Preclinical Efficacy and Pharmacokinetics of AP5346, A Novel Diaminocyclohexane-Platinum Tumor-Targeting Drug Delivery System

Abstract

Purpose: 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. Experimental Design: 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 (0-1) 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 . 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.

Inhibitory effects of oxaliplatin in experimental radiation treatment of colorectal carcinoma: does oxaliplatin improve 5-fluorouracil-dependent radiosensitivity?

“…The concentration of oxaliplatin has been found to be peaking 2 hours after ip injection in another xenograft model (212).…”

The application of inductively coupled plasma mass spectrometry in clinical pharmacological oncology research

“…The digestion procedure can be performed in several ways, varying from heating at high temperatures in concentrated HNO 3 (Tothill, Matheson, & Smyth, 1990;Tothill et al, 1992a,b;Minami et al, 1994;Minami, Ichii, & Okazaki, 1995;Screnci et al, 2000;Liang & Huang, 2002;Siim et al, 2003;Ghezzi et al, 2004;McDonald et al, 2005;Centerwall et al, 2006;Rice et al, 2006;Samimi et al, 2007) to more complex procedures such as digestion with concentrated HNO 3 and 30% H 2 O 2 (Ding et al, 1999;Bible et al, 2000) at elevated temperatures or microwave digestion with HNO 3 , H 2 O 2 , and HCl (Hann et al, 2003a). Perry and Balazs (1994) compared the digestion of cells with sodium hydroxide with the sonication of cells followed by digestion with concentrated HNO 3 .…”

“…Others diluted samples in a HCl (Walker et al, 1999) or HNO 3 (Azim-Araghi et al, 2001;John et al, 2003;Cooper et al, 2004) solution and heated it prior to analysis. A more extensive wet digestion procedure with concentrated HNO 3 and overnight heating was performed by Rice et al (2006). Yamada et al (2005) digested DNA with concentrated HNO 3 and 30% H 2 O 2 .…”

Design of a novel theranostic nanomedicine: synthesis and physicochemical properties of a biocompatible polyphosphazene–platinum(II) conjugate

“…In the early stage, the active moiety (dach)Pt(II) was conjugated simply to the poly(ethylene glycols) (PEG) using a peptide spacer 13 or to the hydrophilic N-(2-hydroxypropyl) methacrylamide using a peptide-aminomalonate spacer (AP5346), which is still in clinical Phase II trials. 14,15 Kataoka's group 16 reported the first micellar polymeric (dach)Pt conjugate prepared by conjugation of the (dach)Pt moiety to the amphiphilic poly(ethylene glycol)-b-poly(glutamic acid) block copolymer. Their initial micellar (dach)Pt conjugate was subjected to optimization to obtain the improved clinical candidate compound (NC-4016), 17 which entered a Phase I clinical trial very recently.…”