Macromolecule-drug conjugates in targeted cancer chemotherapy.
Although clinical trials using macromolecular conjugates of cytotoxic drugs in a treatment of malignant disease are fragmentary at best, a number of carrier systems that have been examined in vitro, in tissue culture, and in vivo animal experiments demonstrate great promise and warrant further extensive examination. The optimal drug delivery and, consequently, maximum therapeutic effect will be accomplished when all available information from diverse disciplines can be integrated. This review has attempted to point out some of the limitations of taking an optimistic view of the question of targeting drug delivery using macromolecule-drug conjugates. For example, a strategy for the development of macromolecular conjugates can be established based on characteristics of the targeted tumors and the drugs in prospect of great success. Biological and physiological features of the tumor such as a cell type, site, and the pharmacological and physicochemical properties of chemical agents such as site of action and chemical stability must be considered at the first step. Selection of the optimum carrier system will be accompanied when all these problems are carefully considered. Similarly, the optimum method of conjugation is likely to vary as a function of the carrier, the chemotherapeutic agent, and the delivery site or site of action of the agent. The stability of the bond must adopt itself to the mode and site of action of the agent, the necessity for release, and the availability of hydrolytic enzymes which break the linkage and release the agent. On the other hand, the success of such conjugates synthesized according to this strategy will depend on physicochemical properties of the conjugates such as molecular size, electric charge, and solubility; chemical and biological stability of active components of conjugates and linkages; interaction with the tumor cells; cytotoxicity in tissue culture system; pharmacokinetics in the body such as absorption profile, localization, and elimination manner; in vivo antitumor activity; and biodegradability and antigenicity of the conjugates. The practitioners of macromolecular conjugate research find themselves in the interesting, but difficult, position of being at the interface between basic information on the drugs and biological systems and an expanding clinical demand for more sophisticated therapeutic agents. Consequently, knowledge is demanded not only of the chemical, physical, and pharmaceutical properties of macromolecules, but also of pathophysiology of the condition being treated.(ABSTRACT TRUNCATED AT 400 WORDS)
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000627:therapeutic use; D000912:Antibodies, Neoplasm / Q000008:administration & dosage; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000378:metabolism / Q000627:therapeutic use; D001798:Blood Proteins / Q000627:therapeutic use; D055598:Chemical Phenomena; D002621:Chemistry; D002986:Clinical Trials as Topic; D003432:Cross-Linking Reagents / Q000627:therapeutic use; D003911:Dextrans / Q000378:metabolism / Q000627:therapeutic use; D004705:Endocytosis; D006801:Humans; D007700:Kinetics; D037102:Lectins / Q000627:therapeutic use; D007939:Leukemia L1210 / Q000188:drug therapy; D008207:Lymphatic Metastasis; D046911:Macromolecular Substances; D051379:Mice; D016685:Mitomycin; D008937:Mitomycins / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use; D009369:Neoplasms / Q000188:drug therapy; D010455:Peptides / Q000627:therapeutic use; D011817:Rabbits / Q000276:immunology; D051381:Rats; D012709:Serum Albumin / Q000627:therapeutic use
D000903:Antibiotics, Antineoplastic; D000912:Antibodies, Neoplasm; D000970:Antineoplastic Agents; D001798:Blood Proteins; D003432:Cross-Linking Reagents; D003911:Dextrans; D037102:Lectins; D046911:Macromolecular Substances; D008937:Mitomycins; D010455:Peptides; D012709:Serum Albumin; D016685:Mitomycin