acids) has been shown to interact exclusively with bone in vitro and in vivo. [19][20][21][22] (Asp) 8 is biodegradable, biocompatible, and has shown strong affinity to more crystalline hydroxyapatite and bone surface. 19,21,22 Therefore, (Asp) 8 -linked PEG-PCL nanoparticles can be a potent hydrophobic anticancer drug carrier targeting the bone niche.…”

Nanoparticles and their potential for application in bone

“…9,10 Similarly, nanoparticle treatment of systemic bone diseases such as osteoporosis might be feasible in the future. To date, several molecules to target bone have been identified, such as bisphosphonates and their derivatives, [11][12][13] as well as oligopeptides targeting specifically bone-resorption 14 or bone-formation surfaces. 15 Summarizing, to achieve the desired effect, nanoparticles should fulfill the following criteria: they should be nontoxic for cells, ie, bioinert or biodegradable; they should effectively carry the molecule of interest, eg, labeling agent or drug; and they should exert their actions specifically on their target, without evoking side effects in other tissues.…”