Amphoteric linear poly(amido-amine)s as endosomolytic polymers: correlation between physico-chemical and biological properties

Five poly(amido-amine)s (PAAs) carrying two ter-amino groups and one carboxyl group per repeating unit were prepared by hydrogen-transfer polyaddition of 2-methylpiperazine (ISA 23), 1, 2-bis(AT-methylamino)ethane (DMEDA-BAC), l, 2-bisOV-ethylamino)ethane (DEEDA-BAC, l, 3-bis(AT-methylamino)propane (DMEPDA-BAC), or l, 6-bisuV-methylamino)hexane (DMEXA-BAC), in each case to 2, 2-bis(acrylamido)acetic acid (BAG). The resultant PAAs had an Mn in the range 7 985-24 980 g/mole and an Afw in the range 11 420-42 710 g/mole. Considerable differences were observed in the basicity of the amino groups present (logK°i = 7.5-9.5; logK°2 = 3.2-8.4), whereas the log.K°3 value (2-3) of the carboxyl groups was consistent with that of a fairly strong acid. DEEDA-BAC, DMEDA-BAC, and ISA 23 were nontoxic (ICso > 5 mg/mL). Those PAAs with the highest log K°z values were more cytotoxic (IC50 = 3.55 mg/mL for DMEPDA-BAC, and IC5o = 0.23 m/mL for DMEXA-BAC). All the PAAs displayed pH-dependent haemolysis (most lytic at pH 5.5), consistent with their proposed use as endosomolytic polymers. © 2000 American Chemical Society.