N2hydroxypropylmethacrylamide Hpma Copolymers For The Delivery Of Anticancer Agents

The use of polymeric drug delivery systems is rapidly becoming an established approach for improvement of cancer chemotherapy. The covalent binding of low molecular weight drugs to water-soluble polymer carriers offers a potential mechanism to enhance the specificity of drug action. The major distinction between low molecular weight anticancer drugs and their macromolecular conjugates is the mechanism of cell entry. While low molecular weight drugs may penetrate into all cell types by diffusion, their attachment to macromolecules such as N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer, limits cellular uptake of the polymer-drug conjugates to the endocytic route. Internalized macromolecules are then transferred via endosomes into the lysosomal compartment of the cell. [10] The rate of (fluid-phase) pinocytosis is low. Consequently, in normal tissue the polymer-drug conjugate is largely confined to the bloodstream. [11] However, the abnormal tissue vasculature found in tumors allows the uptake of large molecules to proceed more efficiently than in normal tissues. Furthermore, the poor lymphatic drainage of tumors allows higher concentrations of macromolecular therapeutics to accumulate. [12-14] Maeda coined the phrase "enhanced permeability and retention (EPR) effect" to describe this phenomenon. [12] The alternative mechanism of cellular entry afforded by HPMA copolymer delivery provides a number of documented benefits and advantages over standard methods of cancer therapy. (Figure 1)

These favorable advantages include: control of biodistribution and accumulation via molecular weight limitations; biodegradability of side chains; minimal immunogenicity; subcellular localization of anticancer drug release; targeting capabilities; enhanced permeability and retention; increased apoptosis, lipid peroxidation, and DNA damage; significantly reduced nonspecific toxicity; and applicability to a wide range of anticancer agents. [10,14-17]

Figure 1. Structure of N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers: R1 =
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