Probing the Superiority of Diselenium Bond on Docetaxel Dimeric Prodrug Nanoassemblies: Small Roles Taking Big Responsibilities

Abstract

The current state of chemotherapy is far from satisfaction, restricted by the inefficient drug delivery and the off‐target toxicity. Prodrug nanoassemblies are emerging as efficient platforms for chemotherapy. Herein, three docetaxel dimeric prodrugs are designed using diselenide bond, disulfide bond, or dicarbide bond as linkages. Interestingly, diselenide bond‐bridged dimeric prodrug can self‐assemble into stable nanoparticles with impressive high drug loading (≈70%, w/w). Compared with disulfide bond and dicarbide bond, diselenide bond greatly facilitates the self‐assembly of dimeric prodrug, and then improves the colloidal stability, blood circulation time, and antitumor efficacy of prodrug nanoassemblies. Furthermore, the redox‐sensitive diselenide bond can specifically respond to the overexpressed reactive oxygen species and glutathione in tumor cells, leading to tumor‐specific drug release. Therefore, diselenide bond bridged prodrug nanoassemblies exhibit discriminating cytotoxicity between tumor cells and normal cells, significantly alleviating the systemic toxicity of docetaxel. The present work gains in‐depth insight into the impact of diselenide bond on the dimeric prodrug nanoassemblies, and provides promising strategies for the rational design of the high efficiency–low toxicity chemotherapeutical nanomedicines.

ROS-responsive dimeric prodrug-based nanomedicine targeted therapy for gastric cancer

“…Dimeric prodrugs can undergo selfassembly into nanoparticles with or without surfactants in an aqueous solution to form the DPNS; therefore, DPNS can achieve high drug-loading efficiency, usually more than 50% (Jiang et al, 2017;Li et al, 2020a). Moreover, for effective conversion of dimeric prodrugs to bioactive parent drugs in cancer cells, various stimuli-sensitive linkages, such as disulfide bonds, diselenide bonds, azobenzene bonds, and the thioketal (TK) moiety have used to prepared DPNS, which can release the active parent drug in response to high levels of glutathione (GSH), reactive oxygen species (ROS), and hypoxic conditions (Luo et al, 2014;Song et al, 2016;Pei et al, 2018;Li et al, 2019Li et al, , 2020aZhou et al, 2020;Zuo et al, 2020). It is reported that ROS-responsive drug delivery systems exhibit higher selectively during drug release in tumor cells than GSH-and acidic pH-sensitive drug delivery systems, because both high concentrations of GSH and lysosomes (with acidic pH) are present in both normal and cancer cells (Ye et al, 2017).…”

A Co-delivery System Based on a Dimeric Prodrug and Star-Shaped Polymeric Prodrug Micelles for Drug Delivery

“…The design of the dimeric prodrug has emerged as one of the new potential strategies for increasing drug loading by hydrophobic interactions, due to the fact that drug dimers can prevent large particle formation (He et al, 2018). Furthermore, the dimeric prodrug possess the stronger intermolecular hydrophobic interactions than the free drug because of the increased surface area and the enhanced tendency of the prodrug to aggregate (Pei et al, 2018;Li et al, 2020;Zuo et al, 2020). Therefore, the design of the drug delivery system based on dimeric prodrug can improve drug loading effectively.…”

ROS-Activated homodimeric podophyllotoxin nanomedicine with self-accelerating drug release for efficient cancer eradication

“…Chemotherapy is one of the primary treatment modalities available for cancer patients. However, the present status of chemotherapy is far from being satisfactory, which is seriously limited to the poor water solubility and the side effects (Zuo et al., 2020 ). Podophyllotoxin (POD), a natural aryltetralin lignan, is an extract of Podophyllum hexandrum, which has been demonstrated to be effective against cancer (Feng et al., 2020 ; Zhao et al., 2021 ).…”