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Novel auristatin E-based albumin-binding prodrugs with superior anticancer efficacy in vivo compared to the parent compound

Author:
Pes, Lara, Koester, Stephan David, Magnusson, Johannes Pall, Chercheja, Serghei, Medda, Federico, Abu Ajaj, Khalid, Rognan, Didier, Daum, Steffen, Nollmann, Friederike Inga, Garcia Fernandez, Javier, Perez Galan, Patricia, Walter, Heidi-Kristin, Warnecke, Anna, Kratz, Felix
Source:
Journal of controlled release 2019 v.296 pp. 81-92
ISSN:
0168-3659
Subject:
active ingredients, antineoplastic activity, antineoplastic agents, cytotoxicity, drug carriers, head, humans, hydrazides, hydrazones, lung neoplasms, melanoma, models, neck, ovarian neoplasms, pH, peptides, serum albumin, skin irritation, water solubility
Abstract:
Auristatins are a class of highly cytotoxic tubulin-disrupting peptides, which have shown limited therapeutic effect as free agents in clinical trials.In our continuing effort to develop acid-sensitive albumin-binding anticancer drugs exploiting circulating serum albumin as the drug carrier, we investigated the highly toxic drug payload auristatin E to assess whether the corresponding albumin-binding prodrugs were a viable option for achieving significant and concomitant tolerable antitumor activity. To achieve our goal, we developed a new aromatic maleimide-bearing linker (Sulf07) which enhanced both water solubility and stability of the prodrugs. In this study, we describe two auristatin E-based albumin-binding drugs, AE-Keto-Sulf07 and AE-Ester-Sulf07, which were designed to release the active compound at the tumor site in a pH-dependent manner. These prodrugs incorporate an acid-sensitive hydrazone bond, formed by the reaction of a carbonyl-containing auristatin E derivative with the hydrazide group of the water-solubilizing maleimide-bearing linker Sulf07.A panel of patient- and cell-derived human tumor xenograft models (melanoma A375, ovarian carcinoma A2780, non-small-cell lung cancer LXFA737 and LXFE937, and head and neck squamous cell carcinomas) were screened with starting tumor volumes in the range of either 130–150 mm3 (small tumors) or 270–380 mm3 (large tumors). Both albumin-binding prodrugs showed compelling anticancer efficacy compared to the parent drug auristatin E, inducing statistically significant long-term partial and/or complete tumor regressions. AE-Keto-Sulf07 displayed very good antitumor response over a wide dose range, 3.0–6.5 mg/kg (5–8 injections, biweekly). AE-Ester-Sulf07 was highly efficacious between 1.9 and 2.4 mg/kg (8 injections, biweekly) or at 3.8 mg/kg (4 injections, weekly), but caused cumulative skin irritation due to scratching and biting. In contrast at its MTD, auristatin E (0.3 mg/kg, 8 injections, biweekly) was only marginally active. In summary, AE-Keto-Sulf07 and AE-Ester-Sulf07 are novel acid-sensitive albumin-binding prodrugs demonstrating tumor regressions in all of the evaluated human tumor xenograft models thus supporting the stratagem that albumin can be used as an effective drug carrier for the highly potent class of auristatins.
Agid:
6283822