Novel Delivery of SN38 Markedly Inhibits Tumor Growth in Xenografts, Including a Camptothecin-11–Refractory Model

Abstract

Purpose: Clinical development of SN38, the active metabolite of camptothecin-11 (CPT-11), has been hampered due to its poor solubility. We have developed a novel polymer-drug conjugate, EZN-2208, made by linking SN38 with a multiarm polyethylene glycol via a glycine linker. Experimental Design: The in vitro cytotoxicity of EZN-2208 was tested using the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assay. The therapeutic efficacy of EZN-2208 was evaluated in various xenografts, including an in vivoŝ elected CPT-11^refractory model. Tumor and blood concentration of EZN-2208, CPT-11, and SN38 was determined by high-performance liquid chromatography.Results: In vitro, EZN-2208 was 10-to 245-fold more potent than CPT-11in a panel of human tumor cell lines. In xenograft models of MX-1 breast, MiaPaCa-2 pancreatic, or HT-29 colon carcinoma, treatment with either a single dose or multiple injections of EZN-2208 was more efficacious (and in some cases produced tumor eradication for >16 weeks) compared with CPT-11 at their respective maximum tolerated doses or corresponding dose levels (P < 0.01).Most interestingly, EZN-2208 showed marked antitumor activity in animals that developed resistance to an 8-day course of CPT-11 treatment, as well as outperformed CPT-11 as secondround therapy in mice initially sensitive to CPT-11. EZN-2208 had prolonged circulation in the blood compared with CPT-11, resulting in high tumor exposure. This resulted in higher and longer-lasting tumor exposure of free SN38 in mice given EZN-2208 compared with those given CPT-11. Conclusions: Preclinical data suggest that EZN-2208 may be a promising anticancer agent in a wide variety of clinical settings, including tumors refractory to CPT-11treatment.

Correlating preclinical animal studies and human clinical trials of a multifunctional, polymeric nanoparticle

“…Likewise, the MAG-CPT gave released CPT dynamics of the same type (35,36). However, the polymeric micelle of SN-38 shows the same behavior for released SN-38 in animals (37) and humans (28), as does PEG-bound SN-38 in animals (38) and humans (39). When CPT binding to albumin is properly accounted for, the PK parameters of the unconjugated CPT in animals and humans can be correlated.…”

Marked therapeutic efficacy of a novel polyethylene glycol-SN38 conjugate, EZN-2208, in xenograft models of B-cell non-Hodgkin's lymphoma

“…11 Apoptosis analysis was performed using the annexin V-FITC/propidium iodide assay. (Invitrogen/ Molecular Probes, Eugene, OR, USA) (further details are included in the Online Supplementary Appendix).…”

“…10 We have previously shown in pre-clinical models using multiple solid tumors (including a model of in vivo CPT-11 resistance), that EZN-2208 has a significantly enhanced therapeutic index compared with CPT-11. 11 In these studies, EZN-2208 provides higher exposure of tumors to SN38 via the preferential accumulation of EZN-2208 in the solid tumors (enhanced permeability and retention [EPR] effect) compared with CPT-11.…”

Chapter 8. Polymeric Nanoparticles and Cancer: Lessons Learnt from CRLX101

“…Preclinical studies showed that EZN-2208 was active against several in vivo tumour models that are resistant to CPT-11 and showed prolonged circulation in the blood and thus longer tumour exposure compared to the free drug. 48,49 Moreover, EZN-2208 exhibited antitumour activity against TPT-resistant malignant tumours. 50 A dose-escalation phase I study was conducted to evaluate the safety, tolerability, pharmacokinetics, and activity of EZN-2208 in 39 patients with advanced malignancies (ClinicalTrials.gov identifiers NCT00520637 and NCT00520390).…”