Polymer-drug linkers

Biological and clinical studies have underlined the fundamental importance of the polymer-drug linker. When a conjugate is administered parenterally its stability in the circulation and ability to release drug at an appropriate rate on arrival in the target tissue is a principal determinant of therapeutic index. A variety of chemistries can be used to create pendant linkers (Fig. 5) (10). Lysosomally degradable peptides ensure site-specific intracellular activation, but many drug candidates do not have a convenient aliphatic -NH2 for this purpose. 

Designing appropriate polymer-drug linkers for orally administered conjugates is another challenge. Peptidyl sequences tailored for site-specific cleavage by brush border enzymes, i.e., at the enterocyte smface (263), were explored, and also azo hnkers for colon-specific, e.g., of anti-inflammatory agents like aminosalicyfic acid (264). 

Polymer-drug (linker) Name Company Status Refs. 

A phase I clinical and pharmacokinetic study of PKl comprising doxorubicin covalently bound to N-(2-hydroxypropyl)-methacrylamide copolymer by a peptidyl linker, was carried out in 36 patients with refractory or resistant cancers [94], PKl demonstrated anti-tumour activity, and that polymer-drug conjugation decreased doxorubicin dose-limiting toxicities. Phase II studies are in progress. 

Fig. 3 A tumor-targeted polymer-drug conjugate. The major elements include (i) a polymeric drug-carrier that is water-soluble, bicompatible or biodegradable, non-immunogenic (ii) targeting moieties (iii) a linker between a drug and the carrier. The linker can be a) a chemical bond such as ester or amide. An ester bond is more stable at lysosomal pH than at plasma pH (7.4) while an amide bond is stable at both lysosomal and plasma pH b) an oligopeptide linker that is degradable by specific enzymatic hydrolysis and c) an acid labile linker that is degradable at lysosomal pH but stable at plasma pH.

The first polymer-drug conjugate to be tested in humans for anticancer therapy is doxorubicin coupled with iV-(2-hydroxypropyl)methacrylamide copolymer via a linker that is degraded in lysosomes, thereby releasing the drug [29]. In contrast to the free drug doxorubicin, which has a distribution half-life of 0.08 h and an elimination half-Ufe of 30 h (see Table 8.6), the doxorubicin conjugate has a distribution half-life of 1.8 h and an elimination half-life of 90 h. 

O. Peramal, J. Khandare, P. Kolhe, S. Kannan, M. Lieh-Lai, R.M. Kannan, Effects of branching architecture and linker on the activity of hyperbranched polymer-drug conjugates, Bioconjug. Chem. 20 (2009) 842-846. 

Linking the drug to the polymer via covalent bond-covalent polymer drug combinations. In this type, the drug can be incorporated in the macromolecule (i) without linker 1 (ii) with linker 2 (iii) as a comonomer unit in the backbone 3. 

Covalent conjugation of a cytotoxic drug to a soluble, biocompatible polymer can improve the efficacy of the dnig. The three main parts of a polymer-drug conjugate are polymer, pendent chain linker and conjugated drug. 

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