LYSOSOMAL DEGRADABILITY OF POLY(ALPHA-AMINO ACIDS)

The lysosomal degradability of poly(alpha-amino acids) based on poly(L -glutamic acid) and its derivatives/copolymers was evaluated to gain i nsight into the subcellular fate of the macromolecules as water solubl e polymeric drug carriers. The results indicate that both the incorpor ation of hydrophobic comonomers and modification of the carboxylic gro ups of glutamic acid side chains with hydroxyalkylamine increase the l ysosomal degradability of the copolymers. Decreased lysosomal degradab ility of L-glutamic acid copolymers containing tripeptides terminated in p-nitroanilide (drug model) in the side chains confirmed that drug conjugation alters the degradation pattern of the polymeric carriers. The percentages of the enzymatic release of p-nitroaniline from its po lymeric complex with time is relatively independent of the contents of the tripeptidyl p-nitroanilides attached to the polymeric conjugates. Determination of the degradation products by electrospray mass spectr oscopy showed that no fragments less than 10(3) D were generated by ly sosomal enzymes, whereas the main degradation products by papain and c hymotrypsin were tripeptides and tetrapeptides. The conclusions derive d from these data strongly suggest that these macromolecules, if used as lysosomotropic drug carriers, may accumulate in the lysosomes and l imit their usefulness in some applications. (C) 1997 John Wiley & Sons , Inc.