Abstract 4528: Improving carboplatin therapy: A novel albumin-targeted platinum(IV) prodrug with superior anticancer activity in vivo

卡铂 体内 前药 医学 药理学 白蛋白 铂金 癌症研究 化学 化疗 内科学 顺铂 生物化学 生物 生物技术 催化作用
作者
Hemma Schueffl,Regina Weinmuellner,Nadine S. Sommerfeld,Bernhard K. Keppler,Walter Berger,Christian R. Kowol,Petra Heffeter
出处
期刊:Cancer Research [American Association for Cancer Research]
卷期号:84 (6_Supplement): 4528-4528
标识
DOI:10.1158/1538-7445.am2024-4528
摘要

Abstract Platinum(II)-based chemotherapeutics are among the most commonly used anticancer drugs and are part of nearly every second treatment scheme. However, they lack in tumor specificity, causing severe sides effects, dose-dependent toxicity as well as drug resistance development. Due to their higher tolerability, platinum(IV) prodrugs are currently in the focus of interest. However, comparable to their platinum(II) counterparts, they show insufficient tumor accumulation and are frequently prematurely activated. A promising strategy to improve tumor targeting of anticancer drugs is to exploit the enhanced consumption and accumulation of albumin in the malignant tissue. Thus, we developed a new albumin-targeted maleimide-containing platinum(IV) prodrug, which releases carboplatin in a highly tumor-specific manner. The maleimide moieties enable the drug to selectively bind the endogenous albumin via its free thiol of cysteine 34. The aim of this study was to in-depth characterize the pharmacological behavior and anticancer activity in vivo of the new prodrug. To this end, several xenograft and allograft experiments were performed. To investigate tissue distribution and pharmacokinetics serum, urine, tumor and organ samples of mice were collected after drug treatment and were evaluated by (size-exclusion chromatography) inductively-coupled plasma mass spectrometry and immunohistochemistry (e.g cleaved caspase-3). These experiments revealed that the new prodrug fast and selectively binds to the serum albumin after intravenous injection, leading to an enhanced plasma half-life and an increased tumor accumulation in comparison to its corresponding platinum(II) drug carboplatin. Additionally, the new complex resulted in superior anticancer activity and prolonged overall survival based on the distinctly improved pharmacokinetic profile and enhanced apoptosis induction. In conclusion, these data support that albumin binding is a potent tool to increase the tumor specificity of platinum(IV) drugs and prevent their premature activation in other body compartments. Consequently, this very promising prodrug will be further developed towards clinical phase I testing. Citation Format: Hemma Schueffl, Regina Weinmuellner, Nadine Sommerfeld, Bernhard K. Keppler, Walter Berger, Christian R. Kowol, Petra Heffeter. Improving carboplatin therapy: A novel albumin-targeted platinum(IV) prodrug with superior anticancer activity in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4528.

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