Macromolecular drug conjugates

Generally there are two possible ways of synthesis of macromolecular-drug conjugates (Fig. 5) [140] ... 

The ability of a tumor cell to manufacture proteins is a result of intact DNA, RNA and biochemical intracellular mechanisms. Interference with any one of these structures or processes will result in the inability of the cell to produce required proteins. Hence, quantitation of tumor cell protein synthesis over a period of time may constitute a marker allowing determination of the efficacy of a macromolecular drug conjugate. The technique is based on the fact that decreased cell viability in the presence of radiolabeled amino adds correlates to a decrease in radioactivity relative to a control cell population. For example, 3H-leucine [175, 208], a mixture of [14C]-labeled amino acids [205], and 75Se-lenomethionine [54, 209] have been used to evaluate the activity of conjugates. 

A number of macromolecular drug conjugates have taken advantage, sometimes inadvertently, of the EPR effect. One of the best-characterized is the conjugate... 

As already mentioned the macromolecular drug conjugates differ from low molecular weight drugs in how they behave in the body at both tissue and cellular level. Therefore the barriers to be overcome are different and can be exploited to enhance the specificity... 

Numerous experimental therapeutics have shown potency in vitro however, when they are tested in vivo, they often lack significant efficacy. This is often attributed to unfavorable pharmacokinetic properties and systemic toxicity, which limit the maximum tolerated dose. These limitations can be overcome by use of drug carriers. Two general types of carrier systems have been designed drug conjugation to macromolecular carriers, such as polymers and proteins and drug encapsulation in nanocarriers, such as liposomes, polymersomes and micelles. 

The in vitro methods by which macromolecular anticancer drug conjugates are evaluated for efficacy are similar to those used to screen for the anticancer activity of low molecular weight compounds. A thorough review of in vitro models used for the evaluation of antitumor therapy was published several years ago [174]. 

Cultures consisting of cell suspensions may be used directly to determine the efficacy of macromolecular antitumor agents. For example, suspensions of L12 10 leukemia cells were used to show the activity of HPMA copolymer anticancer drug conjugates [39], The cells, while in exponential growth, were diluted in culture medium to produce a cell density of approximately... 

It is clear that macromolecule-drug conjugates or, more accurately, macromolecular prodrugs may well alter the pharmacological and immunological 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... 

Maeda H. SMANCS and polymer-conjugated macromolecular drugs advantages in cancer chemotherapy. Adv Drug Deliv Rev 1991 6 181-202. 

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