Dually Enzyme- and Acid-Triggered Self-Immolative Ketal Glycoside Nanoparticles for Effective Cancer Prodrug Monotherapy

Abstract

The use of glycoside prodrugs is a promising strategy for developing new targeted medicines for chemotherapy. However, the in vivo utility of such prodrugs is hindered by insufficient activation and the lack of convenient synthetic methods. We have developed an innovative strategy for synthesizing ketal glycoside prodrugs that are unique in being activated by a dual enzyme- and acid-triggered self-immolative mechanism. Amphiphilic glucosyl acetone-based ketal-linked etoposide glycoside prodrug isomers were synthesized and fabricated into excipient-free nanoparticles for effective cancer prodrug monotherapy. Hydrolysis of the glycosidic linkage or the ketal linkage triggered hydrolysis of the other linkage, which resulted in spontaneous self-immolative hydrolysis of the prodrugs. Nanoparticles of the prodrug isomer that was the most labile in a lysosome-mimicking environment displayed high intratumoral accumulation and strong antitumor activity in an A549 xenograft mouse model. Our strategy may be useful for the development of stimulus-responsive self-immolative prodrugs and their nanomedicines.

Encapsulated Polyethyleneimine Enables Synchronous Nanostructure Construction and In Situ Functionalization of Nanofiltration Membranes

“…In the current work, we propose, for the first time, the concurrent construction of the well-defined molecular sieving architectures and tunable surface charges of NF membranes through precisely controlled release of the nanocapsule decorated polyethyleneimine (Scheme and Figure S1). Inspired by sugar coating in the preparation of pharmaceutical capsules, , a universal membrane functional modifier is encapsulated by a “protective agent” to form the “nanocapsules”. The process is named as the functional group preprotection (FGPP) strategy.…”

Precise design strategies of nanomedicine for improving cancer therapeutic efficacy using subcellular targeting

“…After reaching lysosomes, NDDSs need to respond to the lysosomal microenvironment effectively to release their cancer therapeutic agents, which need to act rapidly on the lysosome and trigger LMP. This response mainly relies on some pH-sensitive liposomes and stimulus-responsive polymers containing specific pH-triggered switches (such as disulfide bonds, 32 hydrazone bonds, acrylic acid, and diethylaminophenyl units 33 ) and enzyme response switches (such as cathepsin B-sensitive dipeptide linker, 34 glycosidic bond hydrolyzed by glycosidase, 35 vSIRPαprobe activated by lysosomal endopeptidases 36 ). Additional important triggering methods are the delivery of photosensitizers 37 and magnetic agents 24 to lysosomes by NDDSs.…”

A Stimuli‐Responsive Small‐Molecule Metal‐Carrying Prochelator: A Novel Prodrug Design Strategy for Metal Complexes

“…Especially in cancer therapy, various prodrugs have shown great promise in reducing the systemic toxicity of chemotherapeutics [2] . Prodrugs can be activated by removing the temporary moiety via enzyme catalysis [3] or chemical reactions in response to specific triggers, such as acidity [4] or reactive oxygen species (ROS), [5] which are unique characteristics of the tumor microenvironment [6] . Owing to the significant improvement in the pharmacokinetics or targeting ability of such prodrugs, some have successfully reached the clinical applications [7] .…”