Wm. Choi et al., Synthesis of HPMA copolymer containing adriamycin bound via an acid-labilespacer and its activity toward human ovarian carcinoma cells, J BIOACT C, 14(6), 1999, pp. 447-456
N-(2-Hydroxypropyl)methacrylamide (HPMA) copolymer-adriamycin (ADR) conjuga
te (P-aconityl-ADR) was synthesized by the attachment of cis-aconityl-ADR t
o an HPMA copolymer precursor using 1-ethyl-3-(3-dimethylaminopropyl)carbod
iimide (EDC) as the condensing agent. The ADR release from the HPMA copolym
er conjugate was pH sensitive. After 48 h incubation at pH 5, 6, and 7, the
amount of ADR released was 63.4, 9.2, and 2.8% respectively. The in vitro
cytotoxicity of time conjugate was evaluated toward A2780 sensitive and A27
80/AD resistant human ovarian carcinoma cells. An HPMA copolymer, containin
g ADR bound via a tetrapeptide (GFLG) sequence susceptible to cleavage cata
lyzed by lysosomal enzymes (P-GFLG-ADR), was used as control. The IC50 dose
s seemed to indicate that the total hydrolysis of P-aconityl-ADR in prelyso
somal and lysosomal compartments proceeded faster than the release of ADR f
rom P-GFLG-ADR catalyzed by lysomal cysteine proteinases. Both HPMA copolym
er-ADR conjugates appeared to overcome the ATP-driven P-glycoprotein efflux
pump expressed in A2780/AD cells.