AP5280 is a novel
N-(2-hydroxypropyl)methacrylamide (
HPMA) copolymer-bound
platinum (Pt) therapeutic designed to increase the therapeutic index relative to conventional, small-molecule
platinum agents. The
platinum-
polymer construct accumulates in solid tumours on the basis of increased capillary permeability. The bound
platinum moiety is present as an N,O-Pt chelate at the distal end of a tetrapeptide linker,
glycine-
phenylalanine-
leucine-
glycine, and the weight-average molecular weight (Mw) of the construct is 22 kDa. The antitumour activity and toxicity of
AP5280 were assessed in the syngeneic murine B16F10 and Lewis lung tumour models, and in the human ovarian
carcinoma 2008 and head and neck
squamous carcinoma UMSCC10b xenograft models. The maximum tolerated dose (MTD) of
AP5280 was 6-fold greater than that of
carboplatin (
CBDCA) in vivo.
AP5280 was active in all four tumour models, and it displayed a higher therapeutic index than
CBDCA in each of these tumour models. The antitumour effect of
AP5280 given at 16% of its MTD was equivalent to that produced by a MTD of
CBDCA. Thus, consistent with the design goal for this
drug, and despite being less potent than
CBDCA,
AP5280 produced less systemic toxicity relative to its antitumour activity and thus has a greater therapeutic index. On the basis of the improved therapeutic index evidenced in these models,
AP5280 has been advanced into clinical trials.