Drug Targeting Organ-Specific Strategies

Monomethoxy-polyethylene glycol
CH 3 –(OCH 2 CH 2 )–O–C–CH 2 –CH 2 –C
O
8.5 Strategies to Deliver Drugs to Targets within the Tumour (Cells) 219
succinic acid
O
Linker
Soluble polymer conjugates have also been proposed as macromolecular pro-drugs for
controlled release and targeting of various low molecular weight, (non-protein) chemicals
[91,92]. In this case, polymer conjugation not only serves to alter drug biodistribution by restricting
cellular capture to the lysosomotropic route, but the polymer–drug linkage can also
be designed to allow site-specific enzymatic or hydrolytic cleavage. Thus, both the rate and
the site of drug delivery can in principle be controlled. Enhanced permeability of the microvasculature
at certain sites, particularly within solid tumours, can be exploited to facilitate
site-specific accumulation of polymer–drug conjugates [93]. Other (co)polymers of interest
besides PEG are SMANCS (styrene-co-maleic anhydride neocarzinostatin; zinostatin stimalar)
and HPMA (N-(2-hydroxypropyl) methylacrylamide).
Targeting moieties such as sugars (galactose, mannose), proteins and antibodies have been
incorporated into the conjugates to promote receptor-mediated recognition.Thus, cell- or organ-specific
localization of therapy may be achieved [98]. It should be noted however, that
various cell types in the liver and spleen are important target cells for sugar-derivatized proteins
(see Chapter 4) and that hepatic clearance will always compete with extrahepatic distribution.
Polymer conjugates are most useful in the context of immuno-conjugates. Other protein
constructs such as fusion proteins can assist their future development. Soluble polymer con-
PEG
Protein
NH-L-asparaginase
Figure 8.4. Schematic diagram showing the structure of a typical polyethylene glycol (PEG) conjugate
and the chemical structure of PEG-asparaginase.