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Abstract
Numerous water-soluble macromolecular conjugates have been proposed as carriers for therapeutic agents. The rationale for using a high molecular weight (MW) carrier is based on the potential for superior pharmacokinetic and targeting performance compared to the low MW drug. Polyphosphazenes are a class of inorganic polymers proposed as drug carriers for controlled release of a wide variety of bioactive agents and have the potential for biodegrading to non-toxic by-products.
Many low MW peptides exhibit high in vitro potency but are not pharmaceutically acceptable due to poor in vitro stability or short duration of action in vivo. The incorporation of hydrophilic peptide pendants onto the phosphazene polymer backbone offers the potential for a soluble polymer with controlled-release capability. The feasibility of this concept was determined by in vitro evaluation of a model poly(peptide)phosphazene, poly(trialanine methyl ester)phosphazene (polyTame). The biodegradation of polyTame would ultimately lead to the formation of ammonia, phosphate, alanine, methanol and hydrochloric acid. However, the release of free tripeptide, trialanine methyl ester or trialanine, used here as model peptides, could occur during intermediate degradation processes under physiological conditions. Results from polymeric hydrolysis and peptide release experiments in vitro indicate that these processes are dependent on pH and temperature; however, there does not exist a direct kinetic relationship between polymeric degradation and peptide release. There does exist a direct positive correlation between the rates of ester hydrolysis and polymeric degradation.
We conclude that polyTame would not be suitable as a drug delivery platform for release of free peptides, but would be useful if the pendant peptide retained its pharmacological activity attached to the phosphazene backbone during degradation. In addition, incorporation of an enzymatically labile ester at the peptide C-terminus with a covalent N-terminus attachment to a polyphosphazene backbone would be an effective method for controlling the biodegradation rate.
