In vivotailor-made protein corona of a prodrug-based nanoassembly fabricated by redox dual-sensitive paclitaxel prodrug for the superselective treatment of breast cancer

Abstract

Prodrug self-nanoassemblies have many advantages for anticancer drug delivery, including high drug loading rate, resistance to recrystallization, and on-demand drug release. However, few studies have focused on their protein corona, which is inevitably formed after entering the blood and determines their subsequent fates in vivo. To actively tune the protein corona of prodrug nanoassemblies, three maleimide-paclitaxel prodrugs were synthesized via different redox-sensitive linkers (ester bond, thioether bond and disulfide bond). After incubation with rat plasma, the surface maleimide groups effectively captured albumins, resulting in albumin-enriched protein corona. The recruited albumin corona enabled enhanced tumor accumulation and facilitated cellular uptake, ensuring the high-efficiency delivery of nanoassemblies to tumor cells. Surprisingly, we found that the traditionally reduction-sensitive disulfide bond could also be triggered by reactive oxygen species (ROS). Such a redox dual-responsive drug release property of the disulfide bond-containing prodrug nanoassemblies further increased the selectivity in cytotoxicity between normal and tumor cells. Moreover, the disulfide bond-containing prodrug nanoassemblies exhibited the highest antitumor efficacy in vivo compared to marketed Abraxane® and other prodrug nanoassemblies. Thus, the fabrication of the maleimide-decorated disulfide bond bridged prodrug nanoassembly, integrating a tunable protein corona and on-demand drug release, is a promising strategy for improved cancer chemotherapy.

Polydopamine-modified ROS-responsive prodrug nanoplatform with enhanced stability for precise treatment of breast cancer

“…The cytotoxicity of PTX-sol and prodrug NPs toward cancer cell lines (4T1) and normal cell line (NIH/3T3) were evaluated by MTT assays. 25,36 According to previous studies, the group of free anticancer drug always showed a higher cytotoxicity than prodrug nano-formulations due to the delayed drug release and the P-glycoprotein to exocytose of anticancer drugs. 24,30,37 However, compared to PTX-sol group in this study, the prodrug NPs exhibited a considerable cytotoxicity of 4T1 cancer cells ( Fig.…”

“…In our previous study, the thioether bond in the prodrug-based NPs could be cleaved by ROS for on-demand drug release. 22,25 In this section, the in vitro release of PTX from NPs were studied under different concentration of H 2 O 2 ( Fig. 2c and d), to investigate the efficiency of the thioether bond in this prodrug-based NPs response to ROS.…”

“…The stability of the prodrug NPs in rat plasma was further tested. 25 The slowly released anticancer drug during the blood circulation would be favorable for reducing systemic toxicity and enhancing therapeutic effect. 36 As shown in Fig.…”

“…30 Aer conrming the high selectivity of the response of the prodrugs to ROS under different concentration of H 2 O 2 , we subsequently examined their cytotoxicity in cancer cell lines (4T1) and normal cell line (NIH/3T3). 25 The half maximal inhibitory concentrations (IC 50 ) values of the two cell lines were summarized in Tables S2 and S3. † Prodrug NPs exhibited high cytotoxicity in 4T1 cancer cell lines, while showed low cytotoxicity against normal NIH/3T3 cells ( Fig.…”

“…However, we noticed that thioether-bonded prodrugs might be easily hydrolyzed during the blood circulation, due to be oxidized into sulfoxide or sulphone. 22,23 In some recent years, continuous efforts have been made to enhance the stability of ROSresponsiveness NPs, including PEGylation, 24 albumin-enriched protein corona 25 and cell membrane protection. 26 However, most of these strategies did not show an ideal performance.…”