Toxicity and Polymer Biodegradation

It is well accepted that polymeric drug carriers for systemic administration to humans need the search for biodegradable polymers. After intravenous administration of nonbiodegradable polymeric particles, the polymer will concentrate in certain intracellular compartments (e.g., lyso-somes) or tissues (MPS), inducing severe overloading of nonmetabolized material. Thus, to assess advantages and disadvantages of one polymer in comparison to another, it is essential to identify the way by which the polymeric carrier will be degraded, as well as to approach the release rate and cellular/tissular concentrations of the degradation products. In particular, one has to distinguish between biodegradation and bioerosion. In the biodegradation process (e.g., copoly-mers of lactic and glycolic acid or some polyaminoacids), the main chain of the polymer will be hydrolized either by a chemical or by an enzymatic pathway. In the bioerosion process (e.g., polyalkylcyanoacrylates), the hydrocarbon chain of the polymer remains unchanged, while the enzymatic attack of some lateral functions induces the solu-bilization of the polymer, leading to a progressive disaggre-gation of the nanoparticles. These processes are, of course, nonequivalent from the point of view of the toxicity. In the first situation (biodegradation), the metabolization products should be easily filtered through the kidney, whereas in the second (bioerosion), the entire excretion of the polymer material will only occur if nanoparticles have been designed using low molecular weight polymers. But, if the condition of biodegradability/bioerodibility is necessary, it is not sufficient to allow the complete excretion of the polymer. In fact, nanoparticles undergoing cell capture may be hydrolyzed and reduced into small fragments, but, if the degradation products do not cross the lysosomal membrane, they will not be excreted. The above considerations emphasize the molecular weights of the polymer but also the polymer's degradation mechanism, and the diffusibility of its metab-olization products have to be identified properly to allow an evaluation of the risk of polymeric overloading in vivo. In connection with the molecular weights, one has to bear in mind that the polymeric molecular weight profile may be disrupted when drug molecules are associated with the colloidal system, especially if nanoparticles are prepared by emulsion polymerization of monomers.

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