Soluble macromolecular carriers

Soluble macromolecular carriers

Both natural and synthetic water-soluble polymers have been used as macromolecular drug carriers. Soluble carriers include antibodies and soluble polymers such as poly(hydroxypropyl methacrylate), poly(l-lysine), poly(aspartic acid), poly(vinylpyrrolidone), poly(N-vinyl-2-pyrrolidone-co-vinylamide), and poly(styrene co-maleic acid/anhydride). The drug can be attached to the polymer chain either directly or via a biodegradable spacer. Conjugation of a drug to a polymer ensures that this free drug is not available for diffusion to all body systems; hence reducing unintended effects (side effects) and reducing the dose of the drug required for achiev-ing a given concentration at the target site. The spacer overcomes problems associated with the shielding of the drug moiety by the polymer backbone. The spacer allows greater exposure of the drug to the biological milieu, thereby facilitating drug release. Different components of soluble macro-molecular carrier systems are illustrated in Figure 14.3. 

Figure 14.3 Components of a soluble macromolecular carrier system.

Figure 14.4 Chemical structure of N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer–doxorubicin conjugate.

An example of biodegradable spacer is the tetrapeptide Gly-Phe-Leu-Gly, which is cleaved by cathepsin B in the lysosomal compartment of cells. For example, N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer has been conju-gated to doxorubicin by using this tetrapeptide as a spacer (Figure 14.4).

Attachment of polyethylene glycol (PEG) to proteins can protect them from rapid hydrolysis or degradation within the body and can increase blood circulation time and lower the immunogenicity of proteins. PEGylated forms of interferons, PEG-IntronTM and PegasysTM (for treating hepatitis C and reducing dosing frequency from daily injections to once-a-week injec-tion dosing), adenosine deaminase, and l-asparaginase are currently on the market. PEGylation improves the solubility and stability of macromol-ecule by minimizing the uptake by the cells of the RES. Since PEG drug conjugates are not well absorbed from the gut, they are mainly used as injectables.

The drug–polymer conjugate may also contain a receptor-specific ligand to achieve selective access to, and interaction with, the target cells, while decreasing adverse side effects to healthy cells. For example, galactose receptors are present on liver parenchymal cells, thus the inclusion of galac-tose residues on a drug carrier can deliver the drug to these cells. Similarly, monoclonal antibodies can be used for targeting drug–polymer conjugates to the tumors.