Background: The novel thiocolchicine dimer IDN5404, active on ovarian sublines of A2780 resistant to cisplatin and topotecan, has dual mechanisms of action, i.e., microtubule activity as in the Vincas and topoisomerase-I inhibitory effect different from camptothecin (Raspaglio, 2004, Biochemical Pharmacology, in press). IDN5404 and two other analogs, IDN5800 and IDN5801, all hydrophobic, were evaluated for invitro and invivo activity of the nanoparticle albumin versions, nab-5404, nab-5800 and nab-5801 against Irinotecan and nab-paclitaxel (Abraxane, ABI-007). Methods: Nanoparticle colchicines were prepared using nab technology. Cytotoxicity was evaluated invitro using human MX-1 breast carcinoma cultures. In vivo anti-tumor activity (human HT29 colon tumor xenograft) in nude mice was compared against Irinotecan and Abraxane. Dose levels for the nab-colchicines and Irinotecan were 20 mg/kg, 30 mg/kg, and 40 mg/kg, given q3dx4, i.v. Abraxane was dosed at its MTD, 30 mg/kg, given qdx5. Results: The hydrophobic thiocolchicine dimers yielded nanoparticles with average size ZAve (nm) of 119, 93, and 84 for nab-5404, nab-5800, and nab-5801, respectively. The nanoparticle suspensions were lyophilized. In vitro, nab-5404 was the most potent of the three analogs against MX-1 (p≤0.0005, ANOVA), (IC50 (ug/ml): 18, 36 and 77 for nab-5404, nab-5800 and nab-5801 respectively) as well as against the HT29 xenograft in vivo (p≤ 0.0001, ANOVA). Tumor volume was suppressed by 93%, 79%, and 48% with nab-5404 at doses 40 mg/kg, 30 mg/kg, and 20 mg/kg, respectively. In contrast, tumor volume was only suppressed by 31%, 16%, and 21% with nab-5800; and 17%, 30%, and 23% with nab-5801 at 40 mg/kg, 30 mg/kg, and 20 mg/kg, respectively. Nab-5404 was more effective than Irinotecan at all dose levels (p≤ 0.008, ANOVA) with tumor volumes for Irinotecan suppressed by only 48%, 34%, and 29% at dose levels of 40 mg/kg, 30 mg/kg, and 20 mg/kg, respectively. In comparison to nab-paclitaxel (Abraxane), nab-5404 was more active at equitoxic dose (ETD) based on equal weight loss (p<0.0001, ANOVA). Tumor volume was suppressed 93% by nab-5404 (40 mg/kg, q3dx4) and 80% by Abraxane (30 mg/kg, qdx5) at their respective ETDs. Conclusions: Nab technology was utilized to convert 3 hydrophobic dimeric thiocolchicines (IDN5404, IDN5800, IDN5801) to nanoparticles suitable for I.V. administration. Nab-5404 had superior antitumor activity in vitro and in vivo compared to nab-5800 and nab-5801. Nab-5404 was more potent than Irinotecan at equal dose. At equitoxic dose, defined by weight loss, nab-5404 was more potent than nab-paclitaxel (Abraxane). These data warrant further investigation of nab-5404.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]