title: pH-activated size reduction of large compound nanoparticles for in vivo nucleus-targeted drug delivery.
abstract: Nucleus-targeted drug delivery is a promising strategy for anticancer therapy, but in vivo nucleus-targeted drug delivery has been challenging. Limited by the channel size of the nucleopore, vehicles that enter the nucleus via the nucleopore actively should be small and decorated with nuclear localization signal (NLS). However, the small vehicle size may promote leakage of vehicles into normal tissues, and the positively-charged NLS can lead to strong non-specific interactions in vivo. In the present study, we demonstrate an in vivo nucleus-targeted drug delivery using large compound nanoparticles with detachable PEG shell. The nanoparticles are composed of PEG-benzoic imine-oligo-l-lysine/iridium(III) metallodrug complex and formed in a kinetically-controlled fashion. Under physiological conditions (pH 7.4), the nanoparticles are large (ca. 150 nm) and protected by an inert PEG shell. When internalized into intracellular acidic endo/lysosomes of cancer cells, the nanoparticles dissociate into smaller ones (ca. 40 nm) and the PEG chains detach due to the cleavage of the benzoic imine bond at low pH. The small nanoparticles, with exposure of the oligo-l-lysine after the detachment of the PEG shield, then translocate into the nucleus via the nucleopore due to the small size and nuclear localization ability of the oligo-l-lysine. Importantly, the small particles could significantly release the contained drug into the nucleus, leading to ca. 20-fold higher cytotoxicity compared to the native drug in vitro. Further in vivo application of the nucleus-targeting nano-system in a nude-mice model showed significant tumor inhibition and remarkable life-span elongation.
authors: The State Key Laboratory of Molecular Engineering of Polymers, Department of Macromolecular Science, Fudan University, Shanghai 200433, PR China.
authors: Yanbin
authors: Y
authors: Fan
authors: Department of Chemistry & Institute of Biomedicine Science & Collaborative Innovation Center of Chemistry for Energy Materials, Fudan University, Shanghai 200433, PR China.
authors: Chunyan
authors: C
authors: Li
authors: Department of Chemistry & Institute of Biomedicine Science & Collaborative Innovation Center of Chemistry for Energy Materials, Fudan University, Shanghai 200433, PR China. Electronic address: fyli@fudan.edu.cn.
authors: Fuyou
authors: F
authors: Li
authors: The State Key Laboratory of Molecular Engineering of Polymers, Department of Macromolecular Science, Fudan University, Shanghai 200433, PR China. Electronic address: chendy@fudan.edu.cn.
authors: Daoyong
authors: D
authors: Chen
mesh_terms: D000072283:A549 Cells; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D002467:Cell Nucleus / Q000378:metabolism*; D016503:Drug Delivery Systems / Q000379:methods*; D005260:Female; D006367:HeLa Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007495:Iridium / Q000737:chemistry / Q000494:pharmacology; D008239:Lysine / Q000737:chemistry; D051379:Mice; D008819:Mice, Nude; D053758:Nanoparticles / Q000737:chemistry*; D019913:Nuclear Localization Signals / Q000737:chemistry; D010316:Particle Size; D011092:Polyethylene Glycols / Q000737:chemistry; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D019913:Nuclear Localization Signals; D011092:Polyethylene Glycols; D007495:Iridium; D008239:Lysine
keywords: Cancer therapy; Iridium (III); Nanomedicine; Nucleus-targeting