Biomedical Engineering Reference
In-Depth Information
enhance the circulation times, reduce the drug leakage and minimise haemo-
lytic toxicity due to parent dendrimer. Another strategy could be development of
pH responsive dendrimers which can specifically release the therapeutic cargo
at low pH tumor environments. Jin et al. (2011) developed pH responsive PPD
nanocarrier with poly(2-(
N
,
N
-diethylamino)ethyl methacrylate) (PDEA) chains
introduced onto methoxy-poly(ethylene glycol) (mPEG) poly(amidoamine)
(PAMAM) dendrimer for 5-FU delivery under in vivo conditions. The nanocar-
rier exhibited long half-lives and high tumor targeting ability than free 5-FU.
Under acidic conditions (pH < 6.5) typical of tumor environment, the PDEA
chains were extended allowing release of 5-FU, whereas in neutral or basic con-
ditions (pH > 7.4) the PDEA chains restrict the release of 5-FU and 5-FU was
intact in the nanocarrier.
Moreover, dendrimers with high density of functional groups (such as amine
groups and carboxyl groups) on the surface are also known to electrostatically
interact with the drug molecules enhancing the solubility of hydrophobic drugs.
Non-steroidal anti-inflammatory drugs bearing carbonyl groups such as ibupro-
fen, ketoprofen, naproxen, diflunisal and indomethacin have been reported to
electrostatically interact with dendrimer moieties. Weakly acidic anticancer and
antibacterial drugs with carbonyl groups are also known to complex with amine
terminated dendrimers (Chen et al. 2004). Such properties make dendrimers
highly suitable as drug delivery systems.
2.1.2 Covalent Conjugation of Drugs
Another strategy could be covalent conjugation of drug molecules with the den-
drimer external functional groups. In this approach, the covalently bound drugs
can be released via chemical or enzymatic cleavage of hydrolytically labile
bonds. Complexation of drugs with the dendrimer molecules by simple encap-
sulation or via electrostatic interactions can retain the chemical integrity and
pharmacological properties of drug molecules, while covalent conjugation of
drugs to the surface functional groups of dendrimers through chemical linkages
can enable controlled drug release which cannot be achieved by simple encap-
sulation/electrostatic complexation approaches. A schematic representation of
different strategies by which dendrimer can bind with the drug molecules is
shown in Fig.
4
.
Patri and co-workers compared the release kinetics of covalently conjugated
and hydrophobically complexed methotrexate (MTX) drug to G5 PAMAM den-
drimers. The activity of methotrexate complexed within dendrimer was compara-
ble to free drug in vitro while the covalently conjugated drug was better suited for
targeted drug delivery as it inhibits the premature release of the drug under bio-
logical conditions (Patri et al. 2005). Another study suggested stochastic function-
alization of MTX and TAMRA (tetramethylrhodamine) fluorophore by copper-free
click chemistry to PAMAM dendrimers (Fig.
5
). The reaction involves esterase
