Carbonate esters turn camptothecin-unsaturated fatty acid prodrugs into nanomedicines for cancer therapy

Abstract

We report that carbonate esters could turn hydrophobic camptothecin (CPT)-unsaturated fatty acid prodrugs into nanoaggregates in aqueous solution. The active CPT could be rapidly released once triggered by a reductive stimulus when a carbonate ester was combined with a disulfide bond, resulting in a potent in vivo antitumor activity.

PEGylation of lipophilic SN38 prodrug with DSPE-mPEG2000 versus cremophor EL: comparative study for intravenous chemotherapy

“…Cremophor EL was obtained from BASF (Ludwigshafen, Germany). Lipophilic Cur prodrug was synthesized according to previous report (Li et al., 2018). All solvents used in this study were analytical grade.…”

“…The ratios of lipophilic SN38 prodrug to DSPE-mPEG 2000 or Cremophor EL were set at 1:17, 1:1.7 and 1:0.1 (w/w), respectively. These ratios were determined according to their frequently-used doses in the previous reports (Bradley et al., 2001a; Wolff et al., 2003; Wang Y et al., 2014; Li et al., 2018)…”

“…unsaturated fatty acid, disulfide bond and carbonate esters) are found to be able to self-assemble into pure prodrug nanoaggregates in water, despite of the absence of a typical amphiphilic structure (Dosio et al., 2010; Wang Y et al., 2014; Wang H et al, 2015; Li et al., 2018). Advantages of nanoaggregates formed by small-molecule DHPs include precisely defined chemical structures, high loading capacity (Zhang et al., 2016), good thermodynamic stability (Li et al., 2018), enhanced tumor targeting and reduced toxicity (Bradley et al., 2001a,b). Therefore, DHP strategy has recently received considerable attention in the field of nanomedicine (Wang Y et al., 2017; Zhang et al., 2017a,b; Sun et al., 2018; Zhong et al., 2018).…”

“…In an effort to develop the stable DHP nanoaggregates, DSPE-mPEG 2000 is the most efficient option due to its good biocompatibility and long history of clinical usage. Modifying DHP nanoaggregates with only 10 ∼ 15% (w/w) DSPE-mPEG 2000 can result in a significant improvement in the blood circulation times, without the compromising loading capacity (Wang Y et al., 2014; Li et al., 2018).…”

“…Although both DSPE-mPEG 2000 and Cremophor EL have been extensively used for the PEGylation of DHPs for intravenous chemotherapy (Bradley et al., 2001a,b; Ke et al., 2010; Wang Y et al., 2014; Li et al., 2018), their comparative investigation has never been performed, especially for a redox-sensitive DHP. We have recently reported on the self-assembling nanoparticles (NPs) composed of the redox-sensitive DHP of 7-ethyl-10-hydroxyl-camptothecin (SN38).…”