Conjugation Of Drugs With Macromolecules For Selective Targeting To The Lung

One approach to the selective targeting of drugs into those cells where their action is required is the conjugation of a pharmacologically active agent to a macromolecular vector that is recognized and actively taken up by the target cell, where bound drug can then be released in its active from. Several examples where macromolecules have been used as carriers in an effort to alter the tissue localization of a carrier-linked drug have been reported [159]. Selectivity of targeting is largely dependent on the properties of the macromolecular vector and usually results in an altered distribution of the free drug compared to the parent drug itself when administered by the same route.

It is clear that macromolecule-drug conjugates or, more accurately, macromolecular prodrugs may well alter the pharmacological and immunologi-cal activity of the parent compound. The macromolecular transport vector may vary considerably in size, electrical charges, hydrophobicity and hydrophilicity, and its ability to act as a substrate for transmembrane transport mechanisms.

Desirable properties of the macromolecular vectors are no intrinsic toxicity (e.g., nonantigenic), biodegradability with no accumulation in the body, and presence of functionalized moieties for drug conjugation. In addition, the macromolecule-drug conjugate must not possess the pharmacological activity of

Figure 7 Model for macromolecule-drug conjugates. (From Ref. 102. Reproduced by permission, CRC Press, Inc.)

the parent drug, but the conjugate should retain the desirable targeting specificity of the parent macromolecular vector. With regard to the drug molecule, certain properties are also desirable for the formulation of an effective prodrug. For example, the therapeutic effect of the drug must be shown at relatively low doses to afford a reasonably low load of carrier macromolecule, and the macromolecule-drug conjugate structure must be chemically stable before drug release. Not all therapeutic drug molecules are capable of being conjugated to macromolecular vectors, simply because they lack adequate functional groups in their molecular structure for chemical fixation.

A variety of covalent linkages have been used in the design of macromolecule-drug conjugates, that is, esters, amides, hydrazones, imides, and disulfides. These linkages must be designed to be readily formed without chemical destruction of either the macromolecular vector or the drug during synthesis, and they must be readily broken by chemical or enzymatic hydrolysis. Figure 7 illustrates the various components of a macromolecule-drug conjugate.

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