Targeting of Macromolecule Drug Conjugates to the Lung

In general, the major problem in targeting macromolecules to the lung after intravascular administration is to overcome the biodistribution of such molecules to phagocytes in the reticuloendothelial organs (liver, spleen, and bone marrow). With a growing body of data on the nature of endothelial and epithelial receptors that enhance pulmonary drug clearance, the morphological factors governing transport of molecules through basement membranes, the effects of disease on endothelial and sequestered tissue receptors, and the availability of receptor-binding substrates that can be used for targeting entities in macromolecule-drug conjugates, the efforts to improve pulmonary targeting of drugs is already under way. Recent developments that have effected this progress have been due to new technologies, leading to an improvement in the design and production of drug-carrier molecules and coatings that afford circulating agents with specific affinity for lung endothelium and epithelium. As previously mentioned in the section on structural factors governing drug uptake, several endogenous compounds are known to be actively taken up from the plasma by the pulmonary endothelium, for example, serotonin and norepinephrine. Drugs conjugated to these agents have been suggested to undergo pulmonary targeting; this has yet to be determined conclusively. A more rational approach is to use pharmacologically inactive analogues of these agents or their inactive metabolites, which would still retain their targeting abilities, in drug-drug or macromolecule-drug conjugates.

It is generally recognized that the use of liposomes, microparticulates, and colloidal carriers to achieve drug targeting has proven to be largely unsuccessful because of the difficulties in gaining access to targeted tissues, penetrating vascular barriers, and evading phagocytic capture by the reticuloendothelium system. However, the coating of microspheres and emulsions with block copolymers may overcome the latter problem. Illum et al. [166,167], for example, coated model polystyrene microspheres with a poloxamine-980 block copolymer, and they observed a much longer circulatory half-life in the vascular compartment after intravenous injection, with little or no uptake by the reticuloendothelium system. Deposition of coated microspheres was observed to be significantly reduced in the liver and spleen, with high levels in the lungs. The conjugation of tissue-targeting vectors (e.g., sugar residues, lectins, monoclonal antibodies, apolipoproteins) to appropriate functionalities on a hydrophilic coating may allow colloidal carriers to be actively targeted to specific sites, either by systemic or intracavity administration (N-2-hydroxyporpyl)-methacrylamide copolymer macromolecules have also been used as targetable drug-carrier systems [168,169]. The advantages of these systems is that they can be tailor-made to include oligopeptide drug linkages that are stable in the circulation but are readily digested intracellularly by the lysosomal thiol-dependent (cysteine-) proteinases. They are readily synthesized and are efficiently internalized by cells via pinocytosis, and cleavage of linkages to drug can be controlled by appropriate structural manipulation. Thus, they provide good opportunities for controlled intracellular delivery of drugs. In addition, they can be synthesized to include potentially useful targeting residues, such as sugars, immunoglobulins, and antibodies.

Soluble macromolecule-drug carriers seem to offer greater potential because they can transverse compartmental barriers more efficiently and, therefore, gain access to a greater number of cell types and, in most cases, are not subject to clearance by the reticuloendothelial cells. Dextrans, human serum albumin, polysomes, and even tumor-specific antibodies (see the section on drug monoclonal-antibody conjugates) have all been evaluated as drug carriers for lung targeting [170,171]. Each system has advantages in terms of specificity or ease of chemical conjugation, but each also presents problems of limited body distribution or immunogenicity. Conjugation of methotrexate of poly-L-lysine has markedly increased the drug's tumoricidal activity in vitro [172], and intermittent administration of methotrexate-albumin conjugates has been shown to be more effective than free drug in reducing the number of lung metastases in mice after receiving subcutaneous inoculation of Lewis lung carcinoma [173].

Mammalian macrophages contain a transport system that binds and internalizes glycoproteins with exposed mannose residues. It has been shown that small multivalent synthetic glycopeptides with mannose residues covalently linked through a spacer arm to the a- and e-amino groups of lysine, dilysine, or trilysine are competitive inhibitors of rate alveolar macrophage uptake of the neoglycoprotein-bovine serum albumin with inhibition constants in the low micromolar range [174] (Fig. 8). Various compounds can be covalently attached

Figure 8 Structure of mannosylpeptides.

to the a-carboxyl group of these glycopeptides without substantial loss of inhibition.

These synthetic substrates may be useful models for targeting pharmacological agents to alveolar macrophages as well as other cell types. Monsigny et al. [175] have conjugated the immunostimulant muramyldipeptide with neoglycoprotein and have shown that the conjugate was actively endocy-tosed by murine alveolar macrophages, leading to their dramatic activation, even at very low concentrations of the conjugate. Intravenous and intraperitoneal administration of the conjugate led to maximal activation of alveolar macrophages at 48 hours in mice and 72 hours in rats. This interesting example of drug targeting may have potential usefulness in the design of carrier-mediated anticancer, antiparasitic, or antiviral chemotherapy.

An attempt has been made to target the antitumor drug daunomycin to human squamous lung tumor cell monolayers by conjugating the drug with low-density lipoprotein. Although rapid uptake of the conjugate afforded equilibrium in 3 hours, the in vitro cytotoxicity of the conjugate was no different than that of the parent drug [176]. The high level of expression of high-affinity receptors for EGF on lung tumors may possibly be used as a target for ligand-complexed (conjugated) drugs [177]. Antibodies to EGF have been shown to inhibit tumor growth [178], and ligand-complexed drugs can concentrate in receptor-positive cells by affinity targeting [179].

The correct strategy for accomplishing the successful targeting and delivery of drugs using macromolecule-drug conjugates must be a judicious choice, based on the characteristics of the target tissue or cell type and the drug. Initially, the properties of the cell type, sites of complexation, transport, and internalization mechanisms, as well as the pharmacological and physicochemical properties of the drug molecule, its site of action (i.e., nature of interaction with receptors or enzyme active sites), and chemical stability, must be considered. The conjugation of the drug molecule to the carrier is also an important consideration because the bond must be stable enough to withstand cleavage before reaching the target site but must be designed to release the drug at the site of action.

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