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Extra info for Polymer Therapeutics
Example text
Dextran (mainly α-1,6-polyglucose with some α-1,4 branching) has been particularly popular owing to its clinical approval for use as a plasma expander. A dextran-doxorubicin conjugate (AD-70) was tested clinically. A dextran polymer with a molecular weight of ∼ 70 000 Da was used to prepare the conjugate. Drug conjugation seemed to be by Schiff base formation using oxidised dextran also modified with glycine as a pendant group for reaction with the anthracycline [137]. The rationale of this conjugation approach was to utilise hypoxic conditions in the tumour to promote drug liberation.
Whereas the – COO-Pt released platinum species much too rapidly for useful delivery, the malonate derivative showed a slower, more useful rate of hydrolysis [118]. Using platinum NMR it has been shown that the malonato ring rearranges with time to the more thermodynamically favourable structure (AP5280) shown in Fig. 8. 7. Phase I studies conducted in Europe were recently described [117]. v. infusion every 21 days. Twenty-nine patients were treated at eight dose levels (90–4500 mg Pt/m2 ). The dose-limiting toxicity was Common Toxicity Criteria grade 3 vomiting and was experienced at 4500 mg Pt/m2 in two of six patients.
HPMA copolymer-cathepsin B combined with HPMA copolymer-Gly-Phe-Leu-Gly-doxorubicin (Fig. 14B), and an HPMA copolymer-β-lactamase conjugate and an HPMA copolymer-Gly-Glycephalosporin-doxorubicin combination (Fig. 14C), have shown in vivo proof of concept [45, 221, 222]. To achieve proof of concept HPMA copolymerGly-Phe-Leu-Gly-doxorubicin (PK1) was selected as the model prodrug, and HPMA copolymer-cathepsin B as the activating enzyme conjugate (Fig. 14B). In vivo, 125 I-labelled HPMA copolymer-cathepsin B and PK1 showed tumour targeting by the EPR effect in a sc B16F10 model.
