Chemistry Reference
In-Depth Information
osteoarthritis, postoperative pains, headaches, and so on. Rheumatoid arthritis is often
a severe, chronic, systemic inflammatory disorder that affects many tissues and
organs, but especially the joints and cartilages, causing somemobility problems. For a
sustain relief and a better drug delivery, the development of dendritic prodrugs was
sought after a covalent coupling of common drugs to a dendritic scaffold.
Several examples are known with ibuprofen [196c], naproxen [128,139,239],
5-amino salicylic acid (5-ASA) [240], and salicylic acid [241]. We have already
discussed about N-acetyl cystamine (NAS) in a previous section on disulfide linkers.
In the case of salicylic, the dendrimer was made of many salicylic acid units in its
backbone, and also at its periphery. It was able to sustain a slow delivery of the drug
for several days. As for ibuprofen, a G4 PAMAM scaffold was used and the
dendrimer-conjugate concentrated into the cytoplasm of the A549 cells. It provided
a higher activity, a higher local drug level at the inflammatory site.
H
3
C
H
O
OH
H
CH
3
O
OH
HO
HO
HO
HO
O
O
OCH
3
NH
2
Salicylic acid
5-Amino salicylic acid
(S)-ibuprofen
(S)-(+)-naproxen
The antiinflammatory naproxen drug was covalently bound on a PAMAM core for
making a polyester or a polyamide dendritic prodrug that could be cleaved by
esterases in plasma or by a pH variation (Figure 13.12). Naproxen was directly
linked via some amide or ester bonds, using a spacer as a solubilizing group such as
PEG or
L
-lactic acid. Again, this work confirmed that the amide linkage was too stable
for a slow release of the drugs but the ester functions were slowly cleaved after many
hours. A test of a transepithelial permeability gave an enhancement of the drug
permeation. Another study reported the synthesis of a series of naproxen drugs
conjugated to some small polyols, using 3,5-dihydroxybenzoic acid for creating a
degree of branching [128]. There was a mention of some enzymatic studies but they
were not yet disclosed.
5-ASA modified PAMAM dendrimers were studied for their colonic delivery
behavior. The localized amount of drug, due to the enzyme azoreductase in the colon,
favored some colon-specific properties with a local release. Overall, the conjugation
of the NSAIDs with some dendrimers helped in their transport, their localization, and
FIGURE 13.12
Nonsteroidal-dendrimer conjugates containing (S)-(
รพ
)-naproxen.
