Chemical Delivery Systems (Polymeric Prodrugs)

2. Controlled Drug Release
After administration, it is necessary that the macromolecular prodrug is stable during circulation in the bloodstream but the cytotoxic drug should be released from the macromolecular drug conjugate intracellulary in the lysosomes (lysosomotropic drug delivery) and/or intratumorally (tumoritropic drug delivery).
This controlled release from polymeric drug conjugates by enzymatic or hydrolytic cleavage can only be achieved by proper selection of linkage between drug and polymeric carrier.
In the development of spacers, the most interest has been focussed on pH-sensitive spacers (pH-controlled drug release) and oligopeptide spacers (enzyme-assisted drug release).
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pH Controlled Drug Release:
When the macromolecular drug conjugate is taken up by the cell through endocytosis, the conjugate is predestined to be exposed to the acidic pH of the lysosome. Also in or near the tumor tissue the pH is slightly acidic in comparison with healthy tissue. This relatively low pH can be exploited to design pH-sensitive spacers.
The hydrazon linkage and the N-cis-aconityl spacer are examples for such controlled release:


Drug Release by Lysosomal and/or Tumor-Associated Enzymes:
After the cell uptake of the polymeric prodrug through endocytosis and after fusion of the endosome with the lysosome, the drug conjugate is not only exposed to the acid environment but also to the degrading nature of the lysosomal enzymes.
When the lysosomal hydrolases degrade the spacer—most likely an oligopeptide spacer—the drug is released inside the cell. The lysozymes are not only present in normal cells but are often overexpressed in tumor tissues.
If the substrate is a specific oligopeptide for lysosomal proteases, the cytostatic drug can be released by these enzymes in or near the tumor tissue.
Subsequently, the tumor cells can be selectively destroyed.
For the design of a specific polymer drug conjugate, the site and the rate of the cleavage will then depend on the amino acid composition of the oligopeptide