Programmable site-specific delivery of an alkaline phosphatase-activatable prodrug and a mitochondria-targeted cyclopeptide for combination therapy in colon cancer
The design of advanced carriers that enable time- or stimulus-programmed drug release holds great promise to enhance the treatment efficacy in tumors. Here, hyaluronic acid (HA)-coated liposomes were designed to efficiently deliver multi-organelle-targeted and ALP/GSH dual-responsive prodrugs for co...
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Veröffentlicht in: | Biomaterials science 2023-10, Vol.11 (21), p.7114-7123 |
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Sprache: | eng |
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Zusammenfassung: | The design of advanced carriers that enable time- or stimulus-programmed drug release holds great promise to enhance the treatment efficacy in tumors. Here, hyaluronic acid (HA)-coated liposomes were designed to efficiently deliver multi-organelle-targeted and ALP/GSH dual-responsive prodrugs for combination therapy on colon tumors. In this system (designated CPTP/RA-HALipo), the unique natural cyclopeptide RA-V was linked covalently to a near-infrared (NIR) fluorophore through a disulfide linker, which was subsequently loaded in the cationic liposome core of CPTP/RA-HALipo, while the ALP-activatable phosphate CPT (CPTP) was encapsulated in the HA shell. In the tumor microenvironment, the HA shell of CPTP/RA-HALipo was partially degraded by HAase, thereby allowing the release of CPTP. The released phosphate prodrug CPTP was activated through hydrolysis of the phosphate esters by brush border-associated enzymes. The cationic liposome coated with the remaining HA could selectively enter CD44 overexpressed cells
via
receptor-mediated endocytosis into the lysosome, in which the acidic microenvironment degraded the liposomes to release the mitochondria-targeted theranostic agent RA-S-S-Cy. More significantly, the GSH-activatable NIR fluorescence of Cy5.5 made it possible to realize
in vivo
and
in situ
dynamic monitoring of drug release in a noninvasive manner. The organelle-specific and multi-stimuli responsive nanoparticles have shown precise control over drug delivery and release, leading to superior
in vitro
and/or
in vivo
anti-cancer efficacy. This approach represents a novel interactive drug delivery system that can synergistically differentiate the extracellular, cell membranal and intracellular targets to promote spatial and temporal control of drug release.
This work reports a hyaluronic acid-coated liposome which was designed to efficiently deliver multi-organelle-targeted and ALP/GSH dual-responsive prodrugs for combination therapy on colon tumors. |
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ISSN: | 2047-4830 2047-4849 |
DOI: | 10.1039/d3bm00834g |