The self-assembling camptothecin-tocopherol prodrug: An effective approach for formulating camptothecin

Abstract

Camptothecin (CPT) is a potent antitumor agent and functions via inhibiting the activity of topoisomerase I during DNA replication. However, the clinical application of CPT has been greatly hindered by its extremely poor solubility, the instability of its active lactone ring in blood stream, as well as the non-specific toxicity to normal tissues. In addition, most of the formulations developed so far are not applicable for formulating CPT. In this study, two novel CPT prodrugs were developed by conjugating CPT to α-tocopherol via a carbonate ester bond (CPT-VE) or disulfide linkage (CPT-S-S-VE). Both CPT prodrugs were able to self-assemble into nanofibers with the facilitation of a PEG5K-Fmoc-VE2-based nanomicellar carrier. Both prodrug nanoassemblies exhibited excellent stability. Fluorescence quenching, UV absorbance, and FT-IR studies demonstrated strong interactions between carrier and prodrugs, including hydrophobic interaction, π-π stacking, as well as hydrogen bonding. NMR studies suggested that prodrugs were successfully incorporated into PEG5K-Fmoc-VE2 during self-assembly process. In vitro, PEG5K-Fmoc-VE2/CPT-S-S-VE presented significantly higher level of cytotoxicity on tumor cells compared to PEG5K-Fmoc-VE2/CPT-VE. Biodistribution study showed that CPT-S-S-VE formulated in PEG5K-Fmoc-VE2 micelles was effectively converted to parent CPT following delivery to tumor tissues. Finally, PEG5K-Fmoc-VE2/CPT-S-S-VE nanofibers showed superior tumor growth inhibition in an aggressive murine breast cancer model (4T1.2).

An immunostimulatory dual-functional nanocarrier that improves cancer immunochemotherapy

“…An Fmoc group is also introduced into the conjugate based on our recent discovery of Fmoc as a ‘formulation chemophor' or a structural unit capable of interacting with many pharmaceutical agents22. We have recently shown that incorporation of an Fmoc motif into a micellar system can not only improve the drug loading capacity and formulation stability but also broaden its utility in formulating various therapeutic agents of diverse structures2324. We hypothesize that PEG-Fmoc-NLG represents an immunostimulatory dual-functional nanocarrier that facilitates co-delivery with a chemotherapeutics and improves cancer immunochemotherapy.…”

Influence of supramolecular encapsulation of camptothecin by cucurbit[7]uril: reduced toxicity and preserved anti-cancer activity

“…3 Although CPT has exhibited promising antitumor activity with various in vitro, ex vivo, and in vivo models, 4 its clinical application has been limited by the instability of its lactone ring at physiological pH and severe side-effects that have been associated with this drug's hydrolyzed carboxylate form. 5 In particular, the lactone form ( Fig. 1) plays an essential role in maintaining CPT's antitumor activity, as the hydrolyzed carboxylate form ( Fig.…”

Linker design for the modular assembly of multifunctional and targeted platinum(ii)-containing anticancer agents

“…8 Lipophilic hexadecylamine ( N2 ) and the phospholipid 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE, N3 ) were chosen to turn the cationic, highly water soluble platinum–(benz)acridines into amphiphilic molecules. Such conjugates have the potential to self-assemble into micellar structures 24 or liposomal vesicles, 25 which are known to passively accumulate in tumor tissue. 26 The arginine derivative N4 was introduced as a model of amino acids and oligopeptides that might potentially facilitate uptake of platinum–(benz)acridines into cancer cells.…”