Preclinical efficacy and pharmacokinetics of AP5346, a novel diaminocyclohexane-platinum tumor-targeting drug delivery system.
OBJECTIVE
AP5346 is designed to target a diaminocyclohexane platinum (Pt) moiety to tumors through pH-sensitive linkage to a 25 kDa hydroxypropylmethacrylamide polymer. The goal of these studies was to determine the rate of release of Pt as a function of pH, the antitumor activity, and plasma and tumor pharmacokinetics of AP5346 in preclinical models.


METHODS
Antitumor activity was assessed in mice bearing B16F10 melanoma and M5076 and 2008 ovarian carcinomas. Pt levels in plasma, tumors, and tumor DNA were measured by atomic absorption and inductively coupled plasma mass spectrometry.


RESULTS
AP5346 did not release Pt when suspended in 5% dextrose and released only 3.5% of its Pt in 24 hours in buffer at pH 7.4; the rate of release was 7-fold higher at pH 5.4. When given at their respective maximum tolerated doses, the antitumor activity of AP5346 was superior to that of oxaliplatin against both the B16 melanoma and 2008 human ovarian carcinoma. It was more effective than cisplatin in both cisplatin-sensitive and cisplatin-resistant variants of the M5076 tumor. When given at equitoxic doses, the peak plasma concentration was 25-fold higher, and AUC((0-infinity)) was 93 times higher, for AP5346 than for oxaliplatin. AP5346 delivered 16.3-fold more Pt to the tumor and 14.2-fold more Pt to tumor DNA than oxaliplatin based on AUC((1-168)).


CONCLUSIONS
AP5346 has a substantially better therapeutic index than oxaliplatin. AP5346 produced a marked increase in the delivery of diaminocyclohexane Pt to the tumor and tumor DNA over and above that attainable with oxaliplatin.
Rice
John R
JR
Access Pharmaceuticals, Inc., Dallas, Texas, USA.
Gerberich
Jennifer L
JL
Nowotnik
David P
DP
Howell
Stephen B
SB
D000230:Adenocarcinoma / Q000188:drug therapy*; D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004247:DNA / Q000187:drug effects; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D008545:Melanoma / Q000188:drug therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008819:Mice, Nude; D015394:Molecular Structure; D009944:Organoplatinum Compounds / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; C511763:ProLindac; D004247:DNA